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The “beautiful mechanism” by which an egg becomes an embryo

July 11, 2017

Posted by News under Cell biology, Intelligent Design

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The transition from an egg to a developing embryo is one of life’s most remarkable transformations. Yet little is known about it. Now Whitehead Institute researchers have deciphered how one aspect—control of the all-important translation of messenger RNAs (mRNAs) into proteins—switches as the egg becomes an embryo. That shift is controlled by a beautiful mechanism, which is triggered at a precise moment in development and automatically shuts itself off after a narrow window of 20 to 90 minutes.

As an egg develops, it stockpiles mRNAs from the mother because it will not have time to create new mRNAs during the rapid development of a very early embryo. When fertilized the egg becomes an embryo, the stashed maternal mRNAs are pressed into service for a brief window before the embryo starts transcribing its own mRNAs. This change occurs very early; in humans, only two to four cell divisions occur before this transition is executed. Whitehead Member Terry Orr-Weaver studies the control of translation of maternal mRNAs in the model organism Drosophila, or the fruit fly, because its developmental strategy offers experimental advantages. More.

A reader writes to note that the “beautiful mechanism” is described as a

negative feedback loop,” with the same function as those designed in engineering control systems: Furthermore, the activity of PNG kinase leads to the destruction of GNU, and this feedback loop limits this kinase’s activity to the narrow window of time in which it is needed.

“Active PNG leads to decreased GNU protein levels. This makes a negative feedback to shut down PNG kinase activity, thereby ensuring PNG kinase activity is constrained to the short developmental window of the oocyte-to-embryo transition

Another reader who forwarded this item points out that the authors let in the “d” word (and I don’t mean “Darwin”…. ):

The design of this transition could tell scientists more about how human cells work and embryos develop. For example, the switch could be a model for how cells massively and globally change mRNA translation. Also, similar kinase activity during early development has been noted in worms, which may mean that a comparable approach is used in other organisms, including humans.

Well, if the researchers’ careers take a beating for mentioning design, they will need to join the Free the Universities movement. After a while language Stalinism starts t collapse from its own uncommunicativeness and one must peak clearly again.

See also: Cells communicate to navigate a crowded embryo

442 Responses to The “beautiful mechanism” by which an egg becomes an embryo

1

DionisioJuly 11, 2017 at 8:36 pm

Interesting paper. Thanks.
2

DionisioJuly 12, 2017 at 1:35 pm

The oocyte-to-embryo transition involves extensive changes in mRNA translation, regulated in Drosophila by the PNG kinase complex whose activity we show here to be under precise developmental control.

This short-lived burst in kinase activity links development with maternal mRNA translation and ensures irreversibility of the oocyte-to-embryo transition.

Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation
Masatoshi Hara, Boryana Petrova, Terry L Orr-Weaver
eLife 2017;6:e22219
doi: 10.7554/eLife.22219

Complex complexity
3

DionisioJuly 12, 2017 at 2:45 pm

New egg cells form via a specialized kind of cell division called called meiosis, and will pause at key stages in this process before continuing their development.

One of these pauses occurs before the egg cell is fertilized.

At fertilization, the egg cell becomes “activated”, development resumes, and it starts forming into an embryo.

Molecules deposited in the egg cell when it originally formed are used to control these earliest stages of embryonic development.

Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation
Masatoshi Hara, Boryana Petrova, Terry L Orr-Weaver
eLife 2017;6:e22219
doi: 10.7554/eLife.22219

Complex complexity
4

DionisioJuly 12, 2017 at 2:50 pm

The massive changes in mRNA translation accompanying egg activation occur in a matter of minutes and must be linked to completion of meiosis in the oocyte.

Active PNG leads to decreased GNU protein levels.

This makes a negative feedback to shut down PNG kinase activity, thereby ensuring PNG kinase activity is constrained to the short developmental window of the oocyte-to-embryo transition […]

Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation
Masatoshi Hara, Boryana Petrova, Terry L Orr-Weaver
eLife 2017;6:e22219
doi: 10.7554/eLife.22219

Complex complexity
5

DionisioJuly 12, 2017 at 2:57 pm

[…] the regulatory mechanisms for gnu translational activation remain to be defined […]

The PNG kinase is significant for the understanding of how a kinase can rapidly control translation of hundreds of mRNAs.

[…] identifying and defining the role of regulators involved in triggering the profound changes accompanying the oocyte-to-embryo transition is crucial for our understanding of the onset of development […]

Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation
Masatoshi Hara, Boryana Petrova, Terry L Orr-Weaver
eLife 2017;6:e22219
doi: 10.7554/eLife.22219

Complex complexity
6

DionisioJuly 12, 2017 at 3:02 pm

Here we have shown two forms of regulation of PNG kinase activity: one being regulation of protein expression of PNG kinase complex components and another being regulation of its activity.

Strikingly, a cell cycle regulator, CDK1, controls both.

This implies that CDK1 precisely regulates PNG kinase activity, a translational regulator, thus coordinating cell cycle progression and the translational landscape change during the oocyte-to-embryo transition.

Control of PNG kinase, a key regulator of mRNA translation, is coupled to meiosis completion at egg activation
Masatoshi Hara, Boryana Petrova, Terry L Orr-Weaver
eLife 2017;6:e22219
doi: 10.7554/eLife.22219

Did somebody say “Strikingly”?

Complex complexity
7

DionisioJuly 12, 2017 at 7:36 pm

Elegant switch controls translation in transition from egg to embryo

http://wi.mit.edu/news/archive.....egg-embryo
8

DionisioJuly 12, 2017 at 8:19 pm

perhaps when they write ‘design’ they really mean ‘appearance’?

appearances can be deceiving, can’t they? 🙂
9

DionisioJuly 13, 2017 at 5:11 pm

Functional Amyloids in Reproduction

Aveline Hewetson 1, Hoa Quynh Do 1, Caitlyn Myers 1, Archana Muthusubramanian 1, Roger Bryan Sutton 2, Benjamin J. Wylie 3 and Gail A. Cornwall

Biomolecules 2017, 7(3), 46;
doi:10.3390/biom7030046

[…] functional amyloids play important roles in several reproductive processes including gametogenesis and fertilization.

Some functional amyloids are evolutionarily conserved emphasizing the critical role amyloids play in reproduction and that nature favors the amyloid fold for these processes.

Further study of reproductive functional amyloids, including their formation and disassembly, will not only provide a better understanding of basic mechanisms of reproduction, but knowledge that could be used to develop new therapies for diseases caused by pathological amyloids.

“nature favors the amyloid fold for these processes”?

“nature favors”?

huh?
10

DionisioJuly 13, 2017 at 6:42 pm

Diploid budding yeast (Saccharomyces cerevisiae) can adopt one of several alternative differentiation fates in response to nutrient limitation, and each of these fates provides distinct biological functions.

When different strain backgrounds are taken into account, these various fates occur in response to similar environmental cues, are regulated by the same signal transduction pathways, and share many of the same master regulators.

Similar environments but diverse fates: Responses of budding yeast to nutrient deprivation
Saul M. Honigberg
DOI: 10.15698/mic2016.08.516
http://www.microbialcell.com

Complex functional complexity
11

DionisioJuly 13, 2017 at 7:01 pm

Further work is required to ask if the activity level of one pathway relative to another contributes to fate choice.

[…] a Boolean representation tracking the presence or absence of a given cue or cues (or a discrete threshold) is not sufficient to describe the relationship between environmental cues and fate choice.

Similarly, the relationship between fate choice and signal pathway/master regulator activity also cannot be accurately represented by Boolean logic.

Similar environments but diverse fates: Responses of budding yeast to nutrient deprivation
Saul M. Honigberg
DOI: 10.15698/mic2016.08.516
http://www.microbialcell.com

Complex functional complexity
12

DionisioJuly 13, 2017 at 9:33 pm

[…] the activity of a given signal transduction pathway likely also depends on interactions with other signaling pathways.

[…] cell-to-cell signals are fundamental to life and may be nearly as ancient.

Similar environments but diverse fates: Responses of budding yeast to nutrient deprivation
Saul M. Honigberg
DOI: 10.15698/mic2016.08.516
http://www.microbialcell.com

Complex functional complexity
13

DionisioJuly 16, 2017 at 7:37 am

Interactions between genes can have important consequences for how selection shapes sequence variation at these genes.

Specifically, genes that have pleiotropic effects by affecting the expression level of many other genes may be under stronger selective constraint.

[…] both connectivity and local regulatory variation are important factors for explaining variation in selection between genes.

The relationship between selection, network connectivity, and regulatory variation within a population of Capsella grandiora.
Josephs EB1, Wright SI2, Stinchcombe JR2, Schoen DJ3.
Genome Biol Evol. 2017 Apr 8.
doi: 10.1093/gbe/evx068

Complex functionally specified informational complexity.

🙂
14

DionisioJuly 17, 2017 at 10:27 pm

“The future of genetic codes and BRAIN codes”
Presentation by professor George M. Church at NIH
2017-Feb-08 @3pm

https://videocast.nih.gov/summary.asp?Live=21803&bhcp=1

@55:30 [in response to a question]

What we are trying to do is we’re trying to make organized organs, not just tissues.
We want to know the rules and we want to know what we can do…
the closer they are to the physiological organs…

@56:15

the basic research is figuring out how organs assemble
15

DionisioJuly 19, 2017 at 9:31 am

Telomeres are essential nucleoprotein structures at linear chromosomes that maintain genome integrity by protecting chromosome ends from being recognized and processed as damaged DNA.

In addition, they limit the cell’s proliferative capacity, as progressive loss of telomeric DNA during successive rounds of cell division eventually causes a state of telomere dysfunction that prevents further cell division.

Over the past years substantial progress has been made in understanding the role of post-translational modifications in telomere-related processes, including telomere maintenance, replication and dysfunction.

This review will focus on recent findings that establish an essential role for ubiquitination and SUMOylation at telomeres.

Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction.
Yalçin Z1, Selenz C1, Jacobs JJL
Front Genet. 2017 May 23;8:67.
doi: 10.3389/fgene.2017.00067

Had we remained in Eden, none of this would have been an issue at all. Too late now.

Complex functionally specified informational complexity
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DionisioJuly 19, 2017 at 9:34 am

Genome stability is essential for cells to function properly and ensure the survival of an organism.

At the ends of chromosomes this stability is maintained by telomeres.

HR is a DNA repair pathway that outside of telomeres is used to correctly repair a DNA break by using the sister chromatid as template.

Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction.
Yalçin Z1, Selenz C1, Jacobs JJL
Front Genet. 2017 May 23;8:67.
doi: 10.3389/fgene.2017.00067

Had we remained in Eden, none of this would have been an issue at all. Too late now.

Complex functionally specified informational complexity
17

DionisioJuly 19, 2017 at 9:35 am

A tight regulation of telomere maintenance, replication and protection is required to ensure safeguarding of genome integrity by telomeres.

If factors in these processes are impaired or exhibit aberrant functions, genome stability is at risk, potentially promoting tumorigenesis.

Therefore, it is crucial to further investigate the processes and factors that ensure proper telomere function.

Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction.
Yalçin Z1, Selenz C1, Jacobs JJL
Front Genet. 2017 May 23;8:67.
doi: 10.3389/fgene.2017.00067

Had we remained in Eden, none of this would have been an issue at all. Too late now.

Complex functionally specified informational complexity
18

DionisioJuly 19, 2017 at 9:37 am

Although many studies have already explored ubiquitination and SUMOylation in different telomeric contexts and thereby identified various targets, the underlying mechanisms, as well as the precise contribution of PTMs are often still undetermined.

[…] it would be interesting to investigate whether additional crosstalk occurs at telomeres and if one aspect of telomere biology, for example DNA repair or maintenance, is more affected by the combination of ubiquitin and SUMO modifications than others.

Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction.
Yalçin Z1, Selenz C1, Jacobs JJL
Front Genet. 2017 May 23;8:67.
doi: 10.3389/fgene.2017.00067

Had we remained in Eden, none of this would have been an issue at all. Too late now.

Complex functionally specified informational complexity
19

DionisioJuly 19, 2017 at 9:38 am

Further studies concerning telomere-specific ubiquitination and SUMOylation will be required to increase our understanding of the complex mechanisms that ensure proper telomere function or contribute to DNA repair at dysfunctional telomeres.

It would be beneficial to distinguish which modifications are unique to telomeric DNA, as these might offer a tool to specifically target DNA repair at telomeres without interfering in an unwanted manner with genome-wide repair at DNA breaks.

Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction.
Yalçin Z1, Selenz C1, Jacobs JJL
Front Genet. 2017 May 23;8:67.
doi: 10.3389/fgene.2017.00067

Had we remained in Eden, none of this would have been an issue at all. Too late now.

Work in progress… stay tuned.

Complex functionally specified informational complexity
20

DionisioJuly 19, 2017 at 8:10 pm

DNA double-strand breaks (DSBs) are mostly repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR) in higher eukaryotes.

In contrast, HR-mediated DSB repair is the major double-strand break repair pathway in lower order organisms such as bacteria and yeast.

Penaeus monodon, commonly known as black tiger shrimp […]

[…] while HR is major DSB repair pathway in shrimp, MMEJ also plays a role in ensuring the continuity and stability of the genome.

DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination.
Srivastava S1, Dahal S1, Naidu SJ1, Anand D2, Gopalakrishnan V1, Kooloth Valappil R2, Raghavan SC
DNA Res. 2017 Apr 1;24(2):117-128.
doi: 10.1093/dnares/dsw059.

Complex functionally specified informational complexity
21

DionisioJuly 19, 2017 at 8:12 pm

DNA in every living organism is constantly exposed to a plethora of mutagens including radiation, chemicals or oxidative stress leading to induction of a variety of DNA damages.

Among different DNA damages, single- and double-strand breaks are considered as most hazardous, if not repaired or misrepaired.

DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination.
Srivastava S1, Dahal S1, Naidu SJ1, Anand D2, Gopalakrishnan V1, Kooloth Valappil R2, Raghavan SC
DNA Res. 2017 Apr 1;24(2):117-128.
doi: 10.1093/dnares/dsw059.

Had we stayed in Eden, none of this would have been an issue at all. Too late now.

Complex functionally specified informational complexity
22

DionisioJuly 19, 2017 at 8:14 pm

From prokaryotes to lower eukaryotes and to higher eukaryotes, several of these DNA repair pathways are conserved.

Several DNA repair proteins also show high degree of amino acid homology across the living world.

However, there are several organisms, where DNA repair pathways are unexplored due to various reasons including non-conservation of polypeptides or lack of complete genome sequence making the study of DNA repair a challenge.

DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination.
Srivastava S1, Dahal S1, Naidu SJ1, Anand D2, Gopalakrishnan V1, Kooloth Valappil R2, Raghavan SC
DNA Res. 2017 Apr 1;24(2):117-128.
doi: 10.1093/dnares/dsw059.

Complex functionally specified informational complexity
23

DionisioJuly 19, 2017 at 8:18 pm

[…] the protein machinery involved in each of these DNA repair pathway needs to be investigated.

[…] we have not investigated the protein machinery involved in HR-mediated repair in shrimp […]

[…] it will be interesting to see whether RAD51 paralogues play any significant role in crustaceans.

DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination.
Srivastava S1, Dahal S1, Naidu SJ1, Anand D2, Gopalakrishnan V1, Kooloth Valappil R2, Raghavan SC
DNA Res. 2017 Apr 1;24(2):117-128.
doi: 10.1093/dnares/dsw059.

Work in progress… stay tuned.

Complex functionally specified informational complexity
24

DionisioJuly 19, 2017 at 8:20 pm

The present study suggested that cell-free extracts prepared from hepatopancreas of P. monodon possess microhomology-mediated end joining, while classical NHEJ was undetectable.

This is surprising, when one considers the fact that joining through MMEJ could lead to deletions in the genome culminating into genomic instability.

DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination.
Srivastava S1, Dahal S1, Naidu SJ1, Anand D2, Gopalakrishnan V1, Kooloth Valappil R2, Raghavan SC
DNA Res. 2017 Apr 1;24(2):117-128.
doi: 10.1093/dnares/dsw059.

Did somebody say “surprising”? 🙂

Complex functionally specified informational complexity
25

DionisioJuly 19, 2017 at 8:24 pm

[…] it will be interesting to look at the levels of MMEJ proteins such as Ligase III, PARP1, FEN1 in P. monodon.

More studies are needed to decipher the importance of MMEJ in crustaceans […]

[…] it will be interesting to evaluate, whether efficient repair system in crustaceans can protect these organisms from infections.

[…] these aspects need to be further investigated in shrimp.

It will be very interesting and significant to understand whether these DNA repair machineries can protect crustaceans against infections.

[…] it will be important to look at the DNA repair genes of crustaceans following viral infection to determine the cause of heavy mortality due to some of the viruses.

DNA double-strand break repair in Penaeus monodon is predominantly dependent on homologous recombination.
Srivastava S1, Dahal S1, Naidu SJ1, Anand D2, Gopalakrishnan V1, Kooloth Valappil R2, Raghavan SC
DNA Res. 2017 Apr 1;24(2):117-128.
doi: 10.1093/dnares/dsw059.

Work in progress… stay tuned.

Complex functionally specified informational complexity
26

DionisioJuly 19, 2017 at 8:28 pm

P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors.

Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2).

These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.
Drané P1, Brault ME1, Cui G2, Meghani K1, Chaubey S1, Detappe A1, Parnandi N1, He Y1, Zheng XF1, Botuyan MV2, Kalousi A3, Yewdell WT4, Münch C5, Harper JW5, Chaudhuri J4,6, Soutoglou E3, Mer G2, Chowdhury D1
Nature. 2017 Mar 9;543(7644):211-216.
doi: 10.1038/nature21358.

Complex functionally specified informational complexity
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DionisioJuly 19, 2017 at 9:10 pm

TIRR has a dual role in regulating 53BP1 function, first by stabilizing 53BP1 and maintaining its sub-nuclear localization prior to DNA damage and second, by influencing the interaction of 53BP1 with effector proteins in response to DSBs.

Accumulation of 53BP1 at DSBs requires recognition of the constitutive and highly abundant histone modification, H4K20me2

TIRR directly blocks the Tudor/methyl-lysine interface and this observation could be potentially utilized to identify factors that inhibit the methyl-lysine binding function of other Tudor proteins.

TIRR regulates 53BP1 by masking its histone methyl-lysine binding function.
Drané P1, Brault ME1, Cui G2, Meghani K1, Chaubey S1, Detappe A1, Parnandi N1, He Y1, Zheng XF1, Botuyan MV2, Kalousi A3, Yewdell WT4, Münch C5, Harper JW5, Chaudhuri J4,6, Soutoglou E3, Mer G2, Chowdhury D1
Nature. 2017 Mar 9;543(7644):211-216.
doi: 10.1038/nature21358.

Complex functionally specified informational complexity
28

DionisioJuly 19, 2017 at 9:26 pm

[…] it will be worth investigating systematically the distribution of hot points of change along the ontogenetic schedules of other animals and to enquire whether/how this research program can be exported to groups other than metazoans.

[…] development is much more than morphological change produced by sequential and tightly controlled gene expression.

[…] the protein encoded by the gene (aphicarus) responsible for wing development in the male aphid is also involved in the female’s developmental response to the environmental stimulus […]

Grand challenges in evolutionary developmental biology
Alessandro Minelli
https://doi.org/10.3389/fevo.2014.00085
Frontiers in Ecology and Evolution

Complex functionally specified informational complexity
29

DionisioJuly 19, 2017 at 9:27 pm

It seems therefore legitimate to ask: what should we regard as fundamental principles of development, if any?

The question is clearly open for debate, in the light of a carefully formulated definition of development but also, perhaps, through the identification of recognizable “modules” to search for possible “fundamental principles.”

A serious problem is the obvious lack of agreement on what “fundamental principles” should eventually be.

Grand challenges in evolutionary developmental biology
Alessandro Minelli
https://doi.org/10.3389/fevo.2014.00085
Frontiers in Ecology and Evolution

Complex functionally specified informational complexity
30

DionisioJuly 21, 2017 at 3:53 pm

In this exciting era of “next-gen cytogenetics,” integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level.

We believe next-generation sequencing technologies will eventually be proposed as a first-line diagnostic method because they can provide details on structural rearrangements that cannot be detected by either karyotyping or CMA.

Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in Prenatal Diagnosis.
Ordulu Z1, Kammin T2, Brand H3, Pillalamarri V4, Redin CE5, Collins RL4, Blumenthal I4, Hanscom C4, Pereira S2, Bradley I6, Crandall BF6, Gerrol P2, Hayden MA2, Hussain N7, Kanengisser-Pines B8, Kantarci S9, Levy B10, Macera MJ11, Quintero-Rivera F9, Spiegel E12, Stevens B13, Ulm JE14, Warburton D15, Wilkins-Haug LE1, Yachelevich N16, Gusella JF17, Talkowski ME18, Morton CC19
Am J Hum Genet. 2016 Nov 3;99(5):1015-1033.
doi: 10.1016/j.ajhg.2016.08.022.

Complex functionally specified informational complexity
31

DionisioJuly 21, 2017 at 4:09 pm

E2A is an essential regulator of early B cell development.

B cell immunity provides acute and long-term protection of the host against infections through the generation and secretion of high-affinity antibodies that recognize a shear unlimited number of pathogens.

[…] these experiments identified E2A and E2-2 as central regulators of B cell immunity.

Five transcription factors, IRF4, Aiolos, Ikaros, Blimp1, and XBP1, are currently known to play essential roles in plasma cell development, in addition to the E-proteins described here […]

[…] E-proteins regulate plasma cell development in a pleiotropic manner, possibly as a result of their important function in shaping the enhancer landscape at their target genes during terminal B cell differentiation.

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development.
Wöhner M1, Tagoh H1, Bilic I1, Jaritz M1, Poliakova DK1, Fischer M1, Busslinger M2
J Exp Med. 2016 Jun 27;213(7):1201-21.
doi: 10.1084/jem.20152002

Complex functionally specified informational complexity
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DionisioJuly 21, 2017 at 4:15 pm

B cells are crucial contributors to immunity both by secreting specific antibodies and by serving as antigen-presenting cells.

B cell immune responses and differentiation to antibody-secreting cells (ASCs) are controlled by the expression and activation of specific transcription factors at different stages and time points in B cell development and functional activation.

Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1
Prontip Saelee,1 Alyssa Kearly,1 Stephen L. Nutt,2,3 and Lee Ann Garrett-Sinha
Front Immunol. 2017; 8: 383.
doi: 10.3389/fimmu.2017.00383

Complex functionally specified informational complexity
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DionisioJuly 21, 2017 at 4:26 pm

Innate-like B-1a cells provide a first line of defense against pathogens, yet little is known about their transcriptional control.

Here we identified an essential role for the transcription factor Bhlhe41, with a lesser contribution by Bhlhe40, in controlling B-1a cell differentiation.

Bhlhe41-/-Bhlhe40-/- B-1a cells were present at much lower abundance than were their wild-type counterparts.

Mutant B-1a cells exhibited an abnormal cell-surface phenotype and altered B cell receptor (BCR) repertoire exemplified by loss of the phosphatidylcholine-specific VH12V?4 BCR.

Expression of a pre-rearranged VH12V?4 BCR failed to ‘rescue’ the mutant phenotype and revealed enhanced proliferation accompanied by increased cell death.

Bhlhe41 directly repressed the expression of cell-cycle regulators and inhibitors of BCR signaling while enabling pro-survival cytokine signaling.

Thus, Bhlhe41 controls the development, BCR repertoire and self-renewal of B-1a cells.

Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells.
Kreslavsky T1, Vilagos B1, Tagoh H1, Poliakova DK1, Schwickert TA1, Wöhner M1, Jaritz M1, Weiss S2, Taneja R3, Rossner MJ4, Busslinger M1
Nat Immunol. 2017 Apr;18(4):442-455.
doi: 10.1038/ni.3694.

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DionisioJuly 21, 2017 at 4:31 pm

[…] future studies on understanding the crosstalk between Wip1 and multiple signaling pathways in different cells, as well as in whole organism level (i.e., immune system and secretion), may help to better develop potential therapeutic strategies based on phosphatase Wip1.

Phosphatase Wip1 in Immunity: An Overview and Update.
Shen XF1, Zhao Y2, Jiang JP3, Guan WX4, Du JF5
Front Immunol. 2017 Jan 17;8:8.
doi: 10.3389/fimmu.2017.00008

Complex functionally specified informational complexity
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DionisioJuly 21, 2017 at 4:49 pm

DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development.

Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress.

WIP1 phosphatase as pharmacological target in cancer therapy
So?a Pechá?ková, Kamila Burdová, and Libor Macurek
J Mol Med (Berl). 2017; 95(6): 589–599.
doi: 10.1007/s00109-017-1536-2

Complex functionally specified informational complexity
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DionisioJuly 21, 2017 at 4:51 pm

Genetic information is continuously endangered by erroneous DNA metabolism as well as by various environmental factors that include ionizing radiation or chemotherapy representing two major non-surgical approaches in cancer therapy.

Cells respond to genotoxic stress by activation of a conserved DNA damage response pathway (DDR) that abrogates cell cycle progression and facilitates DNA repair.

The DDR pathway is regulated by a spatiotemporally controlled cascade of posttranslational modifications of key proteins including protein phosphorylation and ubiquitination

WIP1 phosphatase as pharmacological target in cancer therapy
So?a Pechá?ková, Kamila Burdová, and Libor Macurek
J Mol Med (Berl). 2017; 95(6): 589–599.
doi: 10.1007/s00109-017-1536-2

Complex functionally specified informational complexity
37

DionisioJuly 21, 2017 at 4:57 pm

The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2-2).

[…] lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements.

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification.
Grajkowska LT1, Ceribelli M2, Lau CM3, Warren ME4, Tiniakou I3, Nakandakari Higa S3, Bunin A5, Haecker H6, Mirny LA7, Staudt LM8, Reizis B9
Immunity. 2017 Jan 17;46(1):65-77.
doi: 10.1016/j.immuni.2016.11.006

Complex functionally specified informational complexity
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DionisioJuly 21, 2017 at 5:01 pm

Distinct transcription factors regulate the development of immune cell lineages, and changes in their expression can alter the balance of cell types responding to infection.

[…] Zeb2 is required for the development of two myeloid cell types, the monocyte and the plasmacytoid dendritic cell […]

[…] this factor is not required for the development of classical dendritic cells.

Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate.
Wu X1, Briseño CG1, Grajales-Reyes GE1, Haldar M1, Iwata A1, Kretzer NM1, Kc W1, Tussiwand R1, Higashi Y2, Murphy TL1, Murphy KM
Proc Natl Acad Sci U S A. 113(51):14775-14780.
doi: 10.1073/pnas.1611408114.

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DionisioJuly 21, 2017 at 5:06 pm

Dendritic cells (DCs) comprise several related lineages that initiate and regulate immune responses […]

Dendritic cells (DCs) and monocytes develop from a series of bone-marrow–resident progenitors in which lineage potential is regulated by distinct transcription factors.

[…] Zeb2 activity may engage similar mechanisms to suppress alternative fates in multiple developing lineages.

[…] those cells and their progeny represent further avenues to explore the mechanisms by which this transcription factor regulates the development of immune lineages.

Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate.
Wu X1, Briseño CG1, Grajales-Reyes GE1, Haldar M1, Iwata A1, Kretzer NM1, Kc W1, Tussiwand R1, Higashi Y2, Murphy TL1, Murphy KM
Proc Natl Acad Sci U S A. 113(51):14775-14780.
doi: 10.1073/pnas.1611408114.

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DionisioJuly 21, 2017 at 5:09 pm

Functionally distinct plasmacytoid and conventional dendritic cells (pDC and cDC) shape innate and adaptive immunity.

[…] although a fraction of CDPs transits through precursor stages rapidly to give rise to a first wave of pDCs, the majority of CDP progeny differentiate more slowly and give rise to longer lived precursor cells which are poised to differentiate on demand.

[…] the behaviour of committed DC progenitor cells with regard to division kinetics and acquisition of cell type defining markers is more heterogeneous than previously thought, allowing for plasticity until late steps of development.

Continuous single cell imaging reveals sequential steps of plasmacytoid dendritic cell development from common dendritic cell progenitors.
Dursun E1, Endele M2, Musumeci A1, Failmezger H3,4, Wang SH1, Tresch A3,4, Schroeder T2, Krug AB
Sci Rep. 2016 Nov 28;6:37462.
doi: 10.1038/srep37462

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DionisioJuly 21, 2017 at 5:21 pm

A derepression mode of cell-fate specification involving the transcriptional repressors Tbr1, Fezf2, Satb2, and Ctip2 operates in neocortical projection neurons to specify six layer identities in sequence.

Less well understood is how laminar fate transitions are regulated in cortical progenitors.

The proneural genes Neurog2 and Ascl1 cooperate in progenitors to control the temporal switch from neurogenesis to gliogenesis.

Proneural genes thus act in a context-dependent fashion as early determinants, promoting deep-layer neurogenesis in early cortical progenitors via input into the derepression circuit while also influencing other temporal regulators.

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex.
Dennis DJ1,2,3,4, Wilkinson G1,2,3, Li S1,2,3, Dixit R1,2,3,4, Adnani L1,2,3,4, Balakrishnan A4,5, Han S4,5, Kovach C1,2,3, Gruenig N1,2,3, Kurrasch DM2,3,6, Dyck RH2,3,7, Schuurmans C8,
Proc Natl Acad Sci U S A. 114(25):E4934-E4943.
doi: 10.1073/pnas.1701495114.

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DionisioJuly 21, 2017 at 5:27 pm

[…] the proneural genes Neurog2 and Ascl1, which are together expressed in neocortical progenitors, cooperate to regulate the expression of components of the cortical derepression circuit to specify corticothalamic and subcerebral identities while repressing a callosal fate.

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex.
Dennis DJ1,2,3,4, Wilkinson G1,2,3, Li S1,2,3, Dixit R1,2,3,4, Adnani L1,2,3,4, Balakrishnan A4,5, Han S4,5, Kovach C1,2,3, Gruenig N1,2,3, Kurrasch DM2,3,6, Dyck RH2,3,7, Schuurmans C8,
Proc Natl Acad Sci U S A. 114(25):E4934-E4943.
doi: 10.1073/pnas.1701495114.

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DionisioJuly 21, 2017 at 5:30 pm

Tbr1+ Neurons Expand into the Upper Cortical Plate in Neurog2?/?;Ascl1?/? Cortices.

Neurog2 and Ascl1 Are Required to Generate Fezf2+ and Ctip2+ Layer V Neurons.

Satb2+ Neurons Expand into the Lower CP in Neurog2?/?;Ascl1?/? Cortices.

Satb2+ Neurons Are Generated Precociously in Neurog2?/?;Ascl1?/? Cortices.

Neurog2?/?;Ascl1?/? Cortical Neurons Have a Mixed Tbr1+/Satb2+ Identity and Aberrant Axonal Projections.

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex.
Dennis DJ1,2,3,4, Wilkinson G1,2,3, Li S1,2,3, Dixit R1,2,3,4, Adnani L1,2,3,4, Balakrishnan A4,5, Han S4,5, Kovach C1,2,3, Gruenig N1,2,3, Kurrasch DM2,3,6, Dyck RH2,3,7, Schuurmans C8,
Proc Natl Acad Sci U S A. 114(25):E4934-E4943.
doi: 10.1073/pnas.1701495114.

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DionisioJuly 21, 2017 at 5:36 pm

In an instructive mode of cell-fate specification, genetic switches turn one set of genes on while repressing genes in competing lineages […]

Alternatively, cell fates are specified by a derepression circuit of transcriptional repressors […]

[…] the fate-specification properties of the proneural genes are temporally regulated […]

How Ascl1 selects its downstream transcriptional targets to promote different cell fates is not entirely clear […]

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex.
Dennis DJ1,2,3,4, Wilkinson G1,2,3, Li S1,2,3, Dixit R1,2,3,4, Adnani L1,2,3,4, Balakrishnan A4,5, Han S4,5, Kovach C1,2,3, Gruenig N1,2,3, Kurrasch DM2,3,6, Dyck RH2,3,7, Schuurmans C8,
Proc Natl Acad Sci U S A. 114(25):E4934-E4943.
doi: 10.1073/pnas.1701495114.

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DionisioJuly 21, 2017 at 5:51 pm

Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates.

The cortex is a laminar structure that develops from a single layer of neuroepithelial progenitors cells. As such, the basic principles regulating stem cell proliferation, cell fate specification and regionalization are critical to proper development […]

In the developing neocortex, the decision to proliferate or differentiate is regulated at multiple levels, including epigenetic changes that influence gene regulation.

Forebrain neurogenesis: From embryo to adult.
Dennis D1, Picketts D2, Slack RS3, Schuurmans C4
Trends Dev Biol. 9(1):77-90.

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DionisioJuly 21, 2017 at 5:51 pm

[…] key decision points involving self-renewal and commitment are regulated by a complex network of intrinsic factors that respond to cellular metabolism, epigenetic regulation as well as environmental changes.

[…] Ascl1 is an activation factor that must be suppressed to enable stem cells to enter a resting state, which is essential for their long term maintenance in the adult brain.

[…] the role of Panx1 in the adult brain is context-specific, suggesting that ion channels are critical regulators of neural stem/progenitor population size, which will be an important focus of future studies.

[…] key questions regulating the adult stem cell pool include uncovering the mechanisms by which stem cell quiescence and activation are controlled, defining intrinsic and extrinsic factors that regulate population size, and identifying the signaling pathways that determine their ultimate fate in the healthy and injured brain, all of these will be subjects for intensive investigations.

Forebrain neurogenesis: From embryo to adult.
Dennis D1, Picketts D2, Slack RS3, Schuurmans C4
Trends Dev Biol. 9(1):77-90.

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DionisioJuly 21, 2017 at 5:59 pm

The central nervous system (CNS) is characterized by an astounding diversity of neuronal phenotypes that are generated in a region-specific manner in the neural tube.

Further studies will help to clarify how these pathways mediate the effects of glycine on neurogenesis, and will also address whether these signaling pathways are similarly at play in the forebrain.

Cellular differentiation requires that neural progenitors first acquire a regional identity, which is often conferred by homeodomain transcription factors, followed by subtype specification and differentiation, which are induced by other transcription factors and signaling molecules.

Forebrain neurogenesis: From embryo to adult.
Dennis D1, Picketts D2, Slack RS3, Schuurmans C4
Trends Dev Biol. 9(1):77-90.

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DionisioJuly 21, 2017 at 6:00 pm

While the cortical derepression circuit has been well described, inputs into this circuit are poorly understood.

[…] Mllt11 is required for migration of superficial neurons and the establishment of cell interactions with Reelin-expressing cells in the marginal zone, highlighting the complexity of laminar fate specification in the neocortex.

The regulation of Fezf2 expression is thus a central control mechanism for the formation of corticospinal axon tracts.

Forebrain neurogenesis: From embryo to adult.
Dennis D1, Picketts D2, Slack RS3, Schuurmans C4
Trends Dev Biol. 9(1):77-90.

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DionisioJuly 21, 2017 at 6:02 pm

Proper functioning of the nervous system relies on a delicate equilibrium between excitatory and inhibitory neurotransmission.

One of the challenges of the next century is to fully understand how the brain develops, processes, stores and recalls information.

[…] there remains a bright future for the next generation of upcoming neurodevelopmental scientists and clinicians in the field.

Forebrain neurogenesis: From embryo to adult.
Dennis D1, Picketts D2, Slack RS3, Schuurmans C4
Trends Dev Biol. 9(1):77-90.

Did somebody say “One of the challenges of the next century”? Next century?

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DionisioJuly 21, 2017 at 6:10 pm

Nanofibers are promising tools to guide neurites of stem cell derived neurons within the boundaries and unique organization of the auditory system.

[…] there is still much need for further development of nanofibrous scaffolds […]

Nanofibrous scaffolds for the guidance of stem cell-derived neurons for auditory nerve regeneration
Sandra Hackelberg,1,¤ Samuel J. Tuck,2,3 Long He,1,4 Arjun Rastogi,2 Christina White,2,3 Liqian Liu,1 Diane M. Prieskorn,1 Ryan J. Miller,1,2,3 Che Chan,2,5 Benjamin R. Loomis,1 Joseph M. Corey,2,3,6 Josef M. Miller,1 and R. Keith Duncan
PLoS One. 2017; 12(7): e0180427.
doi: 10.1371/journal.pone.0180427

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DionisioJuly 21, 2017 at 6:15 pm

Histone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions.

Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons.

[…] CHD4 promotes the early proliferation of progenitors, CHD5 facilitates neuronal migration and CHD3 ensures proper layer specification.

[…] NuRD complexes containing specific CHDs are recruited to regulatory elements and modulate the expression of genes essential for brain development.

A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development.
Nitarska J1, Smith JG1, Sherlock WT1, Hillege MM1, Nott A1, Barshop WD2, Vashisht AA2, Wohlschlegel JA2, Mitter R3, Riccio A4
Cell Rep. 2016 Nov 1;17(6):1683-1698.
doi: 10.1016/j.celrep.2016.10.022.

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DionisioJuly 21, 2017 at 6:18 pm

During brain development, chromatin remodeling is essential for the expression of genes that regulate the differentiation of pluripotent cells into mature neurons.

Further investigation will be needed to define whether there is an NuRD-independent role for CHDs during cortical development.

Further studies will be necessary to determine the role of ATP-dependent chromatin remodeling enzymes during the establishment of neuronal circuitry in early brain development […]

A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development.
Nitarska J1, Smith JG1, Sherlock WT1, Hillege MM1, Nott A1, Barshop WD2, Vashisht AA2, Wohlschlegel JA2, Mitter R3, Riccio A4
Cell Rep. 2016 Nov 1;17(6):1683-1698.
doi: 10.1016/j.celrep.2016.10.022.

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DionisioJuly 24, 2017 at 6:12 am

B1a cells, particularly the PD-L2(+) B1a cell subset, are enriched with autoantigen-specific receptors.

However, the underlying molecular mechanism responsible for the skewed selection of autoreactive B1a cells remains unclear.

[…] B1 cells express only Ras guanyl nucleotide-releasing protein (RasGRP) 1, whereas B2 cells express mostly RasGRP3 and little RasGRP1.

RasGRP1 is indispensable for transduction of weak signals. RasGRP1 deficiency markedly impairs B1a cell development and reduces serum natural IgM production; in particular, B1a cells that express autoantigen receptors, such as anti-phosphatidylcholine B1a cells, are virtually eliminated.

Thus, unlike Btk and other signalosome components, RasGRP1 deficiency selectively affects only the B1a cell population with autoantigen receptors rather than the entire pool of B1a cells.

RasGRP1 Is an Essential Signaling Molecule for Development of B1a Cells with Autoantigen Receptors
Guo B, Rothstein TL
DOI: 10.4049/jimmunol.1502132

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DionisioJuly 24, 2017 at 6:18 am

The transcription factor Bhlhe41 determines the survival and repertoire of B-1a cells

To B-1 or not to B-1
Henry H Wortis
Nature Immunology 18, 365–366 (2017)
doi:10.1038/ni.3715

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DionisioJuly 24, 2017 at 11:55 am

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes.

However, their identities and interrelationships are not fully understood.

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors
Alexandra-Chloé Villani, Rahul Satija, Gary Reynolds, Siranush Sarkizova, Karthik Shekhar, James Fletcher
Science 21 Apr 2017:
Vol. 356, Issue 6335, eaah4573
DOI: 10.1126/science.aah4573

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DionisioJuly 24, 2017 at 12:00 pm

[…] miR-34a is an epigenetic regulator of DC function that may contribute to RA.

MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis.
Kurowska-Stolarska M1, Alivernini S2, Melchor EG1, Elmesmari A1, Tolusso B2, Tange C1, Petricca L2, Gilchrist DS1, Di Sante G2, Keijzer C1, Stewart L1, Di Mario C2, Morrison V1, Brewer JM1, Porter D1, Milling S1, Baxter RD1,3, McCarey D3, Gremese E2, Lemke G4, Ferraccioli G2, McSharry C1, McInnes IB
Nat Commun. 2017 Jun 22;8:15877.
doi: 10.1038/ncomms15877.

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DionisioJuly 26, 2017 at 10:59 am

A large and constantly growing body of evidence indicates involvement of BDNF in numerous neurophysiological processes.

In general, the functions of this neurotrophin are related to control of development of neuronal and glial cells, as well as activity-dependent regulation of the synaptic structure and its maintenance, which are critical for memory and cognition.

A wide spectrum of processes are controlled by BDNF, exerting sometimes opposite effects in the brain, which can be explained based on the specific pattern of its synthesis, with several biologically active isoforms that interact with different types of receptor, finally initiating a large number of signaling pathways.

BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity
Przemys?aw Kowia?ski, Gra?yna Lietzau, Ewelina Czuba, Monika Wa?kow, Aleksandra Steliga, Janusz Mory?
Cellular and Molecular Neurobiology pp 1–15
https://link.springer.com/article/10.1007/s10571-017-0510-4

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DionisioJuly 28, 2017 at 3:32 pm

An SMNI model has been developed to calculate coupling of molecular scales of Ca2+ wave dynamics with A ?elds developed at macroscopic regional scales measured by coherent neuronal ?ring activity measured by scalp EEG during STM tasks.

This requires crossing molecular, microscopic (synaptic and neuronal), mesoscopic (minicolumns and macrocolumns), and macroscopic regional scales.

Considerations of both classical and quantum physics give predictions of the in?uence of A on the momenta of Ca2+ waves during STM processing as measured by scalp EEG.

Since the spatial scales of Ca2+ wave and macro-EEG are quite disparate, an experiment would have to be able to correlate both scales in time scales on the order of tens of milliseconds.

Statistical mechanics of neocortical interactions Large-scale EEG in?uences on molecular processes
Lester Ingber
Journal of Theoretical Biology
Volume 395, Pages 144-152
https://doi.org/10.1016/j.jtbi.2016.02.003
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2691682

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DionisioJuly 31, 2017 at 6:18 pm

Compartmentalization of eukaryotic cells into dynamic organelles that exchange material through regulated membrane traffic governs virtually every aspect of cellular physiology including signal transduction, metabolism and transcription.

Much has been revealed about the molecular mechanisms that control organelle dynamics and membrane traffic and how these processes are regulated by metabolic, physical and chemical cues.

From this emerges the understanding of the integration of specific organellar phenomena within complex, multiscale and nonlinear regulatory networks.

In this review, we discuss systematic approaches that revealed remarkable insight into the complexity of these phenomena, including the use of proximity-based proteomics, high-throughput imaging, transcriptomics and computational modeling.

We discuss how these methods offer insights to further understand molecular versatility and organelle heterogeneity, phenomena that allow a single organelle population to serve a range of physiological functions.

We also detail on how transcriptional circuits drive organelle adaptation, such that organelles may shift their function to better serve distinct differentiation and stress conditions.

Thus, organelle dynamics and membrane traffic are functionally heterogeneous and adaptable processes that coordinate with higher-order system behavior to optimize cell function under a range of contexts.

Obtaining a comprehensive understanding of organellar phenomena will increasingly require combined use of reductionist and system-based approaches.

The big and intricate dreams of little organelles: Embracing complexity in the study of membrane traffic
Allen P. Liu, Roberto J. Botelho, Costin N. Antonescu
DOI: 10.1111/tra.12497
http://onlinelibrary.wiley.com.....7/abstract

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DionisioJuly 31, 2017 at 6:23 pm

Resolving the spatial distribution of the human proteome at a subcellular level greatly increases our understanding of human biology and disease.

Here, we present a comprehensive image-based map of the subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry.

Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of 13 major organelle proteomes.

Exploration of the proteomes reveals single-cell variations of abundance or spatial distribution, and localization of approximately half of the proteins to multiple compartments.

This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.

A subcellular map of the human proteome
Peter J. Thul1,*, Lovisa Åkesson1,*, Mikaela Wiking1, Diana Mahdessian1, Aikaterini Geladaki2,3, Hammou Ait Blal1, Tove Alm1, Anna Asplund4, Lars Björk1, Lisa M. Breckels2,5, Anna Bäckström1, Frida Danielsson1, Linn Fagerberg1, Jenny Fall1, Laurent Gatto2,5, Christian Gnann1, Sophia Hober6, Martin Hjelmare1, Fredric Johansson1, Sunjae Lee1, Cecilia Lindskog4, Jan Mulder7, Claire M. Mulvey2, Peter Nilsson1, Per Oksvold1, Johan Rockberg6, Rutger Schutten1, Jochen M. Schwenk1, Åsa Sivertsson1, Evelina Sjöstedt4, Marie Skogs1, Charlotte Stadler1, Devin P. Sullivan1, Hanna Tegel6, Casper Winsnes1, Cheng Zhang1, Martin Zwahlen1, Adil Mardinoglu1, Fredrik Pontén4, Kalle von Feilitzen1, Kathryn S. Lilley2, Mathias Uhlén1,†, Emma Lundberg1
Science 11 May 2017: eaal3321
DOI: 10.1126/science.aal3321

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DionisioJuly 31, 2017 at 6:30 pm

Cells are complex machines constructed from genetic blueprints […], whose information is expressed under the influence of the cellular environment.

Although each cell in any human has the same genes, complex regulatory networks determine which genes are expressed, creating the large variety of specialized cell types that constitute our bodies.

To gain a deeper understanding of how cells function, we need to methodically study gene expression and cell structure in the context of the activities that drive cell behaviors.

This will provide a framework with which to untangle and model the plethora of dynamic, interacting components that enable life.

Recent initiatives, including one reported on page 820 of this issue by Thul et al. (1), and new methodologies suggest that now is the time to undertake an ambitious challenge: conjoin genomic, epigenetic, and structural studies to create a whole cell atlas representing the full variety of cell types and states in the human body.

Whole cell maps chart a course for 21st-century cell biology
Rick Horwitz, Graham T. Johnson
Science 26 May 2017:
Vol. 356, Issue 6340, pp. 806-807
DOI: 10.1126/science.aan5955

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DionisioJuly 31, 2017 at 6:37 pm

A cell is not just a bag of proteins and other molecules; organelles provide niches with specific chemical environments in which certain members-only proteins are allowed.

“Knowing the exact subcellular locations provides good clues for protein function and can also be used as boundaries for protein–protein interactions in systems biology applications,” says Emma Lundberg of KTH Royal Institute of Technology in Stockholm.

“Knowing the whole set of proteins in an organelle also facilitates the understanding of its morphology and function.”

But despite the availability of numerous methods, identifying proteins’ subcellular addresses has turned out to be challenging to do on a proteomic scale.

As a result, most human proteins have not been mapped to specific organelles.

Charting the subcellular proteome
Allison Doerr
Nature Methods 14, 650–651 (2017)
doi:10.1038/nmeth.4359

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DionisioJuly 31, 2017 at 6:39 pm

The HPA team plans to continue work on the Cell Atlas to map the complete subcellular human proteome.

“This means that we will need to work with more specialized cell types, such as primary cells and stem cells,” Lundberg notes.

The team’s ultimate goal is to develop a model of the entire proteome of a human cell over the course of one cell cycle and to understand how protein localization contributes to cell function.

Charting the subcellular proteome
Allison Doerr
Nature Methods 14, 650–651 (2017)
doi:10.1038/nmeth.4359

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Truth Will Set You FreeJuly 31, 2017 at 8:39 pm

Dionisio everywhere: Incredible contributions. Brilliant. Thank you.
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DionisioAugust 3, 2017 at 7:25 am

The development of multicellular organisms is one of the most important fundamental processes in nature.

The most critical question here is how a small set of genetically identical cells in embryos can produce morphologically and functionally different tissues and organs in fully developed organisms.

The central concept of biological development is that the observed complex spatial patterning is due to action of signaling molecules that are also called morphogens.

These signaling molecules can produce non-uniform concentration profiles, the so-called morphogen gradients, that via complex biochemical networks stimulate or suppress specific genes in embryo cells, depending on their local concentrations.

[…] many aspects of the underlying mechanisms that result in the formation of the signaling molecules density profiles remain not fully explained.

Theoretical analysis of degradation mechanisms in the formation of morphogen gradients.
Bozorgui B, Teimouri H, Kolomeisky AB
J Chem Phys. 143(2):025102.
doi: 10.1063/1.4926461.

[emphasis added]

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DionisioAugust 3, 2017 at 7:50 am

[…] the process of degradation or removal of signaling molecules from the system is critically important for the development of morphogen gradients.

[…] specific details of how the degradation influences the formation of morphogen gradients are still not well clarified.

There are many counter-intuitive observations that cannot be explained by current theoretical views.

Theoretical analysis of degradation mechanisms in the formation of morphogen gradients.
Bozorgui B, Teimouri H, Kolomeisky AB
J Chem Phys. 143(2):025102.
doi: 10.1063/1.4926461.

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DionisioAugust 3, 2017 at 8:05 am

TWSYF @64:

It’s my pleasure. However, all I’m doing is referencing a small subset of the enormous volume of biology-related research information available out there.
The real work is done by many seriously dedicated scientists who are trying to figure out how the biological systems work. Unfortunately many of them have been brainwashed with the Darwinian obscenities inserted in otherwise interesting textbooks, thus poisoning the minds of many students.
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DionisioAugust 3, 2017 at 8:30 am

[…] the degradation acts as an effective potential that pushes signaling molecules away from the source region.

[…] the degradation will make the diffusion of morphogen molecules effectively biased.

[…] the removal of signaling molecules works as the effective potential.

[…] the degradation might be an effective tool for tuning the complex biochemical and biophysical processes in biological development.

[…] our approach is oversimplified and it involves many approximations.

It will be important to test the proposed ideas with more advanced theoretical methods as well as in the extensive experimental studies.

Theoretical analysis of degradation mechanisms in the formation of morphogen gradients.
Bozorgui B, Teimouri H, Kolomeisky AB
J Chem Phys. 143(2):025102.
doi: 10.1063/1.4926461.

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DionisioAugust 10, 2017 at 6:20 am

A true understanding of how a gene is controlled in normal function or disease requires identification of the complete inventory of regulatory proteins and complexes that reside in its regulatory regions, as well as their interactions and modifications.

Proteomics to study DNA-bound and chromatin-associated gene regulatory complexes
Michael Wierer and Matthias Mann
Hum Mol Genet. 25(R2): R106–R114.
doi: 10.1093/hmg/ddw208

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DionisioAugust 10, 2017 at 4:23 pm

Tissue patterning, through the concerted activity of a small number of signaling pathways, is critical to embryonic development.

While patterning can involve signaling between neighbouring cells, in other contexts signals act over greater distances by traversing complex cellular landscapes to instruct the fate of distant cells.

Control of signaling molecule range during developmental patterning
Scott G. Wilcockson, Catherine Sutcliffe, and Hilary L. Ashe
Cell Mol Life Sci. 2017; 74(11): 1937–1956.
doi: 10.1007/s00018-016-2433-5

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DionisioAugust 10, 2017 at 4:41 pm

The ability to pattern fields of cells into distinct fates underpins multicellularity.

While the simplest mechanism for regulating signaling range is diffusion of a signaling molecule from its source, studies in many contexts have revealed more elaborate mechanisms.

Control of signaling molecule range during developmental patterning
Scott G. Wilcockson, Catherine Sutcliffe, and Hilary L. Ashe
Cell Mol Life Sci. 2017; 74(11): 1937–1956.
doi: 10.1007/s00018-016-2433-5

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DionisioAugust 10, 2017 at 5:08 pm

Short-range signaling

Restriction of Dpp diffusion by receptors and co-receptors

Propagation of Wnt signaling by cell division and regulation of cell surface levels

Establishment of graded Nodal signaling by autoactivation and timed inhibition

Tissue architecture

ECM-sequestration of BMP

An ECM scaffold directs BMP gradient formation

Tissue morphogenesis drives local ligand entrapment

Tissue morphogenesis directs patterning centre formation

Membranous protrusions

Nanotubes promote BMP signal transduction

Reaching out for ligands

Ligand delivery

Packaging ligands into extracellular vesicles

Long-range action revisited

Control of signaling molecule range during developmental patterning
Scott G. Wilcockson, Catherine Sutcliffe, and Hilary L. Ashe
Cell Mol Life Sci. 2017; 74(11): 1937–1956.
doi: 10.1007/s00018-016-2433-5

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DionisioAugust 10, 2017 at 5:13 pm

The different strategies used to control signaling range that we have described here highlight how few rely on passive diffusion of the signaling molecule.

[…] the reality seems to be that diffusion of signals is often limited by receptors, the extracellular matrix, and/or tissue architecture.

[…] membranous protrusions and extracellular vesicles are highly conserved phenomena that have been shown to drive lipophilic ligand diffusion in a variety of contexts.

Given the multitude of roles that signaling ligands play in development and tissue homeostasis, it is possible that these methods of active morphogen movement may represent common mechanisms for driving long-range movement, even if long-range signaling may in fact be dispensable in some contexts.

Control of signaling molecule range during developmental patterning
Scott G. Wilcockson, Catherine Sutcliffe, and Hilary L. Ashe
Cell Mol Life Sci. 2017; 74(11): 1937–1956.
doi: 10.1007/s00018-016-2433-5

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DionisioAugust 10, 2017 at 6:53 pm

Herein we provide a review of recent molecular insights into how Notch signals are triggered and how cell shape affects these events, and we use the new insights to illuminate a few perplexing observations.

The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force.
Kovall RA, Gebelein B, Sprinzak D, Kopan R
Dev Cell. 41(3):228-241.
doi: 10.1016/j.devcel.2017.04.001.

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DionisioAugust 10, 2017 at 9:21 pm

[…] the flow of information in the Notch signaling pathway: from the outside in.

The functional consequence of glycosylation at this position remains to be determined, as is the identity of the enzyme responsible.

[…] all cell types use this common core complex (CSL/NICD) to mediate Notch transcriptional responses, and yet they often do so in a largely cell-specific manner.

[…] the events surrounding Notch target selection are still shrouded in mystery […]

[…] it currently remains unclear what the constraints (spacing, orientation, etc.) are for the SPS + E/P sites to mediate this synergy. It also remains unclear if this requirement is conserved in vertebrates.

The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force.
Kovall RA, Gebelein B, Sprinzak D, Kopan R
Dev Cell. 41(3):228-241.
doi: 10.1016/j.devcel.2017.04.001.

Work in progress… stay tuned.

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DionisioAugust 10, 2017 at 9:22 pm

[…] while the combinatorial codes that are being uncovered have revealed conserved cooperating factors required for proper Notch-regulated activity, we still do not have a sufficient functional understanding of their integration to enable us to engineer and/or predict the behaviors of these elements in vivo.

[…] it still remains largely unclear how CSL/NICD complexes select the appropriate combinations of target genes within the genome.

[…] much remains to be learned about the Notch signaling pathway.

In addition to questions posed within this review, many others remain.

The answers are within reach, but not without continued investment in time and resources.

The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force.
Kovall RA, Gebelein B, Sprinzak D, Kopan R
Dev Cell. 41(3):228-241.
doi: 10.1016/j.devcel.2017.04.001.

Work in progress… stay tuned.

Complex functionally specified informational complexity
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DionisioAugust 11, 2017 at 7:17 am

It has been a long-standing question as to whether the activation of Notch by its ligands occurs in a specific region of the plasma membrane.

A study now shows that this is indeed the case in the Drosophila sensory organ precursor cell lineage.

Notch Signaling: Where Is the Action?
Jens Januschke, Andreas Wodarz
Current Biology
Volume 27, Issue 15, Pages R760-R762
https://doi.org/10.1016/j.cub.2017.06.072

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DionisioAugust 11, 2017 at 8:19 am

Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life.

In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division.

How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly understood.

More generally, where ligand-dependent activation of Notch occurs at the cell surface is not known, as methods to detect receptor activation in vivo are lacking.

In Drosophila pupae, Notch signals during cytokinesis to regulate the intra-lineage pIIa/pIIb decision in the sensory organ lineage.

Intra-lineage Fate Decisions Involve Activation of Notch Receptors Basal to the Midbody in Drosophila Sensory Organ Precursor Cells
Mateusz Trylinski, Khalil Mazouni, François Schweisguth
https://doi.org/10.1016/j.cub.2017.06.030
Volume 27, Issue 15, Pages 2239-2247.e3

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DionisioAugust 11, 2017 at 8:20 am

Here, we identify two pools of Notch along the pIIa-pIIb interface, apical and basal to the midbody.

Analysis of the dynamics of Notch, Delta, and Neuralized distribution in living pupae suggests that ligand endocytosis and receptor activation occur basal to the midbody.

Using selective photo-bleaching of GFP-tagged Notch and photo-tracking of photo-convertible Notch, we show that nuclear Notch is indeed produced by receptors located basal to the midbody.

Thus, only a specific subset of receptors, located basal to the midbody, contributes to signaling in pIIa.

This is the first in vivo characterization of the pool of Notch contributing to signaling.

We propose a simple mechanism of cell fate decision based on intra-lineage signaling: ligands and receptors localize during cytokinesis to the new cell-cell interface, thereby ensuring signaling between sister cells, hence intra-lineage fate decision.

Intra-lineage Fate Decisions Involve Activation of Notch Receptors Basal to the Midbody in Drosophila Sensory Organ Precursor Cells
Mateusz Trylinski, Khalil Mazouni, François Schweisguth
https://doi.org/10.1016/j.cub.2017.06.030
Volume 27, Issue 15, Pages 2239-2247.e3

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DionisioAugust 11, 2017 at 5:16 pm

Cell and tissue morphogenesis depends on the correct regulation of non-muscle Myosin II, but how this motor protein is spatiotemporally controlled is incompletely understood.

Here, we show that in asymmetrically dividing Drosophila neural stem cells, cell intrinsic polarity cues provide spatial and temporal information to regulate biased Myosin activity.

Using live cell imaging and a genetically encoded Myosin activity sensor, we found that Drosophila Rho kinase (Rok) enriches for activated Myosin on the neuroblast cortex prior to nuclear envelope breakdown (NEB).

After NEB, the conserved polarity protein Partner of Inscuteable (Pins) sequentially enriches Rok and Protein Kinase N (Pkn) on the apical neuroblast cortex.

Our data suggest that apical Rok first increases phospho-Myosin, followed by Pkn-mediated Myosin downregulation, possibly through Rok inhibition.

We propose that polarity-induced spatiotemporal control of Rok and Pkn is important for unequal cortical expansion, ensuring correct cleavage furrow positioning and the establishment of physical asymmetry.

Cell Polarity Regulates Biased Myosin Activity and Dynamics during Asymmetric Cell Division via Drosophila Rho Kinase and Protein Kinase N
Anna Tsankova, Tri ThanhPham, David Salvador Garcia, FabianOtte, ClemensCabernard
Volume 42, Issue 2, Pages 143-155.e5
https://doi.org/10.1016/j.devcel.2017.06.012
Developmental Cell

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DionisioAugust 12, 2017 at 5:03 pm

Signal location is a critical parameter that cells use to decode complex signaling circuitries and to compute specific biological responses.

While signaling initiates at the plasma membrane (PM), it requires membrane dynamics for its sustainment/extinction and, more importantly, for its deconvolution.

Endocytosis provides this dimension through numerous mechanisms […] enacted in different subcellular compartments.

Overall, these studies highlight the importance of monitoring endocytic and signaling events at the system level, coupling single cell measurements to quantitative computational analysis of large datasets and mathematical modeling, to untangle the impact of the endocytic machinery on cell regulation.

Endocytic control of signaling at the plasma membrane
Elisa Barbieri, Pier Paolo Di Fiore, Sara Sigismund
Current Opinion in Cell Biology
Volume 39, Pages 21-27
https://doi.org/10.1016/j.ceb.2016.01.012

Complex functionally specified informational complexity
82

DionisioAugust 12, 2017 at 5:26 pm

Endocytosis is essential for all eukaryotic cells to internalize macromolecules and proteins such as receptors, channels and transporters from plasma membrane.

[…] the mechanism for ultrafast endocytosis is not understood yet […]

Future studies should reveal the molecular basis and physiological functions of fast and ultrafast endocytosis and expand our understanding of receptor internalization and recycling of synaptic vesicles.

Fast and ultrafast endocytosis
Shigeki Watanabe and Emmanuel Boucrot
Current Opinion in Cell Biology 2017, 47:64–71
This review comes from a themed issue on Cell organelles
Edited by Bruno Antonny and Catherine Rabouille
http://dx.doi.org/10.1016/j.ceb.2017.02.013

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DionisioAugust 15, 2017 at 10:57 am

As a repeating unit in eukaryotic chromatin, a nucleosome wraps DNA in superhelical turns around a histone octamer. Mattiroli et al. present the crystal structure of an archaeal histone-DNA complex in which the histone-mediated DNA geometry is exactly the same as that in the nucleosome.

DNA wraps around an extended polymer, formed by archaeal histone homodimers, in a quasi-continuous superhelix with the same geometry as DNA in the eukaryotic nucleosome.

Substitutions of a conserved glycine at the interface of adjacent protein layers destabilize archaeal chromatin, reduce growth rate, and impair transcription regulation, confirming the biological importance of the polymeric structure.

Structure of histone-based chromatin in Archaea
Francesca Mattiroli, Sudipta Bhattacharyya, Pamela N. Dyer, Alison E. White, Kathleen Sandman, Brett W. Burkhart, Kyle R. Byrne, Thomas Lee, Natalie G. Ahn, Thomas J. Santangelo, John N. Reeve, Karolin Luger
Science 11 Aug 2017:
Vol. 357, Issue 6351, pp. 609-612
DOI: 10.1126/science.aaj1849

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DionisioAugust 17, 2017 at 7:51 pm

Central nerve terminals contain a limited number of synaptic vesicles (SVs) which mediate the essential process of neurotransmitter release during their activity-dependent fusion.

The rapid and accurate formation of new SVs with the appropriate cargo is essential to maintain neurotransmission in mammalian brain.

Generating SVs containing the correct SV cargo with the appropriate stoichiometry is a significant challenge, especially when multiple modes of endocytosis exist in central nerve terminals, which occur at different locations within the nerve terminals.

These endocytosis modes include ultrafast endocytosis, clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) which are triggered by specific patterns of neuronal activity.

Whether ADBE has specific adaptor molecules to perform this task remains to be determined, possibly cargo—cargo interactions similar to those observed with iTRAPs may be sufficient in this instance.

Integration of Synaptic Vesicle Cargo Retrieval with Endocytosis at Central Nerve Terminals
Michael A. Cousin
Front. Cell. Neurosci.| https://doi.org/10.3389/fncel.2017.00234

Complex functionally specified informational complexity
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DionisioAugust 17, 2017 at 8:13 pm

[…] the link between v-ATPase and the endocytosis machinery remains to be elucidated.

The role of V1C1 during the v-ATPase assembly/disassembly cycle remains elusive.

[…] the available data point to tripartite disassembly of v-ATPase with a rather special, but not fully understood, functional role of V1C1.

The human brain consumes 20% of total energy produced, half of it for synaptic transmission

[…] the functional significance of the v-ATPase assembly/disassembly cycle for this very precise resorting of at least one v-ATPase per SV remains to be elucidated.

The Presynaptic v-ATPase Reversibly Disassembles and Thereby Modulates Exocytosis but Is Not Part of the Fusion Machinery
Anna Bodzeta, Martin Kahms, Jurgen Klingauf
Cell Reports 20, 1348–1359
DOI: 10.1016/j.celrep.2017.07.040

Complex functionally specified informational complexity
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DionisioAugust 18, 2017 at 2:31 am

Off topic?

https://uncommondescent.com/plants/photosynthesis-genes-source-still-unclear/#comment-636305
87

DionisioAugust 18, 2017 at 2:41 pm

Those who would like to learn basic biology concepts associated with development, may benefit from watching MIT free courses by professor Hazel Sive.
Lecture 21 Development 1
Lecture 22 Development 2
Lecture 23 Stem Cells
Lecture 24 Nervous System 1
Lecture 25 Nervous System 2
Lecture 26 Nervous System 3

https://ocw.mit.edu/courses/biology/7-013-introductory-biology-spring-2013/video-lectures/lecture-21-development-1/

You may download the videos and watch them offline at your own convenience.
88

DionisioAugust 19, 2017 at 8:41 pm

The human genome sequence has a smaller number of genes than expected: 19 000 compared to 6.7 million genes in earlier estimates [1].

It has remained largely unclear how this small number of genes can be sufficient to support human complexity.

In recent years, hierarchical layers of regulation have been revealed that give rise to some of the functional complexity observed in living cells despite the compact nature of the protein coding genome.

These are directly linked to spatiotemporal dynamics on all levels of protein structure from their sequence, three-dimensional structure to alternative cellular localizations and spatial organization of specific proteins in tissues and organs.

Time, space, and disorder in the expanding proteome universe
David-Paul Minde, A. Keith Dunker and Kathryn S. Lilley
Proteomics 00, 0, 2017, 1600399
DOI 10.1002/pmic.201600399

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DionisioAugust 19, 2017 at 8:46 pm

Significant computational science community efforts are needed to maximize the knowledge gain from rapidly accumulating and diversifying multi-omics datasets to ultimately reveal fascinating new hidden ordered patterns in complex cellular dynamic systems […]

Time, space, and disorder in the expanding proteome universe
David-Paul Minde, A. Keith Dunker and Kathryn S. Lilley
Proteomics 00, 0, 2017, 1600399
DOI 10.1002/pmic.201600399

Complex functionally specified informational complexity
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DionisioAugust 20, 2017 at 6:39 am

Protein de novo folding simulations have reached near-atomic precision for small folded domains and IDRs.

Higher-order structures are less readily predictable so far.

Complicating factors are the intracellular and environmental fluctuations, which can be observed even in the most simple model systems […]

Time, space, and disorder in the expanding proteome universe
David-Paul Minde, A. Keith Dunker and Kathryn S. Lilley
Proteomics 00, 0, 2017, 1600399
DOI 10.1002/pmic.201600399

Complex functionally specified informational complexity
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DionisioAugust 20, 2017 at 6:45 am

An improved proteome-wide understanding of the hidden order in apparent disorder of higher-order protein structures in living organisms can pave the way to de novo spatiotemporal engineering of organisms with beneficial properties.

It will become increasingly possible to avoid late-stage failures in drug discovery pipelines due to an improved understanding of cellular dynamics.

Plenty of dynamics at the bottom of biology (Fig. 3).

Time, space, and disorder in the expanding proteome universe
David-Paul Minde, A. Keith Dunker and Kathryn S. Lilley
Proteomics 00, 0, 2017, 1600399
DOI 10.1002/pmic.201600399

Work in progress… stay tuned.

Biology researchers should focus in on understanding how the marvelous biological systems function, instead of wasting time on OOL pseudoscientific hogwash.

Complex functionally specified informational complexity
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DionisioAugust 20, 2017 at 7:34 am

[…] a timely and important task for the philosophy of biology is to critically discern the ontological commitments of that [evo-devo] framework and assess whether and to what extent our current metaphysical models are able to accommodate them.

Evo-devo: a science of dispositions
Christopher J. Austin
European Journal for Philosophy of Science
Volume 7, Issue 2, pp 373–389
DOI: 10.1007/s13194-016-0166-9

As the researchers will dig deeper into their reductionist evo-devo framework, eventually they could realize that the currently-accepted metaphysical models can’t explain the “surprising” and “unexpected” discoveries they’ll make.

Complex functionally specified informational complexity
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DionisioAugust 20, 2017 at 7:51 am

In this paper, I argue that one particular model is a natural fit: an ontology of dispositional properties coherently and adequately captures the crucial casual-cum-explanatory role that the fundamental elements of evo-devo play within that framework.

Evo-devo: a science of dispositions
Christopher J. Austin
European Journal for Philosophy of Science
Volume 7, Issue 2, pp 373–389
DOI: 10.1007/s13194-016-0166-9
https://link.springer.com/article/10.1007/s13194-016-0166-9

casual? Did the author mean “causal” instead?
How many people read the abstract of this paper before it was approved for publishing? Proofreaders? Peer-reviewers? Did they read the text carefully?

They seem struggling with complex functionally specified informational complexity. Poor things.
94

DionisioAugust 20, 2017 at 8:05 am

In this paper, I argue that one particular model is a natural fit: an ontology of dispositional properties coherently and adequately captures the crucial casual-cum-explanatory role that the fundamental elements of evo-devo play within that framework.

Evo-devo: a science of dispositions
Christopher J. Austin
European Journal for Philosophy of Science
Volume 7, Issue 2, pp 373–389
DOI: 10.1007/s13194-016-0166-9
https://link.springer.com/article/10.1007/s13194-016-0166-9

casual? Did the author mean “causal” instead?
How many people read the abstract of this paper before it was approved for publishing? Proofreaders? Peer-reviewers? Did they read the text carefully? At least the abstract? Do they pay attention to details? How much attention? Do they know that “casual” means something different than “causal” ?

They seem struggling with complex functionally specified informational complexity. Poor things.
95

DionisioAugust 28, 2017 at 5:57 pm

These data reveal the unique composition of the endothelium in developing bones and indicate that vascular patterning plays a role in determining bone shape by forming a template for deposition of bone matrix.

Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology
Adi Ben Shoham, Chagai Rot, Tomer Stern, Sharon Krief, Anat Akiva, Tali Dadosh, Helena Sabany, Yinhui Lu, Karl E. Kadler, Elazar Zelzer
Development 143: 3933-3943;
doi: 10.1242/dev.139253

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DionisioAugust 28, 2017 at 10:35 pm

[…] the vasculature plays active roles in morphogenesis of other tissue, such as the pancreas and lungs […]

[…] what happens to the ECs that undergo collagen I coating and mineralization?

There are several possible mechanisms that may determine which vessels will undergo mineralization and which will retain their integrity and function.

It will be interesting to study the involvement of this integrin in the mechanism that mediates the interaction between blood vessels and collagen I.

[…] what mechanism regulates BM formation or degradation?

To date, the regulation of BM formation is poorly understood.

It would be interesting to examine whether the H type vessels lack BM and, if so, what role this absence plays in the ability of the vasculature to regulate bone growth.

[…] the endothelium serves as a template on which bone-forming cells build new bone tissue, implying that vascular patterning directs bone formation.

Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology
Adi Ben Shoham, Chagai Rot, Tomer Stern, Sharon Krief, Anat Akiva, Tali Dadosh, Helena Sabany, Yinhui Lu, Karl E. Kadler, Elazar Zelzer
Development 143: 3933-3943;
doi: 10.1242/dev.139253

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DionisioAugust 28, 2017 at 11:43 pm

Blood vessels supplying bones orchestrate the process of bone development and remodeling as well as regulate the skeleton regeneration by delivering the nutrients, oxygen, hormones or growth factors to the bone cells.

Blood vessels localized in the bone marrow cavity of the long bones also coordinate the process of hematopoiesis and provide the niches occupied by the precursors of blood cells.

The role of vasculature in bone development, regeneration and proper systemic functioning
Joanna Filipowska, Krzysztof A. Tomaszewski, ?ukasz Nied?wiedzki, Jerzy A. Walocha, Tadeusz Nied?wiedzki
Angiogenesis
Volume 20, Issue 3, pp 291–302
DOI10.1007/s10456-017-9541-1

Complex functionally specified informational complexity
98

DionisioSeptember 3, 2017 at 10:05 am

Morphogens are signaling factors that direct cell fate and tissue development at a distance from their source, and various modes of transport and interpretation have been suggested for morphogens.

(1) morphogen gradient formation;
(2) morphogen gradient interpretation;
(3) signaling networks and feedback in morphogenesis;
(4) emergence of patterns;
(5) scaling of patterns;
(6) the control of growth;
(7) new techniques in the field.

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
99

DionisioSeptember 3, 2017 at 10:11 am

How genetically identically daughter cells are directed to take different developmental paths in a reliable time- and position-dependent manner has fascinated developmental biologists for over a century.

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
100

DionisioSeptember 3, 2017 at 10:29 am

How morphogens are transported has been intensively studied.

In addition to simple diffusion, a number of other transport mechanisms have been proposed and are actively being investigated, including shuttling via other proteins, transport via vesicles (e.g. exosomes and exovesicles) and delivery via cellular projections (e.g. cytonemes).

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
101

DionisioSeptember 3, 2017 at 10:31 am

A number of model systems have been established to study morphogen transport, gradient formation and interpretation, as well as position-dependent cell differentiation in various biological contexts.

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
102

DionisioSeptember 3, 2017 at 10:40 am

Although there are many examples in biology that look like Turing-based patterning, molecular proof is still outstanding and is a focus of intense study in the field.

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
103

DionisioSeptember 3, 2017 at 10:43 am

Much experimental evidence suggests that morphogen gradients form as a result of diffusion from a source and removal in the target tissue.

The relative contributions of fast, unhindered diffusion and of slow, hindered diffusion to the formation of diffusion-based gradients are, however, a matter of controversy.

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
104

DionisioSeptember 3, 2017 at 10:49 am

[…] it seems clear now that morphogens can be transported in several ways, but it remains unclear to what extent the different routes contribute to patterning.

A number of studies highlighted the dynamic nature of morphogen read-out and the importance of feedbacks and a network context.

Important open problems concern the mechanistic basis of scaling and growth control – as well as the role of Turing patterns.

Studies of morphogens: keep calm and carry on
Angelike Stathopoulos, Dagmar Iber
Development 140: 4119-4124;
doi: 10.1242/dev.095141

This was over 4 years ago. What’s the situation now?
105

DionisioSeptember 3, 2017 at 2:02 pm

[…] pure reaction–diffusion ideas do not produce a satisfactory explanation of biological growth and form.

Critical waves and the length problem of biology
Robert B. Laughlin
Proc Natl Acad Sci U S A. 112(33): 10371–10376.
doi: 10.1073/pnas.1422855112
PMCID: PMC4547306
Biophysics and Computational Biology, Physics

This was 2 years ago. What’s the situation now?

Turing, please can you explain this for us? 🙂
106

DionisioSeptember 3, 2017 at 2:09 pm

[…] oscillation is necessary to achieve the necessary design stability and plasticity.

[…] the system must be tuned to criticality to stabilize the propagation velocity, thus enabling clocks to function as meter sticks.

Critical waves and the length problem of biology
Robert B. Laughlin
Proc Natl Acad Sci U S A. 112(33): 10371–10376.
doi: 10.1073/pnas.1422855112
PMCID: PMC4547306
Biophysics and Computational Biology, Physics

This was 2 years ago. What’s the situation now?

Did somebody say ‘design’? 🙂
107

DionisioSeptember 3, 2017 at 2:25 pm

[…] a fundamental piece of the machinery of life is probably invisible to present-day biochemical methods because they are too slow.

Critical waves and the length problem of biology
Robert B. Laughlin
Proc Natl Acad Sci U S A. 112(33): 10371–10376.
doi: 10.1073/pnas.1422855112
PMCID: PMC4547306
Biophysics and Computational Biology, Physics

This was 2 years ago. What’s the situation now?

Work in progress… stay tuned.
108

DionisioSeptember 3, 2017 at 2:45 pm

[…] the simplicity of growth and form identified a century ago by D’Arcy Thompson is probably a symptom of biological engineering strategies, not primitive law.

Critical waves and the length problem of biology
Robert B. Laughlin
Proc Natl Acad Sci U S A. 112(33): 10371–10376.
doi: 10.1073/pnas.1422855112
PMCID: PMC4547306
Biophysics and Computational Biology, Physics

This was 2 years ago. What’s the situation now?

Did somebody say “biological engineering strategies”?
109

DionisioSeptember 3, 2017 at 2:52 pm

It is not known how living things measure their lengths.

This is true notwithstanding the immense progress made over the past 30 y in understanding morphogen gradients in embryogenesis

Critical waves and the length problem of biology
Robert B. Laughlin
Proc Natl Acad Sci U S A. 112(33): 10371–10376.
doi: 10.1073/pnas.1422855112
PMCID: PMC4547306
Biophysics and Computational Biology, Physics

This was 2 years ago. What’s the situation now?
110

DionisioSeptember 3, 2017 at 8:26 pm

During development, cells use specialized filopodia called cytonemes to deploy the signaling proteins that coordinate growth and direct morphogenesis.

Cytonemes are dynamic structures that can extend long distances across tissues to either deliver or take up signaling proteins.

Signaling proteins transfer between cells at the tips of cytonemes where specific contacts termed morphogenetic synapses form.

Distributing signaling proteins in space and time: the province of cytonemes
Thomas B Kornberg
Current Opinion in Genetics & Development
Volume 45, Pages 22–27

https://doi.org/10.1016/j.gde.2017.02.010

Complex functionally specified informational complexity
111

DionisioSeptember 3, 2017 at 8:49 pm

Mechanisms that disseminate the proteins that orchestrate organ and tissue development have been a major focus of cell and developmental biology.

Macrophages Help Cells Connect to Pattern Zebrafish Stripes.
Thomas B. Kornberg
Developmental Cell
Volume 40, Issue 6, Pages 520-521
DOI: 10.1016/j.devcel.2017.03.012

Did somebody say ‘orchestrate’?

Complex functionally specified informational complexity
112

DionisioSeptember 3, 2017 at 9:07 pm

Proper functioning of an organism requires cells and tissues to behave in uniform, well-organized ways.

How this optimum of phenotypes is achieved during the development of vertebrates is unclear.

We discovered a previously unrecognized role for specific vertebrate miRNAs to protect tissue development against phenotypic variability.

This discovery marks an important advance in our comprehension of how miRNAs function in the development of higher organisms.

MicroRNAs Establish Uniform Traits during the Architecture of Vertebrate Embryos
Dionna M. Kasper, Albertomaria Moro, Emma Ristori, Anand Narayanan, Guillermina Hill-Teran, Elizabeth Fleming, Miguel Moreno-Mateos, Charles E. Vejnar, Jing Zhang, Donghoon Lee, Mengting Gu, Mark Gerstein, Antonio Giraldez,
Stefania Nicol
Developmental Cell
Volume 40, Issue 6, Pages 552–565.e5
DOI: 10.1016/j.devcel.2017.02.021

Complex functionally specified informational complexity
113

DionisioSeptember 8, 2017 at 2:31 am

Biological Cybernetics

Advances in Computational Neuroscience

https://link.springer.com/journal/422
114

DionisioSeptember 12, 2017 at 6:50 am

Examination of the dynamics of neural or mechanical aspects of moving animals has yielded important insight […]

Understanding these symmetries and this phase shift would allow this behaviour to be replicated in robotic systems […]

If these symmetries and the phase shift are adaptive, then this could correspond to an enhanced performance of these robotic systems.

Morphology and the gradient of a symmetric potential predict gait transitions of dogs
Simon Wilshin, G. Clark Haynes, Jack Portions, Daniel Koditschek, Shai Revzen, Andrew J. Spence
Biological Cybernetics
August 2017, Volume 111, Issue 3–4, pp 269–277

Complex functionally specified informational complexity.
115

DionisioSeptember 12, 2017 at 7:12 am

Although nervous systems are studied at many levels of abstraction, there is no general agreement on which details matter, at a particular level, and which do not.

[…] the main reason for studying nerve cells is to better understand nervous systems, in particular, their functional role in adaptive, animal behavior.

[…] starting from the neuron level, a working understanding or model of this functional role is still far a way.

[…] the analysis of networks of modeled neurons can quickly become prohibitively complex.

Synapse fits neuron: joint reduction by model inversion
H. T. van der Scherer, A. Doelman
Biological Cybernetics
August 2017, Volume 111, Issue 3–4, pp 309–334

Complex functionally specified informational complexity.
116

DionisioSeptember 14, 2017 at 8:13 am

Nucleoporins are the main components of the nuclear-pore complex (NPC) and were initially considered as mere structural elements embedded in the nuclear envelope, being responsible for nucleocytoplasmic transport.

Nevertheless, several recent scientific reports have revealed that some nucleoporins participate in nuclear processes such as transcription, replication, DNA repair and chromosome segregation.

Thus, the interaction of NPCs with chromatin could modulate the distribution of chromosome territories relying on the epigenetic state of DNA.

In particular, the nuclear basket proteins Tpr and Nup153, and the FG-nucleoporin Nup98 seem to play key roles in all these novel functions.

Nucleoporins redistribute inside the nucleus after cell cycle arrest induced by histone deacetylases inhibition.
Pérez-Garrastachu M, Arluzea J, Andrade R, Díez-Torre A, Urtizberea M, Silió M, Aréchaga J
Nucleus. 11:1-19.
doi: 10.1080/19491034.2017.1320001

Complex functionally specified informational complexity.
117

DionisioSeptember 14, 2017 at 8:20 am

[…] after HDACi treatment, Tpr, Nup153 and Nup98 are translocated from the nuclear pore toward the interior of the cell nucleus, accumulating as intranuclear nucleoporin clusters.

These transitory structures are highly dynamic, and are mainly present in the population of cells arrested at the G0/G1 phase of the cell cycle.

[…] the redistribution of these nucleoporins from the nuclear envelope to the nuclear interior may be implicated in the early events of cell cycle initialization, particularly during the G1 phase transition.

Nucleoporins redistribute inside the nucleus after cell cycle arrest induced by histone deacetylases inhibition.
Pérez-Garrastachu M, Arluzea J, Andrade R, Díez-Torre A, Urtizberea M, Silió M, Aréchaga J
Nucleus. 11:1-19.
doi: 10.1080/19491034.2017.1320001

Complex functionally specified informational complexity.
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DionisioSeptember 20, 2017 at 5:08 am

gpuccio,

Would it be interesting to analyze the information in the proteins mentioned @116-117: Tpr, Nup153 and Nup98 ?

Thank you.
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gpuccioSeptember 20, 2017 at 8:56 am

Dionisio:

Nucleoporins are a rather heterogeneous group of proteins. Most of them have some important information jump in vertebrates, and another one between amphibia and reptiles. However, they differ a lot in the amount of human-conserved information present in pre-vertebrates, which can range from almost 0 to about 1.8 bits per AA.

That said, the three proteins you mention are rather similar in their behaviour:

TPR (P12270): length: 2563 AAs

human-conserved information in pre-vertebrates: 0.4646636 baa

jump to vertebrates:
0.676259 baa, 1598 bits

NUP 98-96 complex (P52948): length 1817 AAs

human-conserved information in pre-vertebrates: 0.5701706 baa

jump to vertebrates:
0.5365988 baa, 975 bits

NUP 153 (P49790): length 1475 AAs

human-conserved information in pre-vertebrates: 0.1566102 baa

jump to vertebrates:
0.5023729 baa, 741 bits

As you can see, all of them exhibit a vertebrate jump slightly greater than 0.5 baa (about one quarter if the total potential information in the protein), which translates into absolute bit jumps ranging from 741 to 1598, according to the protein length.

While the first two proteins start with some amount of human-conserved information even in pre-vertebrates (about 0.5 baa), the third one differs, because it shows almost no human-conserved information before the vertebrate jump (0.15 baa).

However, the vertebrate jump in these proteins (ranging from 0.50 to 0.67 baa) is about double than the mean vertebrate jump in the human proteome (0.28796 baa)
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DionisioSeptember 20, 2017 at 3:09 pm

The position of GAL1-10 within the nucleus is controlled by small, cis-acting DNA elements called GRS4 and GRS5.

Both of these elements function as DNA zip codes: they are necessary and sufficient to confer targeting to the nuclear periphery.

However, the GRS4 zip code can also promote interchromosomal clustering with loci having the same zip code.

Subnuclear positioning and interchromosomal clustering of the GAL1-10 locus are controlled by separable, interdependent mechanisms
Donna Garvey Brickner, Varun Sood, Evelina Tutucci, Robert Coukos, Kayla Viets, Robert H. Singer, and Jason H. Bruckner
Mol Biol Cell. 27(19): 2980–2993.
doi: 10.1091/mbc.E16-03-0174

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DionisioSeptember 20, 2017 at 8:21 pm

gpuccio,

Thank you for the detailed analysis of the given proteins.
Very interesting indeed.
122

DionisioSeptember 21, 2017 at 1:01 am

Gene positioning has been proposed to facilitate the spatial and functional compartmentalization of the genome.

The subnuclear positioning of the GAL1-10 locus provides an excellent model for this notion.

The positioning of GAL1-10 within the nucleus and its positioning with respect to other genes in the genome are controlled by two interdependent, mechanistically distinct phenomena: targeting to the nuclear pore complex and interchromosomal clustering.

Subnuclear positioning and interchromosomal clustering of the GAL1-10 locus are controlled by separable, interdependent mechanisms
Donna Garvey Brickner, Varun Sood, Evelina Tutucci, Robert Coukos, Kayla Viets, Robert H. Singer, and Jason H. Bruckner
Mol Biol Cell. 27(19): 2980–2993.
doi: 10.1091/mbc.E16-03-0174

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DionisioSeptember 21, 2017 at 1:14 am

The budding yeast Saccharomyces cerevisiae is a long-standing model for the three-dimensional organization of eukaryotic genomes.

However, even in this well-studied model, it is unclear how homolog pairing in diploids or environmental conditions influence overall genome organization.

Surprisingly, we observe a localized increase in homologous interactions between the HAS1-TDA1 alleles specifically under galactose induction and saturated growth.

[…] the diploid yeast genome has a dynamic and complex 3D organization.

The dynamic three-dimensional organization of the diploid yeast genome.
Kim S1, Liachko I1, Brickner DG2, Cook K1, Noble WS1, Brickner JH2, Shendure J1,3, Dunham MJ1.
Elife. 6. pii: e23623.
doi: 10.7554/eLife.23623.

Did somebody say ‘Surprisingly’? 🙂

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DionisioSeptember 21, 2017 at 1:19 am

Many questions remain about how and why DNA is organized the way it is, both in yeast and in other organisms.

These findings will help guide future experiments testing how the two copies of each chromosome pair, as well as what purpose, if any, this pairing might serve for the cell.

A better understanding of the fundamental process of DNA organization and its implications may ultimately lead to improved treatments for genetic diseases including developmental disorders and cancers.

The dynamic three-dimensional organization of the diploid yeast genome.
Kim S1, Liachko I1, Brickner DG2, Cook K1, Noble WS1, Brickner JH2, Shendure J1,3, Dunham MJ1.
Elife. 6. pii: e23623.
doi: 10.7554/eLife.23623.

Work in progress… stay tuned.

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DionisioSeptember 21, 2017 at 1:25 am

The genome is actively organized in the nucleus in both space and time, and this organization impacts fundamental biological processes like transcription, DNA repair, and recombination (Taddei et al., 2010).

[…] the genetic requirements of HAS1-TDA1 relocalization and pairing differ from that of previously known relocalized genes, suggesting a potentially novel mechanism.

Together, our results demonstrate the underappreciated complexity of the 3D organization of the yeast genome.

The dynamic three-dimensional organization of the diploid yeast genome.
Kim S1, Liachko I1, Brickner DG2, Cook K1, Noble WS1, Brickner JH2, Shendure J1,3, Dunham MJ1.
Elife. 6. pii: e23623.
doi: 10.7554/eLife.23623.

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DionisioSeptember 21, 2017 at 1:40 am

In all tested hybrids, the HAS1-TDA1 locus exhibits surprisingly strong homolog proximity […]

[…] more experiments are needed to fully elucidate the role and mechanism of the nuclear pore complex in HAS1-TDA1 homolog pairing.

Other questions remain about the mechanism and functional implications of HAS1-TDA1 pairing and peripheral relocalization.

The principles and functional implications of genome conformation remain open questions.

Our study illustrates both the utility of combining orthogonal methodologies and that we have much more to learn about genome organization, even in the simple budding yeast.

The dynamic three-dimensional organization of the diploid yeast genome.
Kim S1, Liachko I1, Brickner DG2, Cook K1, Noble WS1, Brickner JH2, Shendure J1,3, Dunham MJ1.
Elife. 6. pii: e23623.
doi: 10.7554/eLife.23623.

Did somebody say ‘surprisingly’?

Work in progress… stay tuned.

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DionisioSeptember 21, 2017 at 2:49 am

Chromatin and chromosomes of fungi are highly diverse and dynamic, even within species.

[…] major knowledge gaps remain to be closed.

A Matter of Scale and Dimensions: Chromatin of Chromosome Landmarks in the Fungi.
Erlendson AA1, Friedman S1, Freitag M1.
Microbiol Spectr. ;5(4).
doi: 10.1128/microbiolspec.FUNK-0054-2017.

Work in progress… stay tuned.

But I don’t like knowledge gaps, because every new discovery points to designed biological systems.

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DionisioSeptember 21, 2017 at 3:05 am

Super-resolution fluorescence microscopy plays a major role in revealing the organization and dynamics of living cells.

Combining Primed Photoconversion and UV-Photoactivation for Aberration-Free, Live-Cell Compliant Multi-Color Single-Molecule Localization Microscopy Imaging.
Virant D1, Turkowyd B2, Balinovic A3, Endesfelder U4
Int J Mol Sci. 18(7). pii: E1524.
doi: 10.3390/ijms18071524.
129

DionisioSeptember 21, 2017 at 3:40 am

The yeast GAL genes localize to the nuclear periphery and physically interact with the NPC during both activation and memory […]

Targeting to the nuclear periphery is downstream of Gal1 protein; loss of Gal1 disrupts peripheral retention during memory and ectopic expression of Gal1 leads to MRSGAL1 zip code dependent targeting of GAL1 to the nuclear periphery even under repressing conditions.

However, the association of GAL genes with the NPC is not necessary for faster reactivation, suggesting that it is a product, rather than a driver, of memory.

[…] we do not yet understand how growth in glucose impinges upon GAL memory […]

Epigenetic Transcriptional Memory of GAL Genes Depends on Growth in Glucose and the Tup1 Transcription Factor in Saccharomyces cerevisiae.
Sood V1, Cajigas I1, D’Urso A1, Light WH1, Brickner JH2.
Genetics. 2017 Aug;206(4):1895-1907.
doi: 10.1534/genetics.117.201632.

Did somebody say ‘zip code’? 🙂

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DionisioSeptember 24, 2017 at 5:16 am

Functions for MeCP2 other than transcriptional are not well understood.

Alternative splicing of pre-mRNAs of active genes is ubiquitous in the eukaryotic genome.

It is estimated that as many as 90% of genes are affected by alternative splicing and its importance in brain has recently received a great deal of attention […]

MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle.
Zheng Z1, Ambigapathy G1, Keifer J1.
Elife. 6. pii: e25384.
doi: 10.7554/eLife.25384.

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DionisioSeptember 24, 2017 at 5:19 am

These findings suggest a new perspective for understanding mechanisms underlying RTT; that MeCP2 loss of function generates unexpected secondary deficits in patterns of gene methylation that results both in aberrant binding by DNA regulatory proteins and in alternative splicing.

Further, and importantly, we show that the deficits are exposed in a physiological learning-dependent context, conditioning, and not under steady state conditions.

MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle.
Zheng Z1, Ambigapathy G1, Keifer J1.
Elife. 6. pii: e25384.
doi: 10.7554/eLife.25384.

Did somebody say ‘unexpected’?

Did they expect something else or nothing at all?

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DionisioSeptember 24, 2017 at 5:26 am

While loop or kink formation may be possible (Pasi and Lavery, 2016), whether these functionally insulate DNA is unknown.

[…] depletion of MeCP2 protein may alter DNA methylation status indirectly by preventing binding of other DNA modifying proteins, including Tet.

How loss of MeCP2 binding results in a reduction in Tet1 binding to the tBDNF gene is unclear.

[…] MeCP2 and Tet1 are binding partners (Cartron et al., 2013; Ambigapathy et al., 2015) but the functional impact of this relationship has been largely unstudied.

MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle.
Zheng Z1, Ambigapathy G1, Keifer J1.
Elife. 6. pii: e25384.
doi: 10.7554/eLife.25384.

Why largely unstudied? Lack of recourses? lack of time?

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DionisioSeptember 24, 2017 at 5:29 am

Further work on the activity-dependent regulation of MeCP2, Tet1 and DNA methylation will be required to resolve their interactions and functional consequences on gene expression.

MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle.
Zheng Z1, Ambigapathy G1, Keifer J1.
Elife. 6. pii: e25384.
doi: 10.7554/eLife.25384.

Work in progress… stay tuned.

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DionisioSeptember 24, 2017 at 5:37 am

There is increasing evidence for inter-individual methylation differences at CpG dinucleotides in the human genome, but the regional extent and function of these differences have not yet been studied in detail.

Allele-specific DNA methylation occurs in discrete chromosomal regions and is driven by genetic variation in cis and trans, but in general has little effect on gene expression.

Regions of common inter-individual DNA methylation differences in human monocytes: genetic basis and potential function.
Schröder C1, Leitão E2, Wallner S3, Schmitz G3, Klein-Hitpass L4, Sinha A5, Jöckel KH6, Heilmann-Heimbach S7,8, Hoffmann P7,8,9,10, Nöthen MM7,8, Steffens M11, Ebert P12,13, Rahmann S1, Horsthemke B14.
Epigenetics Chromatin. 2017 Jul 26;10(1):37.
doi: 10.1186/s13072-017-0144-2.

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DionisioSeptember 24, 2017 at 5:41 am

allelic DNA methylation differences can be caused by genetic variation in cis.

Interestingly, DNA methylation at some loci may also be affected by genetic variation in trans, namely at KRAB zinc finger genes.

In general, hap-ASM, especially hap-ASM in repressive chromatin domains, appears to have little functional consequences.

Regions of common inter-individual DNA methylation differences in human monocytes: genetic basis and potential function.
Schröder C1, Leitão E2, Wallner S3, Schmitz G3, Klein-Hitpass L4, Sinha A5, Jöckel KH6, Heilmann-Heimbach S7,8, Hoffmann P7,8,9,10, Nöthen MM7,8, Steffens M11, Ebert P12,13, Rahmann S1, Horsthemke B14.
Epigenetics Chromatin. 2017 Jul 26;10(1):37.
doi: 10.1186/s13072-017-0144-2.

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DionisioSeptember 24, 2017 at 5:54 am

Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited.

Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes.

Our study provides a comprehensive picture of the islet DNA methylome in individuals with and without diabetes and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.

Whole-Genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis.
Volkov P1, Bacos K1, Ofori JK2, Esguerra JL2, Eliasson L2, Rönn T1, Ling C3.
Diabetes. 2017 Apr;66(4):1074-1085.
doi: 10.2337/db16-0996.

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DionisioSeptember 24, 2017 at 5:59 am

Dynamic DNA modifications, such as methylation/demethylation on cytosine, are major epigenetic mechanisms to modulate gene expression in both eukaryotes and prokaryotes.

In addition to the common methylation on the 5th position of the pyrimidine ring of cytosine (5mC), other types of modifications at the same position, such as 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC), are also important.

Recently, 5hmC, a product of 5mC demethylation by the Ten-Eleven Translocation family proteins, was shown to regulate many cellular and developmental processes, including the pluripotency of embryonic stem cells, neuron development, and tumorigenesis in mammals.

New Insights into 5hmC DNA Modification: Generation, Distribution and Function.
Shi DQ1, Ali I1, Tang J1, Yang WC1.
Front Genet. ;8:100.
doi: 10.3389/fgene.2017.00100.

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DionisioSeptember 24, 2017 at 6:07 am

From two decades of studies, it is clear that the primary sequence information of DNA can be enhanced by epigenetic modifications.

There can be various epigenomes in different cell types, although there is only one genome of an organism.

[…] the epigenetic information of the epigenome is maintained and translated by the dynamic activity of DNA methylases (writers) and demethylases (erasers) and reader proteins who recognize and interpret the information in both mammals and plants […]

New Insights into 5hmC DNA Modification: Generation, Distribution and Function.
Shi DQ1, Ali I1, Tang J1, Yang WC1.
Front Genet. ;8:100.
doi: 10.3389/fgene.2017.00100.

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DionisioSeptember 24, 2017 at 6:10 am

[…] many questions remain to be answered.

How DNA is actively demethylated?

Where does 5hmC exist, and what roles does 5hmC have during development?

New Insights into 5hmC DNA Modification: Generation, Distribution and Function.
Shi DQ1, Ali I1, Tang J1, Yang WC1.
Front Genet. ;8:100.
doi: 10.3389/fgene.2017.00100.

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DionisioSeptember 24, 2017 at 6:17 am

It is suggested that 5hmC most likely plays a role in gene expression, pluripotency of stem cells, stress response, disease and aging.

However, functional studies on 5hmC are still ahead.

There are still some fundamental questions to be addressed: […]

New Insights into 5hmC DNA Modification: Generation, Distribution and Function.
Shi DQ1, Ali I1, Tang J1, Yang WC1.
Front Genet. ;8:100.
doi: 10.3389/fgene.2017.00100.

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DionisioSeptember 24, 2017 at 11:09 pm

Cytosine modifications diversify and structure the genome thereby controlling proper development and differentiation.

The dynamics of cytosine modification create a more diverse genome and regulate cellular differentiation by controlling gene expression.

For proper development, the maintenance and removal of cytosine modifications have to be thoroughly regulated.

It would be very interesting to assess whether these processes are Mbd1 isoform dependent and whether Mbd1 regulates these processes by affecting Tet1-mediated 5mC oxidation.

Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner.
Zhang P1, Rausch C1, Hastert FD1, Boneva B1, Filatova A2, Patil SJ1, Nuber UA2, Gao Y3, Zhao X3, Cardoso MC1.
Nucleic Acids Res. 2017 Jul 7;45(12):7118-7136.
doi: 10.1093/nar/gkx281

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DionisioSeptember 25, 2017 at 5:40 am

Although valproic acid (VPA), has been shown to induce neuronal differentiation of neural stem cells (NSCs), the underlying mechanisms remain poorly understood.

Neural stem cells (NSCs) can differentiate into functional neurons and glial cells (e.g., astrocytes and oligodendrocytes) in the mammalian CNS […]

However, the underlying molecular mechanisms for their fate specification remain ill defined. Accumulating evidence has confirmed that the differentiation of NSCs is regulated by various intrinsic and extrinsic factors […]

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications
Xi Zhang,1,2,7 Xiaosong He,1,2,7 Qingqing Li,1,2,7 Xuejian Kong,1,2 Zhenri Ou,1,2 Le Zhang,1,2 Zhuo Gong,1,2 Dahong Long,1,2 Jianhua Li,3 Meng Zhang,4 Weidong Ji,5 Wenjuan Zhang,6 Liping Xu,1,2 and Aiguo Xuan
Stem Cell Reports. 8(5): 1256–1269.
doi: 10.1016/j.stemcr.2017.04.006

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DionisioSeptember 25, 2017 at 5:42 am

The transcriptional regulation of cell-type-specific gene expression involves complicated epigenetic events such as DNA demethylation, histone modifications, and chromatin remodeling.

Some recent studies have shown that VPA reduces HDAC activity and promotes neuronal differentiation of NSCs (Hsieh et al., 2004). However, the underlying mechanisms are not fully understood.

Although both mTOR signaling and epigenetic regulation are essential for the differentiation of NSCs in developing or adult brains, a direct connection between mTOR signaling and epigenetic modifications remains uncharacterized in NSCs.

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications
Xi Zhang,1,2,7 Xiaosong He,1,2,7 Qingqing Li,1,2,7 Xuejian Kong,1,2 Zhenri Ou,1,2 Le Zhang,1,2 Zhuo Gong,1,2 Dahong Long,1,2 Jianhua Li,3 Meng Zhang,4 Weidong Ji,5 Wenjuan Zhang,6 Liping Xu,1,2 and Aiguo Xuan
Stem Cell Reports. 8(5): 1256–1269.
doi: 10.1016/j.stemcr.2017.04.006

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DionisioSeptember 25, 2017 at 6:06 am

[…] the mechanism by which VPA activates the PI3K/AKT pathway is currently unknown […]

The post translational modifications of the amino-terminal tails of the H3 and H4 histones also involve in general changes in condensation of chromatin connected with various tissue-specific genes, which maintain them in either an activated or repressed state.

Histone acetylation and DNA methylation operate in a concerted manner.

[…] mTOR signaling may critically link cell-signaling mechanisms with DNA methylation.

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications
Xi Zhang,1,2,7 Xiaosong He,1,2,7 Qingqing Li,1,2,7 Xuejian Kong,1,2 Zhenri Ou,1,2 Le Zhang,1,2 Zhuo Gong,1,2 Dahong Long,1,2 Jianhua Li,3 Meng Zhang,4 Weidong Ji,5 Wenjuan Zhang,6 Liping Xu,1,2 and Aiguo Xuan
Stem Cell Reports. 8(5): 1256–1269.
doi: 10.1016/j.stemcr.2017.04.006

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DionisioSeptember 25, 2017 at 6:16 am

Epigenetic control of long-distance gene expression by histone modifications is a pivotal mechanism determining cell-fate and cell-phenotype maintenance […]

Compared with the generally permissive histone acetylation, histone methylations are more diverse in function and their regulation is complex and dynamic.

Enzymes responsible for these modifications are histone methyltransferases and demethylases.

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications
Xi Zhang,1,2,7 Xiaosong He,1,2,7 Qingqing Li,1,2,7 Xuejian Kong,1,2 Zhenri Ou,1,2 Le Zhang,1,2 Zhuo Gong,1,2 Dahong Long,1,2 Jianhua Li,3 Meng Zhang,4 Weidong Ji,5 Wenjuan Zhang,6 Liping Xu,1,2 and Aiguo Xuan
Stem Cell Reports. 8(5): 1256–1269.
doi: 10.1016/j.stemcr.2017.04.006

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DionisioSeptember 26, 2017 at 12:40 pm

[…] there are relatively few papers on cellular electromagnetics as compared with those on proteins, biochemistry, and cellular anatomy.

[…] cellular electromagnetic fields appear to arise from longitudinal vibrations of the filaments making up the walls of the microtubules.

Microtubules are long hollow cylinders which form the overall structure of the centrioles.

The microtubules, and therefore the centrioles themselves, are arranged in nine sets of parallel blades with each blade having three microtubules.

The centrioles occur in pairs perpendicularly to each other.

During mitosis (cell division) the centriole pair becomes two pair which then separate and divide the cell into two.

It seems that electromagnetic forces play a central role in this division.

A Review of Electromagnetic Activity in Cellular Mechanics
ABB> Vol.7 No.9
DOI: 10.4236/abb.2016.79035
Ronald L. Huston

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DionisioSeptember 26, 2017 at 12:53 pm

[…] electromagnetic effects are not only important but also essential in cellular mechanics.

Unfortunately, however, the electromagnetic effects are often omitted, or not discussed in depth, in biology papers and books.

A Review of Electromagnetic Activity in Cellular Mechanics
ABB> Vol.7 No.9
DOI: 10.4236/abb.2016.79035
Ronald L. Huston

Why are they often omitted or not discussed in depth?

Can somebody provide a valid reason?

Is it lack of resources?
148

DionisioSeptember 26, 2017 at 1:41 pm

http://file.scirp.org/Html/3-7301233_70534.htm

A Review of Electromagnetic Activity in Cellular Mechanics
ABB> Vol.7 No.9
DOI: 10.4236/abb.2016.79035
Ronald L. Huston

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DionisioSeptember 26, 2017 at 3:21 pm

[…] vibrations of filaments of the microtubules (MT filaments) establish oscillating magnetic and electric fields.

[…] the microtubules form the structure of the centrioles: specifically, each centriole consists of nine “blades” of microtubule triplets (thus a total of 27 microtubules per centriole).

The microtubules themselves are hollow cylinders whose walls are composed of 13 longitudinal filaments.

The filaments are strings of ?/? tubulin dimers connected end-to-end.

A Review of Electromagnetic Activity in Cellular Mechanics
ABB> Vol.7 No.9
DOI: 10.4236/abb.2016.79035
Ronald L. Huston

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DionisioSeptember 26, 2017 at 5:38 pm

[…] the details of centriole duplication and development are still under investigation […]

Surrounding the centrioles is a pool of as many as 100 proteins, an abundance of which are the ?/?, and ? tubulins.

This protein pool is known as the “centrosome” and also as the “microtubule organizing center” or MTOC.

The MTOC is believed to be “electron dense” and thus the base of the centrioles is negatively charged and the distal ends are then positive.

A Review of Electromagnetic Activity in Cellular Mechanics
ABB> Vol.7 No.9
DOI: 10.4236/abb.2016.79035
Ronald L. Huston

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DionisioSeptember 26, 2017 at 5:59 pm

The most impressive evidence of cellular electromagnetic activity occurs during mitosis […]

[…] improvements in microscopy and measurement techniques are likely to produce new findings in both the geometrical and physical characteristics of centrioles and their microtubules.

Much remains to be done before these concepts can be developed and tested.

A Review of Electromagnetic Activity in Cellular Mechanics
ABB> Vol.7 No.9
DOI: 10.4236/abb.2016.79035
Ronald L. Huston

Work in progress… stay tuned.

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DionisioSeptember 26, 2017 at 6:50 pm

Microtubules are the principal structures making up the centrioles.

The centrioles in turn are the principal agents in cell duplication and division (mitosis).

Each normal eukaryotic (human and animal) cell, not in mitosis, has two perpendicular centrioles connected at their proximal (base) ends.

During mitosis, these two become four, resulting in a total of 108 centriolar microtubules.

The structure of the microtubules themselves is found to consist of 13 parallel filaments making up the cylinder walls.

The longitudinal vibrations of the filaments are believed to create an electro-magnetic field within the cell which plays an important role in mitosis.

Mechanics of Centriole Microtubules
Ronald L. Huston
Advances in Bioscience and Biotechnology
Vol.07 No.06(2016), Article ID:67762,12 pages
10.4236/abb.2016.76025

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DionisioSeptember 26, 2017 at 7:04 pm

For many years the purpose of centrioles and their function were unknown.

Also, others regarded centrioles as being relatively unimportant since they do not occur in plant cells or in bacteria.

Near the beginning of the 21st century, however, it became generally accepted that centrioles were the principal organelles driving cell division and duplication (mitosis) in eukaryotic cells (human and animal cells) despite being absent in prokaryotic cells (bacteria) and in plants

A Review of Centriole Activity, and Wrongful Activity, during Cell Division
Ronald L. Huston
Advances in Bioscience and Biotechnology
Vol.07 No.03(2016), Article ID:65163,14 pages
10.4236/abb.2016.73015

If we don’t know their function, then they must not be important.

If they don’t appear in all biological systems, then they must not be important.

Haven’t we read that kind of nonsense before?

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DionisioSeptember 26, 2017 at 7:08 pm

As the centriole duplication is happening, the DNA of the nucleus is also being duplicated and separated.

That is, the current research shows that centriole duplication and DNA separation are, in some way, entangled.

A Review of Centriole Activity, and Wrongful Activity, during Cell Division
Ronald L. Huston
Advances in Bioscience and Biotechnology
Vol.07 No.03(2016), Article ID:65163,14 pages
10.4236/abb.2016.73015

Did somebody say ‘entangled’?

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DionisioSeptember 26, 2017 at 7:13 pm

The centriole pairs at either end of the mitotic spindle appear to be driving influences during this entire cell division process.

Moreover these influences appear to be occurring due to forces exerted at a distance via the centrioles electromagnetic fields […]

A Review of Centriole Activity, and Wrongful Activity, during Cell Division
Ronald L. Huston
Advances in Bioscience and Biotechnology
Vol.07 No.03(2016), Article ID:65163,14 pages
10.4236/abb.2016.73015

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DionisioSeptember 26, 2017 at 7:25 pm

From the beginning of the 21st century, centriolar studies have and are becoming increasingly important in the minds of cell biologists, physicists, chemists and medical researchers.

This is remarkable in that only a couple of decades ago centrioles were largely regarded as relatively unimportant, or even perhaps unessential for cell division.

A Review of Centriole Activity, and Wrongful Activity, during Cell Division
Ronald L. Huston
Advances in Bioscience and Biotechnology
Vol.07 No.03(2016), Article ID:65163,14 pages
10.4236/abb.2016.73015

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DionisioSeptember 27, 2017 at 6:57 am

The centriole is one of the most recognizable structures in all of biology.

There are many intriguing questions about centrioles and basal bodies, including what proteins are found in the structures, how such complex structures are built and how cells use centrioles and basal bodies to organize even larger structures, namely the centrosome and the cilium.

Centriole structure
Mark Winey and Eileen O’Toole
Philos Trans R Soc Lond B Biol Sci.
369(1650): 20130457.
doi: 10.1098/rstb.2013.0457

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DionisioSeptember 27, 2017 at 7:02 am

[…] observing the centriole or basal body structural complexity does remind one of the work left to accomplish.

In the future, we must continue to define the proteins present at centrioles and basal bodies and apply ever improving labelling and imaging technologies to these structures.

Beyond completing the list of conserved components, the function or structural contributions of these proteins will need to be determined, some of which will be challenging such as the role of the minor tubulin isoforms.

This will be needed to fully understand how centrioles are assembled, maintained and serve to organize the PCM or cilia.

Centriole structure
Mark Winey and Eileen O’Toole
Philos Trans R Soc Lond B Biol Sci.
369(1650): 20130457.
doi: 10.1098/rstb.2013.0457

This is a 4-year old paper. Let’s see how much more information on this subject has been gathered since then.

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DionisioSeptember 27, 2017 at 7:08 am

The primary cilium is nucleated by the mother centriole-derived basal body (BB) via as yet poorly characterized mechanisms.

Our work provides a framework for future investigations into the mechanisms underlying BB remodeling.

Centriolar remodeling underlies basal body maturation during ciliogenesis in Caenorhabditis elegans
Inna V Nechipurenko,1,*† Cristina Berciu,2,†‡ Piali Sengupta,1,* and Daniela Nicastro2,3
eLife. 2017; 6: e25686.
doi: 10.7554/eLife.25686

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DionisioSeptember 27, 2017 at 7:10 am

Cilia are evolutionarily conserved microtubule (MT)-based organelles that play key roles in regulating embryonic development, sensory signaling, and motility among other cellular functions […]

It remains unclear whether centrioles of distinct ultrastructural organization transition to BBs and nucleate cilia via similar or distinct mechanisms.

Centriolar remodeling underlies basal body maturation during ciliogenesis in Caenorhabditis elegans
Inna V Nechipurenko,1,*† Cristina Berciu,2,†‡ Piali Sengupta,1,* and Daniela Nicastro2,3
eLife. 2017; 6: e25686.
doi: 10.7554/eLife.25686

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DionisioSeptember 27, 2017 at 7:16 am

The mechanisms that mediate centriole wall remodeling are unknown.

In the future, it will be important to correlate the presence (or absence) of distinct subciliary structures with that of their known molecular components in individual cell types across developmental stages in order to obtain a more complete description of early ciliogenic steps.

We expect that the ability to visualize centrioles/BBs and cilia in single cells in vivo together with the genetic power of C. elegans will allow further characterization of the conserved and species-specific mechanisms that underlie biogenesis and maintenance of these important cellular organelles.

Centriolar remodeling underlies basal body maturation during ciliogenesis in Caenorhabditis elegans
Inna V Nechipurenko,1,*† Cristina Berciu,2,†‡ Piali Sengupta,1,* and Daniela Nicastro2,3
eLife. 2017; 6: e25686.
doi: 10.7554/eLife.25686

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DionisioSeptember 27, 2017 at 10:33 am

Neuronal cilia that are formed at the dendritic endings of sensory neurons are essential for sensory perception.

However, it remains unclear how the centriole?derived basal body is positioned to form a template for cilium formation.

[…] the centriole translocates from the cell body to the dendrite tip in the Caenorhabditis elegans sensory neurons.

The centriolar protein SAS?5 interacts with the dynein light?chain LC8 and conditional mutations of cytoplasmic dynein?1 block centriole translocation and ciliogenesis.

The components of the central tube are essential for the biogenesis of centrioles, which later drive ciliogenesis in the dendrite; however, the centriole loses these components at the late stage of centriole translocation and subsequently recruits transition zone and intraflagellar transport proteins.

Centriole translocation and degeneration during ciliogenesis in Caenorhabditis elegans neurons
Wenjing Li, Peishan Yi, Zhiwen Zhu, Xianliang Zhang, Wei Li, Guangshuo Ou
DOI 10.15252/embj.201796883
The EMBO Journal (2017) 36, 2553-2566

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DionisioSeptember 27, 2017 at 11:10 am

The primary cilium is a nonmotile organelle that emanates from the surface of multiple cell types and receives signals from the environment to regulate intracellular signaling pathways.

The primary cilium (PC) is a microtubule-based antenna-like structure that emanates from the surface of different cell types [1]. Primary cilia receive signals from the environment and control different intracellular signaling pathways […]

New Roles of the Primary Cilium in Autophagy.
Ávalos Y1, Peña-Oyarzun D2,3, Budini M4, Morselli E1, Criollo A2,4.
Biomed Res Int. 2017;2017:4367019.
doi: 10.1155/2017/4367019.

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DionisioSeptember 27, 2017 at 11:17 am

[…] the effect of lack of autophagy in hypothalamic neurons/hypothalamic tissue on ciliogenesis and in the regulation of appetite and energy homeostasis is still unknown.

[…] it is currently unknown if the mechanism that leads to hyperleptinemia in these mice is the same as in cilia depleted mice.

[…] future studies need to be performed in different cell types/tissues to determine if the mechanisms are general or cell type/tissue specific.

[…] future research needs to focus on better understanding the interplay that exists between autophagy and ciliogenesis to identify therapeutic targets that, through the modulation of autophagy, might represent effective treatments for different ciliopathies.

New Roles of the Primary Cilium in Autophagy.
Ávalos Y1, Peña-Oyarzun D2,3, Budini M4, Morselli E1, Criollo A2,4.
Biomed Res Int. 2017;2017:4367019.
doi: 10.1155/2017/4367019.

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DionisioSeptember 27, 2017 at 11:38 am

Recent ultrastructural characterization of basal body architecture and remodeling have laid the foundation for future studies into mechanisms underlying different aspects of basal body genesis, remodeling, and intracellular positioning.

We expect that ongoing and future investigations into the biology of the nematode basal body will continue to provide new insights into the structure and function of this important organelle.

The rise and fall of basal bodies in the nematode Caenorhabditis elegans.
Nechipurenko IV1, Sengupta P1
Cilia. 2017 Jul 26;6:9.
doi: 10.1186/s13630-017-0053-9.

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DionisioSeptember 27, 2017 at 12:03 pm

The position of the mitotic spindle is tightly controlled in animal cells as it determines the plane and orientation of cell division.

Contacts between cytoplasmic dynein and astral microtubules (MTs) at the cell cortex generate pulling forces that position the spindle.

An evolutionarily conserved G?-GPR-1/2Pins/LGN-LIN-5Mud/NuMA cortical complex interacts with dynein and is required for pulling force generation, but the dynamics of this process remain unclear.

[..] dynein exists in two distinct cortical populations. One population directly depends on LIN-5, whereas the other is concentrated at MT plus ends and depends on end-binding (EB) proteins.

[…] EB protein-dependent dynein plus end tracking was found to contribute to force generation in embryos with a partially perturbed dynein function, indicating the existence of two mechanisms that together create a highly robust force-generating system.

Two populations of cytoplasmic dynein contribute to spindle positioning in C. elegans embryos.
Schmidt R1,2, Fielmich LE1, Grigoriev I2, Katrukha EA2, Akhmanova A3, van den Heuvel S
J Cell Biol. 216(9):2777-2793.
doi: 10.1083/jcb.201607038.

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DionisioSeptember 27, 2017 at 12:49 pm

The anaphase spindle determines the position of the cytokinesis furrow, such that the contractile ring assembles in an equatorial zone between the two spindle poles.

Contractile ring formation is mediated by RhoA activation at the equator by the centralspindlin complex and midzone microtubules.

Astral microtubules also inhibit RhoA accumulation at the poles.

In the Caenorhabditis elegans one-cell embryo, the astral microtubule-dependent pathway requires anillin, NOP-1, and LET-99.

LET-99 is well characterized for generating the asymmetric cortical localization of the G?-dependent force-generating complex that positions the spindle during asymmetric division.

However, whether the role of LET-99 in cytokinesis is specific to asymmetric division and whether it acts through G? to promote furrowing are unclear.

[…] LET-99 contributes to furrowing in both asymmetrically and symmetrically dividing cells, independent of its function in spindle positioning and G? regulation.

LET-99 acts in a pathway parallel to anillin and is required for myosin enrichment into the contractile ring.

These and other results suggest a positive feedback model in which LET-99 localizes to the presumptive cleavage furrow in response to the spindle and myosin.

Once positioned there, LET-99 enhances myosin accumulation to promote furrowing in both symmetrically and asymmetrically dividing cells.

LET-99 functions in the astral furrowing pathway, where it is required for myosin enrichment in the contractile ring.
Price KL1, Rose LS2.
Mol Biol Cell. 28(18):2360-2373.
doi: 10.1091/mbc.E16-12-0874.

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DionisioSeptember 27, 2017 at 1:46 pm

The separation of sister chromatids during anaphase is the culmination of mitosis and one of the most strikingly beautiful examples of cellular movement.

It consists of two distinct processes:

Anaphase A, the movement of chromosomes toward spindle poles via shortening of the connecting fibers, and

anaphase B, separation of the two poles from one another via spindle elongation.

[…] poleward chromosome movement is associated with disassembly of the kinetochore-attached microtubule fibers that link chromosomes to poles.

[…] kinetochore-fiber disassembly often occurs through loss of tubulin subunits from the kinetochore-attached plus ends.

[…] kinetochore-fiber disassembly in many cells occurs partly through ‘flux’, where the microtubules flow continuously toward the poles and tubulin subunits are lost from minus ends.

Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles.
Asbury CL1.
Biology (Basel). 2017 Feb 17;6(1). pii: E15.
doi: 10.3390/biology6010015

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DionisioSeptember 27, 2017 at 3:19 pm

For a true, mechanistic understanding of anaphase, it is not enough simply to describe the motions of the kinetochores, the microtubules, and the poles relative to one another.

We need to understand where and how the motive forces are generated.

[…] the force-producing machinery at a kinetochore can adopt two distinct states, an active state in which it generates pole-directed pulling force, and a ‘neutral’ state in which it remains stationary or passively slips anti-poleward in response to external forces.

Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles.
Asbury CL1.
Biology (Basel). 2017 Feb 17;6(1). pii: E15.
doi: 10.3390/biology6010015

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DionisioSeptember 27, 2017 at 3:24 pm

The poleward movement of chromosomes coupled to shortening of microtubule plus ends is one of the most conserved features of mitosis.

It is also one of the most puzzling.

How is it possible for a kinetochore (or a spindle pole) to maintain a persistent and load-bearing grip on the end of a microtubule that is rapidly disassembling?

Any proposed mechanism for anaphase A must explain this ‘tip-coupling’.

Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles.
Asbury CL1.
Biology (Basel). 2017 Feb 17;6(1). pii: E15.
doi: 10.3390/biology6010015

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DionisioSeptember 27, 2017 at 3:56 pm

These observations do not necessarily preclude a role for motors in tip-coupling, but they do argue against simple models in which tip-coupling is based primarily on a single type of conventional motor.

[…] the emerging view is that the kinetochore-microtubule interface includes an array of non-motor, microtubule binding proteins in addition to the conventional motors […]

This scaling suggests modularity.

The kinetochores of humans and other ‘higher’ eukaryotes might consist of large, parallel arrays of discrete microtubule-binding sites, each resembling a single budding yeast kinetochore

Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles.
Asbury CL1.
Biology (Basel). 2017 Feb 17;6(1). pii: E15.
doi: 10.3390/biology6010015

No room for reductionist solutions?

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DionisioSeptember 27, 2017 at 4:01 pm

The biochemical complexity of the kinetochore poses a major challenge for understanding how it functions.

There are a variety of different microtubule-binding proteins likely to contribute, including the motor and non-motor proteins discussed above, and additional components as well.

Unfortunately, our current understanding is too rudimentary to identify distinct roles for all of them.

An intriguing possibility is that the various microtubule-binders at kinetochores might interact with different structural features at the microtubule tip.

More work is needed to test this idea.

Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles.
Asbury CL1.
Biology (Basel). 2017 Feb 17;6(1). pii: E15.
doi: 10.3390/biology6010015

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DionisioSeptember 27, 2017 at 4:28 pm

Whether a similar mechanism could drive the steady flux of kinetochore-attached microtubules during anaphase is uncertain.

Questions also remain about how depolymerase activity is engaged when the motors and minus ends reach the pole.

Anaphase is the dramatic finale of mitosis when, after careful preparations are finished, the actual business of segregating duplicated chromosomes takes place in a beautifully orchestrated manner.

Anaphase A: Disassembling Microtubules Move Chromosomes toward Spindle Poles.
Asbury CL1.
Biology (Basel). 2017 Feb 17;6(1). pii: E15.
doi: 10.3390/biology6010015

Did somebody say ‘orchestrated’?

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DionisioSeptember 27, 2017 at 4:51 pm

One of the main goals of cell biology is to understand how a cell works as a machine: where and how key proteins interact and achieve a desired function.

As experimental biology becomes more quantitative and complex, the number of cases in which modeling accompanies experimental studies grows.

There are, however, many difficulties with using mathematics in biology.

One of them is that modeling approaches have diversified so much recently that it is not easy to grasp how models work.

Until recently, a majority of models in biology used differential equations (DEs).

Recently DE models started to lose out to so-called agent-based (AB) models.

The growing popularity of AB models is explained by many factors, one of which is that biological systems are, in fact, often characterized by complex emergent behavior, almost impossible to intuit, and based on simple interactions of a great number of molecular agents.

Agent-based modeling: case study in cleavage furrow models.
Mogilner A1, Manhart A2.
Mol Biol Cell.;27(22):3379-3384.
DOI: 10.1091/mbc.E16-01-0013

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DionisioSeptember 28, 2017 at 11:19 am

The question of how cell division orientation is determined is fundamentally important for understanding tissue and organ shape in both healthy or disease conditions.

[…] the core planar polarity proteins Celsr1 and Frizzled-6 (Fz6) communicate the long axis orientation of interphase basal cells to neighbouring basal mitoses so that they align their horizontal division plane along the same axis.

Horizontal (planar) cell divisions that generate symmetric daughters contribute new cells to epithelia thus driving tissue shape and growth.

How planar cell division orientation is regulated is of significant interest […]

The complex interplay between planar cell division orientation and interphase cell shape however is not well understood.

[…] cell surface asymmetry of planar polarity proteins communicates interphase long axis geometry to a neighbouring dividing cell to directly orient the mitotic spindle.

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin
Fazal Oozeer, Laura L. Yates, Charlotte Dean, and Caroline J. Formstone
Sci Rep. 2017; 7: 1880.
doi: 10.1038/s41598-017-01971-2

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DionisioSeptember 28, 2017 at 11:28 am

The interphase cell long axis is linked to cell division orientation in a number of different cell and tissue contexts.

[…] the axial bias in skin spreading is reinforced during embryonic growth via alignment of planar cell shape and horizontal cell division downstream of the core planar polarity pathway.

[…] in the skin, planar cell shape is disconnected from skin planar cell division in the same cell.

This mechanism may derive from the greater complexity of skin core protein distribution […]

[…] core proteins also impact on axial bias in interphase long axis geometry […]

Their precise roles in this important process are however currently unclear.

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin
Fazal Oozeer, Laura L. Yates, Charlotte Dean, and Caroline J. Formstone
Sci Rep. 2017; 7: 1880.
doi: 10.1038/s41598-017-01971-2

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DionisioSeptember 28, 2017 at 11:40 am

It is highly relevant here that Prickle protein isoforms drive variation in core protein signalling in the latter to concomitantly align wing hairs and wing cuticle ridges along perpendicular wing axes.

[…] variant Celsr1 proteins co-exist across the mammalian skin epithelium, raising the intriguing question of whether they could elicit unique responses to the same or possibly different skin planar polarity signals.

The intracellular accumulation of core proteins during mitosis is, as far as we are aware, unique to the mammalian skin.

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin
Fazal Oozeer, Laura L. Yates, Charlotte Dean, and Caroline J. Formstone
Sci Rep. 2017; 7: 1880.
doi: 10.1038/s41598-017-01971-2

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DionisioSeptember 28, 2017 at 11:41 am

It is clear therefore that much is still to be uncovered with respect to core protein function in skin planar polarity.

Moreover the exact nature of the putative Celsr1 protein variants and their potential impact on the epithelia of other mammalian tissues and organs including the nervous system and lung remains an additional but exciting challenge for the future.

A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin
Fazal Oozeer, Laura L. Yates, Charlotte Dean, and Caroline J. Formstone
Sci Rep. 2017; 7: 1880.
doi: 10.1038/s41598-017-01971-2

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DionisioSeptember 29, 2017 at 1:41 pm

Proper assembly and orientation of the bipolar mitotic spindle is critical to the fidelity of cell division.

Mitotic precision fundamentally contributes to cell fate specification, tissue development and homeostasis, and chromosome distribution within daughter cells.

Defects in these events are thought to contribute to several human diseases.

The underlying mechanisms that function in spindle morphogenesis and positioning remain incompletely defined, however.

Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity.
Dewey EB1, Johnston CA2
Mol Biol Cell. 2017 Sep 15;28(19):2555-2568.
doi: 10.1091/mbc.E17-04-0219.

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DionisioSeptember 29, 2017 at 1:56 pm

The cytoskeleton, consisting of microtubules (MTs), intermediate filaments, and filamentous actin filaments (F-actin), vitally contributes to diverse cellular processes including signal transduction, intracellular transport, chromosome segregation, and cytokinesis […]

[…] the general requirement of Shot in pole focusing as well as the dependence on its intact actin- and MT-binding domains (Figure 4), although the precise mechanism will require further investigation […]

The precise mechanism by which Shot loss induces apoptosis is not yet elucidated […]

[…] further investigations will be necessary to determine the relative contributions of defective spindle assembly and orientation in the apoptotic response seen following Shot loss.

[…] alternative pathways likely play a role in apoptotic induction […]

What the relative contributions of Shot?s mitotic functions are to these defects will be an important future question to resolve.

Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity.
Dewey EB1, Johnston CA2
Mol Biol Cell. 2017 Sep 15;28(19):2555-2568.
doi: 10.1091/mbc.E17-04-0219.

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DionisioSeptember 29, 2017 at 2:03 pm

Mitotic spindles, which consist of microtubules (MTs) and associated proteins, play critical roles in controlling cell division and maintaining tissue homeostasis.

The orientation of the mitotic spindle is closely related with the duration of mitosis.

However, the molecular mechanism in regulating the orientation of the mitotic spindles is largely undefined.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

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DionisioSeptember 29, 2017 at 2:04 pm

[…] Palladin is a novel MT-associated protein and regulator of spindle orientation, which maintains proper spindle orientation by stabilizing astral MTs.

Palladin depletion distorted spindle orientation, prolonged the metaphase, and impaired proliferation of HeLa cells.

[…] Palladin depletion-induced spindle misorientation and astral MT instability could be rescued by constitutively active AKT1 or dominant negative GSK3?.

[…] Palladin regulates spindle orientation and mitotic progression mainly through the AKT1-GSK3? pathway.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

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DionisioSeptember 29, 2017 at 2:13 pm

Spindle orientation determines the axis of cell division.

Thus, precise orientation and architectural integrity of the mitotic spindle is critical for mitosis.

Various force generators and cytoskeleton-related kinases have been found to be involved in the regulation of spindle orientation 2,5–12, but the molecular mechanism is largely unknown.

[…] PALLD is responsible for cell morphology, mobilization, adhesion, invasion and metastasis of cancer cells15–18.

However, the function of PALLD in regulating mitosis remains unknown.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

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DionisioSeptember 29, 2017 at 2:17 pm

[…] PALLD influenced cell proliferation mainly through regulating mitotic progression, especially at the metaphase.

[…] PALLD was a novel MT-associated protein involved in spindle orientation regulation.

[…] PALLD interacted with AKT1 via the third IgC domain to maintain AKT1-GSK3? activation and spindle orientation.

[…] PALLD played important roles in spindle orientation maintenance and mitotic progression.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

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DionisioSeptember 29, 2017 at 2:29 pm

As an actin-binding and microfilament-associated protein, PALLD has been reported to regulate cell morphology, mobilization, adhesion, invasion, and metastasis of cancer cells 27–30.

Surprisingly, our data showed that PALLD also is a novel MT-associated protein and plays an important role in cell proliferation and mitosis.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

Did somebody say ‘surprisingly’?

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DionisioSeptember 29, 2017 at 2:47 pm

[…] the third IgC domain of PALLD was required for its interaction with MTs.

It also mediated its interaction with F-actin 14,32,33.

The interaction between MT and microfilament cytoskeleton exists at the cell cortex and around mitotic spindles 34,35.

However, we do not know whether simultaneous or competitive binding to PALLD exists between MTs, F-actin, and other proteins.

Therefore, we presumed that PALLD plays different roles through interacting the third IgC domain with different partners.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

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DionisioSeptember 29, 2017 at 3:00 pm

[…] AKT1–GSK3? might be the major downstream pathway of PALLD for sustaining proper spindle orientation, but the detailed mechanisms of how PALLD regulated AKT1 activation need to be further investigated in future.

Interestingly, PALLD regulates spindle orientation acting as a novel MT-associated protein and modulator of the AKT1–GSK3? pathway, which was quite different from known regulators.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

Why does it have to be like known regulators? Where is such a rule written in?

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DionisioSeptember 29, 2017 at 3:19 pm

Whether PALLD could directly control MTs anchoring to the cell cortex still needs to be investigated.

We speculated that PALLD is a linker of the AKT1–GSK3? pathway and MTs.

It might be a new class of spindle orientation regulators, which anchor cytoskeleton-related kinase to the cytoskeleton.

Palladin is a novel microtubule-associated protein responsible for spindle orientation.
Zhang X1, Chen X1, Liu J1, Xu X1, Zhang Y1, Ruan Z1, Xie Y1, Huang Q2, Yin T3,4, Chen Z1,5, Chen S6
Sci Rep. 2017 Sep 18;7(1):11806.
doi: 10.1038/s41598-017-12051-w.

A new class of regulators?

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DionisioSeptember 30, 2017 at 10:07 pm

Hair follicles of the mammalian epidermis display local order and global alignment, a complex pattern instructed by the core planar cell polarity (PCP) pathway.

[…] similar to Fz6 mutants, the disordered hair patterns of Vangl2 mutants are refined over time and eventually corrected.

[…] tissue-level reorientation occurs through locally coordinated follicle rotation at stereotyped locations.

Strikingly, Vangl2 and Fz6 mutant follicles collectively rotate with opposing directionalities, suggesting that redundant core PCP signals contribute to their directed realignment.

Consistently, global follicle alignment is not restored upon conditional ablation of both Vangl1 and Vangl2 genes.

Instead, spatially distinct patterns of whorls and crosses emerge and persist even after a complete cycle of hair follicle regeneration.

Thus, local refinement of hair follicles into higher order patterns can occur independently of the core PCP system, however, their global alignment with the body axes requires PCP function throughout morphogenesis, growth and regeneration.

Planar cell polarity-dependent and independent functions in the emergence of tissue-scale hair follicle patterns.
Cetera M1, Leybova L1, Woo FW1, Deans M2, Devenport D
Dev Biol. 428(1):188-203.
doi: 10.1016/j.ydbio.2017.06.003.

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DionisioSeptember 30, 2017 at 10:32 pm

The cell-cell boundaries of epithelial cells form cellular frameworks at the apical side of tissues.

[…] some future perspectives on how recent knowledge about single cell boundary-level mechanics will contribute to our understanding of epithelial tissue morphogenesis are discussed.

Contraction and elongation: Mechanics underlying cell boundary deformations in epithelial tissue.
Hara Y
Dev Growth Differ. 59(5):340-350.
doi: 10.1111/dgd.12356.

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DionisioOctober 1, 2017 at 5:43 pm

In response to a pulling force, a material can elongate, hold fast, or fracture.

During animal development, multi-cellular contraction of one region often stretches neighboring tissue.

Such local contraction occurs by induced actomyosin activity, but molecular mechanisms are unknown for regulating the physical properties of connected tissue for elongation under stress.

[…] cytohesins, and their Arf small G protein guanine nucleotide exchange activity, are required for tissues to elongate under stress during both Drosophila dorsal closure (DC) and zebrafish epiboly.

[…] the cytohesin Steppke reduces tissue tension by inhibiting actomyosin activity at adherens junctions.

[…] actomyosin network assembly is necessary and sufficient for local Steppke accumulation, where live imaging shows Steppke recruitment within minutes.

This rapid negative feedback loop provides a molecular mechanism for attenuating the main tension generator of animal tissues.

Such attenuation relaxes tissues and allows orderly elongation under stress.

An Actomyosin-Arf-GEF Negative Feedback Loop for Tissue Elongation under Stress.
West JJ1, Zulueta-Coarasa T2, Maier JA1, Lee DM1, Bruce AEE1, Fernandez-Gonzalez R3, Harris TJC4
Curr Biol. 27(15):2260-2270.e5.
doi: 10.1016/j.cub.2017.06.038.

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DionisioOctober 1, 2017 at 5:58 pm

The spreading of mesenchymal-like cell layers is critical for embryo morphogenesis and tissue repair, yet we know little of this process in vivo.

[…] the extra-embryonic epithelial enveloping cell layer, thought mainly to provide protection to the embryo, directs cell migration and the spreading of embryonic tissue during early development.

This function relies on the ability of embryonic cells to couple their autonomous random motility to non-autonomous signals arising from the expansion of the extra-embryonic epithelium, mediated by cell membrane adhesion and tension.

Extra-embryonic tissue spreading directs early embryo morphogenesis in killifish.
Reig G1,2, Cerda M1,2, Sepúlveda N3, Flores D1,2, Castañeda V1,2, Tada M4, Härtel S1,2,5, Concha ML1,2,6.
Nat Commun. 2017 Jun 5;8:15431.
doi: 10.1038/ncomms15431.

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DionisioOctober 1, 2017 at 6:17 pm

[…] the coupling of mesenchymal-like tissues to adhesive and tensile properties of adjacent epithelia might represent a fundamental cellular principle of mesenchymal-like tissue spreading in developmental contexts […]

[…] upon this primary principle, more elaborate patterns of tissue spreading can emerge as a consequence of increased cell density, synchronous patterning signals, or concomitant morphogenetic events.

The situation in zebrafish is more complex, as cells of the DCL form several layers and exhibit extensive radial cell intercalation while undergoing concurrent movements of epiboly and axis formation7

[…] radial cell intercalation might emerge as a consequence of the mechanical coupling that the DCL establishes with an expanding EVL during epiboly.

Future works including more direct mechanical perturbations and measurements will have to test this hypothesis directly.

Extra-embryonic tissue spreading directs early embryo morphogenesis in killifish.
Reig G1,2, Cerda M1,2, Sepúlveda N3, Flores D1,2, Castañeda V1,2, Tada M4, Härtel S1,2,5, Concha ML1,2,6.
Nat Commun. 2017 Jun 5;8:15431.
doi: 10.1038/ncomms15431.

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DionisioOctober 1, 2017 at 6:25 pm

Embryo morphogenesis relies on highly coordinated movements of different tissues.

However, remarkably little is known about how tissues coordinate their movements to shape the embryo.

In zebrafish embryogenesis, coordinated tissue movements first become apparent during “doming,” when the blastoderm begins to spread over the yolk sac, a process involving coordinated epithelial surface cell layer expansion and mesenchymal deep cell intercalations.

[…] active surface cell expansion represents the key process coordinating tissue movements during doming.

[…] epithelial surface cells not only trigger blastoderm expansion by reducing tissue surface tension, but also drive blastoderm thinning by inducing tissue contraction through radial deep cell intercalations.

[…] coordinated tissue expansion and thinning during doming relies on surface cells simultaneously controlling tissue surface tension and radial tissue contraction.

The Physical Basis of Coordinated Tissue Spreading in Zebrafish Gastrulation.
Morita H1, Grigolon S2, Bock M3, Krens SF1, Salbreux G4, Heisenberg CP5
Dev Cell. 40(4):354-366.e4.
doi: 10.1016/j.devcel.2017.01.010.

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DionisioOctober 1, 2017 at 6:31 pm

Coordinated motion of cells and tissues is a common feature of tissue and embryo morphogenesis in development […]

[…] the fundamental processes driving cellular rearrangements within a tissue are beginning to be unraveled […]

[…] very little is yet known about how different tissues interact to coordinate their movements at the embryo scale.

The Physical Basis of Coordinated Tissue Spreading in Zebrafish Gastrulation.
Morita H1, Grigolon S2, Bock M3, Krens SF1, Salbreux G4, Heisenberg CP5
Dev Cell. 40(4):354-366.e4.
doi: 10.1016/j.devcel.2017.01.010.

Did somebody say ‘coordinated’?

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DionisioOctober 1, 2017 at 6:37 pm

[…] how these different processes are spatiotemporally coordinated during doming, and how they contribute to the force-generating processes underlying tissue shape changes during doming is only poorly understood.

[…] tissue spreading during doming is driven by two distinct yet interdependent force-generating processes: epithelial surface cells actively expanding by reducing their surface tension, and deep cells undergoing radial cell intercalations and thus generating anisotropic active stress within the bulk of the tissue.

[…] active surface cell expansion not only triggers tissue expansion but also induces active radial deep cell intercalations required for homogeneous tissue thinning during spreading.

The Physical Basis of Coordinated Tissue Spreading in Zebrafish Gastrulation.
Morita H1, Grigolon S2, Bock M3, Krens SF1, Salbreux G4, Heisenberg CP5
Dev Cell. 40(4):354-366.e4.
doi: 10.1016/j.devcel.2017.01.010.

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DionisioOctober 1, 2017 at 6:53 pm

The molecular and cellular mechanisms by which deep cells undergo radial cell intercalations are not yet fully understood […]

Whether such elaborate relationship exists and to what extent it would be needed to explain the effect of surface cell expansion on radial deep cell intercalations remains to be investigated.

The coordinated spreading of multiple tissues constitutes a universal mechanism by which embryos take shape during gastrulation […]

[…] elucidating the force-generating processes by which tissues undergo coordinated spreading is central for understanding the physical basis of embryo morphogenesis.

[…] for spreading of complex multilayered tissues consisting of both epithelial surface cells and mesenchymal deep cells, surface cells play a key role.

[…] by simultaneously reducing tissue surface tension and increasing radial tissue contraction, active surface cell expansion allows complex tissues to undergo coordinated tissue expansion and thinning.

The Physical Basis of Coordinated Tissue Spreading in Zebrafish Gastrulation.
Morita H1, Grigolon S2, Bock M3, Krens SF1, Salbreux G4, Heisenberg CP5
Dev Cell. 40(4):354-366.e4.
doi: 10.1016/j.devcel.2017.01.010.

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DionisioOctober 1, 2017 at 7:20 pm

During embryonic gastrulation, coordinated cell movements occur to bring cells to their correct position.

Among them, epiboly produces the first distinct morphological changes, which is essential for the early development of zebrafish.

Despite its fundamental importance, little is known to understand the underlying molecular mechanisms.

[…] Atrn prefers to interact with the active form of Alkbh4 and functions together with it to regulate the demethylation of Actin, the actomyosin formation, and subsequently the embryonic epiboly.

Alkbh4 and Atrn Act Maternally to Regulate Zebrafish Epiboly
Qingrui Sun,* Xingfeng Liu,* Bo Gong, Di Wu, Anming Meng, and Shunji Jia
Int J Biol Sci. 13(8): 1051–1066.
doi: 10.7150/ijbs.19203

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DionisioOctober 1, 2017 at 8:22 pm

[…] the underlying molecular mechanism of actomyosin formation during epiboly remains to be elucidated.

[…] it is unknown what role of Alkbh4 plays in zebrafish embryonic development.

[…] nothing is known of Atrn functions during zebrafish embryonic development, especially in the epiboly process.

[…] zebrafish maternal genes alkbh4 and atrn are both critical for the embryo epibolic morphogenesis.

They are both required for the formation of actomyosin in the E-YSL, […]

[…] Atrn interacts with Alkbh4 and promotes the binding affinity between Actin and NMII, subsequently regulates the formation of actomyosin band in the E-YSL during zebrafish epibolic movement.

Alkbh4 and Atrn Act Maternally to Regulate Zebrafish Epiboly
Qingrui Sun,* Xingfeng Liu,* Bo Gong, Di Wu, Anming Meng, and Shunji Jia
Int J Biol Sci. 13(8): 1051–1066.
doi: 10.7150/ijbs.19203

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DionisioOctober 1, 2017 at 8:33 pm

[…] Alkbh4 functions in zebrafish embryonic cell movements by regulating actomyosin band formation in the E-YSL.

[…] we speculate that alkbh4 but not atrn might be functional in keeping the integrity of yolk cortical cytoplasmic layer. It will be of great interest to figure out the detailed mechanisms in the future.

[…] the molecular mechanisms of Atrn regulating actomyosin formation are not clear until now […]
Atrn might work together with Alkbh4 to participate in the same process.

Whether there is a potential cross talk between Atrn-MC1R and Alkbh4-Atrn signaling need to be investigated further.

Our studies identified Atrn as a new regulator of actomyosin formation and reflect the importance of maternal genes in early embryonic development.

Alkbh4 and Atrn Act Maternally to Regulate Zebrafish Epiboly
Qingrui Sun,* Xingfeng Liu,* Bo Gong, Di Wu, Anming Meng, and Shunji Jia
Int J Biol Sci. 13(8): 1051–1066.
doi: 10.7150/ijbs.19203

A new regulator?

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DionisioOctober 1, 2017 at 9:00 pm

Tricellular contacts are the places where three cells meet. In vertebrate epithelial cells, specialized structures called tricellular tight junctions (tTJs) and tricellular adherens junctions (tAJs) have been identified. tTJs are important for the maintenance of barrier function […]

Although the molecular components, regulation, and function of tTJs and tAJs, as well as of invertebrate tricellular junctions, are beginning to be characterized, many questions remain.

Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells.
Higashi T1, Miller AL1.
Mol Biol Cell. 28(15):2023-2034.
doi: 10.1091/mbc.E16-10-0697.

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DionisioOctober 1, 2017 at 9:10 pm

It would be interesting to test directly whether vertebrate tricellular junctions serve as a spatial landmark to orient cell division.

Although it is likely that angulins and Anakonda make up the primary structure of tTJs and tSJs, respectively, how they recognize the tricellular contact points is unclear.

Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells.
Higashi T1, Miller AL1.
Mol Biol Cell. 28(15):2023-2034.
doi: 10.1091/mbc.E16-10-0697.

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DionisioOctober 1, 2017 at 9:17 pm

Because there is no direct evidence proving this “leak-detection” model, future studies will be required to test this attractive hypothesis.

Other possibilities for how proteins may recognize the tricellular contact points invite further investigation.

Future studies using new techniques such as the BioID approach may reveal additional interacting partners for tTJ and tSJ components.

The physical basis of the leak pathway is unclear […]

The molecular machinery comprising tricellular junctions is starting to be uncovered.

Because tricellular junctions are critical for barrier function, mechanohomeostasis of epithelial tissues, development, and several diseases, it will be exciting to further investigate tricellular junction components and their functional roles in both cultured epithelial cells and in vivo models.

Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells.
Higashi T1, Miller AL1.
Mol Biol Cell. 28(15):2023-2034.
doi: 10.1091/mbc.E16-10-0697.

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rvb8October 1, 2017 at 9:44 pm

Dionisio, Heh:),

of the 202 comments so far, you have authored 200. Are you on medication?

You are interrupted twice by, Truth Will Set You Free, @64, and, gpuccio @119, other than that it is a ‘Dionisio’ love fest.

This is not a good look for ID, it points to a kind of Narcissistic personality disorder; were you bullied?

Do you even realise that there is no feedback. Afterall, we speak so as to be heard. If there are no listeners, why speak?

From all ofyour output, am I to take it that you think, all life is sacred from conception?

I disagree strongly, so your effort is wasted. The courts also agree with me. You have God and the Bible. Let’s see which is stronger?
205

DionisioOctober 2, 2017 at 2:25 am

Epithelia represent a unique situation where polarized cells must maintain sufficiently strong cell-cell contacts to guarantee the epithelial integrity indispensable for barrier functions.

Nevertheless, epithelia must also keep sufficient plasticity which is crucial during development and morphogenesis.

Adherens junctions and mechanical forces produced by the actomyosin cytoskeleton are major players for epithelial integrity maintenance and plasticity regulations.

To understand how the epithelium is able to meet such a challenge, it is indispensable to determine how cellular junctions and mechanical forces acting at adherens junctions are regulated.

[…]^the Xenopus epithelium is under tension, approximately 3 pN which remains stable, indicating that tensile forces acting on cadherin at the adherens junction are at equilibrium.

Unexpectedly, mechanical tension across cadherin was similar between dividing and non-dividing epithelial cells.

Actomyosin-generated tension on cadherin is similar between dividing and non-dividing epithelial cells in early Xenopus laevis embryos.
Herbomel G1,2, Hatte G1,2, Roul J1,2, Padilla-Parra S1,2, Tassan JP1,2, Tramier M1,
Sci Rep. 7:45058.
doi: 10.1038/srep45058.

Did somebody say ‘unexpectedly’?
What else did they expect? Why?

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DionisioOctober 2, 2017 at 2:35 am

Morphogenesis is driven by cellular events such as division, intercalation or extrusion.

Actomyosin contractility is a central event in these crucial processes of tissue remodeling.

Cadherin is a transmembrane protein whose extracellular domain creates homophilic interactions with cadherin of neighboring cells and which indirectly links, via association of ? and ? catenins to its intracytoplasmic tail, the actin cytoskeleton3

[…] the role cadherin plays in correlating extracellular to intracellular mechanical events remains unclear.

[…] the exact role of the cadherin junction appears more complex than just a tension transmitter.

Actomyosin-generated tension on cadherin is similar between dividing and non-dividing epithelial cells in early Xenopus laevis embryos.
Herbomel G1,2, Hatte G1,2, Roul J1,2, Padilla-Parra S1,2, Tassan JP1,2, Tramier M1,
Sci Rep. 7:45058.
doi: 10.1038/srep45058.

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DionisioOctober 2, 2017 at 2:39 am

During cell division in epithelia, membrane deformation occurs during cytokinesis at the adherens junction.

It has been intensively investigated in drosophila […] but the mechanisms by which this process is driven, in term of molecular tension and membrane deformation, are not well understood

[…] at the end of blastula stage, actomyosin-generated tension on cadherin is approximately 3 pN and remains stable during epithelial cell division.

Actomyosin-generated tension on cadherin is similar between dividing and non-dividing epithelial cells in early Xenopus laevis embryos.
Herbomel G1,2, Hatte G1,2, Roul J1,2, Padilla-Parra S1,2, Tassan JP1,2, Tramier M1,
Sci Rep. 7:45058.
doi: 10.1038/srep45058.

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DionisioOctober 2, 2017 at 2:52 am

To have a clear understanding of how tissue and cell environment influence forces applying to cell-cell junction, future studies will be necessary to compare different type of epithelium or new tensions sensors.

Cytokinesis involves a contractile acto-myosin ring which deforms the plasma membrane and the associated cytoskeleton cortex thus ultimately leading to separation of the two daughter cells.

[…] imbalanced tensile forces are applied on cadherin during cytokinesis at the site of membrane ingression.

Whether this imbalance is unilateral or bilateral, it will be important to uncover the mechanisms leading to membrane ingression in dividing cells.

Cadherins are dynamically localized at the adherens junction.

[…] dynamics of cadherin at the plasma membrane could be the primary mechanism leading to membrane deformation.

Actomyosin-generated tension on cadherin is similar between dividing and non-dividing epithelial cells in early Xenopus laevis embryos.
Herbomel G1,2, Hatte G1,2, Roul J1,2, Padilla-Parra S1,2, Tassan JP1,2, Tramier M1,
Sci Rep. 7:45058.
doi: 10.1038/srep45058.

“future studies will be necessary”

“it will be important to uncover the mechanisms”

As outstanding questions get answered, new questions are raised. In biology, the more we know, more is there to learn.

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DionisioOctober 2, 2017 at 3:01 am

By using new developments in quantitative fluorescence microscopy to measure spatio-temporal dynamics of molecular tension we present unexpected results where cadherin does not seem to be directly stretched to create membrane deformation during cytokinesis of epithelial cell in vertebrate.

Our work paves the way to unveil the molecular mechanisms leading to membrane ingression in vertebrate epithelial dividing cells.

Actomyosin-generated tension on cadherin is similar between dividing and non-dividing epithelial cells in early Xenopus laevis embryos.
Herbomel G1,2, Hatte G1,2, Roul J1,2, Padilla-Parra S1,2, Tassan JP1,2, Tramier M1,
Sci Rep. 7:45058.
doi: 10.1038/srep45058.

Did somebody say ‘unexpected’?

“Our work paves the way to unveil the molecular mechanisms”
How long is that way? How much ‘paving’ work remains to be done?

Work in progress… stay tuned.

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DionisioOctober 2, 2017 at 3:11 am

During epithelial cytokinesis, the remodelling of adhesive cell-cell contacts between the dividing cell and its neighbours has profound implications for the integrity, arrangement and morphogenesis of proliferative tissues.

In both vertebrates and invertebrates, this remodelling requires the activity of non-muscle myosin II (MyoII) in the interphasic cells neighbouring the dividing cell.

However, the mechanisms that coordinate cytokinesis and MyoII activity in the neighbours are unknown.

Transmission of cytokinesis forces via E-cadherin dilution and actomyosin flows.
Pinheiro D1,2,3, Hannezo E4,5, Herszterg S1,2, Bosveld F1,2, Gaugue I1,2, Balakireva M1,2, Wang Z1,2, Cristo I1,2, Rigaud SU1,2, Markova O1,2, Bellaïche Y1,2.
Nature. 545(7652):103-107.
doi: 10.1038/nature22041. Epub 2017 Mar 15.

Did somebody say ‘coordinate’?

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DionisioOctober 2, 2017 at 3:17 am

[…] in the Drosophila notum epithelium, each cell division is associated with a mechanosensing and transmission event that controls MyoII dynamics in neighbouring cells.

[…] the ring pulling forces promote local junction elongation, which results in local E-cadherin dilution at the ingressing adherens junction.

In turn, the reduction in E-cadherin concentration and the contractility of the neighbouring cells promote self-organized actomyosin flows, ultimately leading to accumulation of MyoII at the base of the ingressing junction.

Although force transduction has been extensively studied in the context of adherens junction reinforcement to stabilize adhesive cell-cell contacts, we propose an alternative mechanosensing mechanism that coordinates actomyosin dynamics between epithelial cells and sustains the remodelling of the adherens junction in response to mechanical forces.

Transmission of cytokinesis forces via E-cadherin dilution and actomyosin flows.
Pinheiro D1,2,3, Hannezo E4,5, Herszterg S1,2, Bosveld F1,2, Gaugue I1,2, Balakireva M1,2, Wang Z1,2, Cristo I1,2, Rigaud SU1,2, Markova O1,2, Bellaïche Y1,2.
Nature. 545(7652):103-107.
doi: 10.1038/nature22041. Epub 2017 Mar 15.

Did somebody say ‘controls’?

alternative mechanism? another one?

Did somebody say ‘coordinates’?

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DionisioOctober 2, 2017 at 3:12 pm

Classical cadherins are well known for their essential function in mediating cell-cell adhesion via their extra-cellular cadherin domains and intra-cellular connections to the actin cytoskeleton [1-3].

There is evidence, however, of adhesion-independent cadherin clusters existing outside of cell-cell junctions [4-6].

What function, if any, these clusters have is not known.

HMR-1, the sole classical cadherin in Caenorhabditis elegans, plays essential roles during gastrulation, blastomere polarity establishment, and epidermal morphogenesis [7-11].

Non-junctional E-Cadherin Clusters Regulate the Actomyosin Cortex in the C. elegans Zygote.
Padmanabhan A1, Ong HT1, Zaidel-Bar R2.
Curr Biol. 27(1):103-112.
doi: 10.1016/j.cub.2016.10.032.

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DionisioOctober 2, 2017 at 3:23 pm

[…] non-junctional clusters of HMR-1 form during the one-cell polarization stage and associate with F-actin at the cortex during episodes of cortical flow.

Non-junctional HMR-1 clusters downregulate RHO-1 activity and inhibit accumulation of non-muscle myosin II (NMY-2) at the anterior cortex.

[…] HMR-1 clusters impede cortical flows and play a role in preserving the integrity of the actomyosin cortex, preventing it from splitting in two.

The effect of HMR-1 clusters on cytokinesis is independent of their effect on NMY-2 levels, and is also independent of their extra-cellular domains.

Thus, in addition to their canonical role in inter-cellular adhesion, HMR-1 clusters regulate RHO-1 activity and NMY-2 level at the cell surface, reinforce the stability of the actomyosin cortex, and resist its movement to influence cell-shape dynamics.

Non-junctional E-Cadherin Clusters Regulate the Actomyosin Cortex in the C. elegans Zygote.
Padmanabhan A1, Ong HT1, Zaidel-Bar R2.
Curr Biol. 27(1):103-112.
doi: 10.1016/j.cub.2016.10.032.

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DionisioOctober 2, 2017 at 3:31 pm

Establishment of anterior-posterior polarity in the Caenorhabditis elegans zygote requires two different processes: mechanical activity of the actin-myosin cortex and biochemical activity of partitioning-defective (PAR) proteins.

[…] PARs regulate the behavior of the cortical motor protein nonmuscle myosin (NMY-2) […]

[…] PARs regulate the Rho GTPase CDC-42, which in turn regulates the actin-myosin cortex.

[…] PAR-3 and PAR-6 concentrate CDC-42-dependent NMY-2 in the anterior cortex, whereas PAR-2 inhibits CDC-42-dependent NMY-2 in the posterior domain by inhibiting PAR-3 and PAR-6.

[…] PAR-1 and PAR-3 are necessary for inhibiting movement of NMY-2 across the cortex. PAR-1 protects NMY-2 from being moved across the cortex by forces likely originating in the cytoplasm.

[…] PAR-3 stabilizes NMY-2 against PAR-2 and PAR-6 dynamics on the cortex.

[…] PAR signaling fulfills two roles: localizing NMY-2 to the anterior cortex and preventing displacement of the polarized cortical actin-myosin network.

PAR proteins regulate maintenance-phase myosin dynamics during Caenorhabditis elegans zygote polarization.
Small LE1, Dawes AT2,3.
Mol Biol Cell. 28(16):2220-2231.
doi: 10.1091/mbc.E16-04-0263

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DionisioOctober 2, 2017 at 3:49 pm

The cell cortex is essential to maintain animal cell shape, and contractile forces generated within it by nonmuscle myosin II (NMY-2) drive cellular morphogenetic processes such as cytokinesis.

The role of actin cross-linking proteins in cortical dynamics is still incompletely understood.

[…] actin bundling/cross-linking protein plastin is instrumental for the generation of potent cortical actomyosin contractility in the Caenorhabditis elegans zygote.

[…] by increasing the connectivity of the F-actin meshwork, plastin enables the cortex to generate stronger and more coordinated forces to accomplish cellular morphogenesis.

Plastin increases cortical connectivity to facilitate robust polarization and timely cytokinesis.
Ding WY1, Ong HT1, Hara Y1,2, Wongsantichon J3, Toyama Y1,2,4, Robinson RC3,5, Nédélec F6, Zaidel-Bar R1,7.
J Cell Biol. 216(5):1371-1386.
doi: 10.1083/jcb.201603070.

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DionisioOctober 2, 2017 at 6:05 pm

In multicellular organisms, a stringent control of the transition between cell division and differentiation is crucial for correct tissue and organ development.

In the Arabidopsis root, the boundary between dividing and differentiating cells is positioned by the antagonistic interaction of the hormones auxin and cytokinin.

Cytokinin affects polar auxin transport, but how this impacts the positional information required to establish this tissue boundary, is still unknown.

[…] boundary formation is dependent on cytokinin’s control on auxin polar transport and degradation.

The regulation of both processes shapes the auxin profile in a well-defined auxin minimum.

This auxin minimum positions the boundary between dividing and differentiating cells, acting as a trigger for this developmental transition, thus controlling meristem size.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114

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DionisioOctober 2, 2017 at 6:16 pm

Future challenge will be to understand how the position of the auxin minimum correlates with the programmed cell death of the LRC and how these two inputs are coordinated to control the dynamic of root growth and the entire root system organization.

[…] it may be insightful to reconsider morphogenetic gradient theory in terms of context-dependent profile features, such as minima with an inherent curvature, instead of absolute thresholds only.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114

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DionisioOctober 2, 2017 at 7:21 pm

Tissue patterning during animal development is orchestrated by a handful of inductive signals.

Most of these developmental cues act as morphogens, meaning they are locally produced secreted molecules that act at a distance to govern tissue patterning.

The iterative use of the same signaling molecules in different developmental contexts demands that signal interpretation occurs in a highly context?dependent manner.

Hence the interpretation of signal depends on the specific competence of the receiving cells.

Moreover, it has become clear that the differential interpretation of morphogens depends not only on the level of signaling but also the signaling dynamics, particularly the duration of signaling.

[…] the response to morphogens is determined by differential competence, pathway intrinsic feedback, and the interpretation of signaling dynamics by gene regulatory networks.

Morphogen interpretation: concentration, time, competence, and signaling dynamics
Andreas Sagner 1 and James Briscoe
Wiley Interdiscip Rev Dev Biol. 6(4): e271.
doi: 10.1002/wdev.271

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DionisioOctober 2, 2017 at 7:24 pm

Embryonic development is a progressive program in which a single totipotent cell, the fertilized egg, gives rise to hundreds of distinct differentiated cell types.

For this to result in the successful completion of embryogenesis, and the well?organized assembly of functioning organs, the appropriate cell types must be produced at the right time, at the right place and in the correct number.

Strikingly, a handful of inductive signals, iteratively used during development, coordinate this process.

The repeated use of a limited set of signals means that the identity of a signal is not itself sufficient to confer specificity.

Morphogen interpretation: concentration, time, competence, and signaling dynamics
Andreas Sagner 1 and James Briscoe
Wiley Interdiscip Rev Dev Biol. 6(4): e271.
doi: 10.1002/wdev.271

“at the right time, at the right place and in the correct number”

Did somebody say ‘strikingly’?

Complex functionally specified informational complexity.
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DionisioOctober 2, 2017 at 7:35 pm

[…] how precision in tissue patterning is reproducibly achieved during development remains an open question.

[..] to understand development we need to be able to assay with increasing precision the dynamics of signaling and measure the regulation of multiple genes simultaneously.

Combining theoretical and experimental approaches will likely allow us to construct more detailed and quantitative models and thereby provide a deeper insight into the regulatory logic of the genome.

Morphogen interpretation: concentration, time, competence, and signaling dynamics
Andreas Sagner 1 and James Briscoe
Wiley Interdiscip Rev Dev Biol. 6(4): e271.
doi: 10.1002/wdev.271

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DionisioOctober 2, 2017 at 7:49 pm

Immune cells communicate by exchanging cytokines to achieve a context-appropriate response, but the distances over which such communication happens are not known.

[…] competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries.

The size of these self-assembled niches scaled with the density of cytokine-consuming cells, a parameter that gets tuned during immune responses.

A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System.
Oyler-Yaniv A1, Oyler-Yaniv J2, Whitlock BM3, Liu Z4, Germain RN4, Huse M5, Altan-Bonnet G6, Krichevsky O7.
Immunity. 46(4):609-620.
doi: 10.1016/j.immuni.2017.03.011.

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DionisioOctober 2, 2017 at 8:22 pm

The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs).

It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations.

The mechanisms underpinning the establishment and regulation of these gradients are poorly understood.

A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4.
Jafarnejad M1, Zawieja DC2, Brook BS3, Nibbs RJB4, Moore JE Jr5.
J Immunol. 2017 199(7):2291-2304.
doi: 10.4049/jimmunol.1700377.

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DionisioOctober 2, 2017 at 8:28 pm

Immunosurveillance and immune responses depend on precisely coordinated leukocyte migration.

This is largely orchestrated by chemokines, which are sensed by heptahelical G protein–coupled chemokine receptors on leukocytes […]

A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4.
Jafarnejad M1, Zawieja DC2, Brook BS3, Nibbs RJB4, Moore JE Jr5.
J Immunol. 2017 199(7):2291-2304.
doi: 10.4049/jimmunol.1700377.

Did somebody say ‘coordinated’?

Did somebody say ‘orchestrated’?

Complex functionally specified informational complexity.
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DionisioOctober 2, 2017 at 8:32 pm

The mechanisms that control the formation and regulation of chemokine gradients in vivo are poorly understood but likely involve many interrelated biochemical and physical processes […]

Understanding how these processes are integrated and modulated remains a major challenge in chemokine biology.

The mechanisms that control extracellular chemokine distribution are of significant immunological importance but they are currently poorly understood.

A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4.
Jafarnejad M1, Zawieja DC2, Brook BS3, Nibbs RJB4, Moore JE Jr5.
J Immunol. 199(7):2291-2304.
doi: 10.4049/jimmunol.1700377.

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rvb8October 2, 2017 at 10:27 pm

Heh:)

wonderful. Don’t stop on my account:)

Can you make 300?
226

DionisioOctober 3, 2017 at 2:27 am

Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space.

Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how the cell-based immune system is controlled.

Bias comes in three forms; ligand-, receptor- and tissue-bias.

Biased signaling is increasingly being recognized as playing an important role in contributing to the fine-tuned coordination of immune cell chemotaxis.

CCR7 is expressed by a subset of T-cells and by mature dendritic cells (DCs).

Together with its two endogenous ligands CCL19 and CCL21, of which the carboxy terminal tail of CCL21 displays an extraordinarily strong glycosaminoglycan (GAG) binding, CCR7 plays a central role in coordinating the meeting between mature antigen presenting DCs and naïve T-cells which normally takes place in the lymph nodes (LNs).

This process is a prerequisite for the initiation of an antigen-specific T-cell mediated immune response.

Thus CCR7 and its ligands are key players in initiating cell-based immune responses.

CCL19 and CCL21 display differential interaction- and docking-modes for CCR7 leading to stabilization of different CCR7 conformations and hereby preferential activation of distinct intracellular signaling pathways (i.e. ligand bias).

In general CCL19 seems to generate a strong temporal signal, whereas CCL21 generates a weaker, but more persistent signal.

Tissue differential expression of these two ligands, and the generation of a third ligand “tailless-CCL21”, through DC specific protease activity (tissue bias), orchestrates DC and T-cell LN homing and priming, with each ligand serving overlapping, but also distinct roles.

Biased signaling of G protein-coupled receptors – From a chemokine receptor CCR7 perspective.
Jørgensen AS1, Rosenkilde MM1, Hjortø GM2.
Gen Comp Endocrinol. pii: S0016-6480(17)30399-4.
doi: 10.1016/j.ygcen.2017.07.004

Did somebody say ‘concerted manner’?

Did somebody say ‘complexity’?

Did somebody say ‘controlled’?

Did somebody say ‘fine-tuned coordination’?

Did somebody say ‘coordinating’?

Did somebody say ‘orchestrates’?

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DionisioOctober 3, 2017 at 2:46 am

Two theories address the origin of repeating patterns, such as hair follicles, limb digits, and intestinal villi, during development.

The Turing reaction-diffusion system posits that interacting diffusible signals produced by static cells first define a prepattern that then induces cell rearrangements to produce an anatomical structure.

The second theory, that of mesenchymal self-organisation, proposes that mobile cells can form periodic patterns of cell aggregates directly, without reference to any prepattern.

Early hair follicle development is characterised by the rapid appearance of periodic arrangements of altered gene expression in the epidermis and prominent clustering of the adjacent dermal mesenchymal cells.

Hierarchical patterning modes orchestrate hair follicle morphogenesis.
Glover JD1, Wells KL1, Matthäus F2, Painter KJ3, Ho W1, Riddell J1, Johansson JA1,4, Ford MJ4, Jahoda CAB5, Klika V6, Mort RL7, Headon DJ1.
PLoS Biol. 15(7):e2002117.
doi: 10.1371/journal.pbio.2002117.

Did somebody say ‘orchestrate’?

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DionisioOctober 3, 2017 at 2:50 am

[…] mesenchymal cell condensation at hair follicles is locally directed by an epidermal prepattern.

However, imposing this prepattern’s condition of high FGF and low BMP activity across the entire skin reveals a latent dermal capacity to undergo spatially patterned self-organisation in the absence of epithelial direction.

This mesenchymal self-organisation relies on restricted transforming growth factor (TGF) ? signalling, which serves to drive chemotactic mesenchymal patterning when reaction-diffusion patterning is suppressed, but, in normal conditions, facilitates cell movement to locally prepatterned sources of FGF.

This work illustrates a hierarchy of periodic patterning modes operating in organogenesis.

Hierarchical patterning modes orchestrate hair follicle morphogenesis.
Glover JD1, Wells KL1, Matthäus F2, Painter KJ3, Ho W1, Riddell J1, Johansson JA1,4, Ford MJ4, Jahoda CAB5, Klika V6, Mort RL7, Headon DJ1.
PLoS Biol. 15(7):e2002117.
doi: 10.1371/journal.pbio.2002117.

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DionisioOctober 3, 2017 at 2:53 am

Repeating anatomical units, forming a pattern, are present in different parts of the body.

This is particularly obvious in the skin, where the many hair follicles become regularly arranged and fixed in place in the embryo as a pattern of evenly spaced spots.

The basis for the formation of such repeating patterns has attracted a number of theoretical explanations.

One influential theory is that cells first issue chemical signals to one another to produce a map of the pattern, which they then follow to assemble a structure, like a hair follicle.

Alternative theories instead suggest that cells cluster together directly, without reference to a pre-existing map, to drive pattern formation.

Hierarchical patterning modes orchestrate hair follicle morphogenesis.
Glover JD1, Wells KL1, Matthäus F2, Painter KJ3, Ho W1, Riddell J1, Johansson JA1,4, Ford MJ4, Jahoda CAB5, Klika V6, Mort RL7, Headon DJ1.
PLoS Biol. 15(7):e2002117.
doi: 10.1371/journal.pbio.2002117.

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DionisioOctober 3, 2017 at 3:02 am

[…] a set of chemical signals known to be important for early hair follicle formation form a network capable of producing a patterned template to which cells then respond, moving according to its instructions.

This supports the signal-based theory for pattern formation.

Strikingly, though, by imposing the conditions of the incipient hair follicle evenly across the entire skin, we reveal that skin cells can also form patterns directly by coalescing, without requiring instructions from a pre-existing pattern.

However, this ability of cells to pattern directly is normally subservient to their following of a quickly forming pattern template defined by chemical signals.

[…] different ways of making biological patterns can coexist in the same embryonic organ but that one is normally subordinated to the other.

Hierarchical patterning modes orchestrate hair follicle morphogenesis.
Glover JD1, Wells KL1, Matthäus F2, Painter KJ3, Ho W1, Riddell J1, Johansson JA1,4, Ford MJ4, Jahoda CAB5, Klika V6, Mort RL7, Headon DJ1.
PLoS Biol. 15(7):e2002117.
doi: 10.1371/journal.pbio.2002117.

Did somebody say ‘instructions’?

Did somebody say ‘strikingly’?

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DionisioOctober 3, 2017 at 3:05 am

Diverse structures, such as the skeletal elements of the limb, rugae of the palate, cartilaginous rings of the trachea, intestinal villi, and feathers, scales, or hair follicles, develop in a periodically patterned manner.

[…] many specific models to explain the spontaneous emergence of such repeating patterns in embryonic tissues have been proposed […]

[…] experimental investigation is required to define the contribution made by each mechanism during organ development.

Hierarchical patterning modes orchestrate hair follicle morphogenesis.
Glover JD1, Wells KL1, Matthäus F2, Painter KJ3, Ho W1, Riddell J1, Johansson JA1,4, Ford MJ4, Jahoda CAB5, Klika V6, Mort RL7, Headon DJ1.
PLoS Biol. 15(7):e2002117.
doi: 10.1371/journal.pbio.2002117.

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DionisioOctober 3, 2017 at 3:17 am

[…] the dermal mesenchyme does possess pattern-generating ability but that this is preceded by a rapid, primarily epidermal, pre-patterning system that acts to specify the restricted locations at which mesenchymal organisation is permitted.

Hierarchical patterning modes orchestrate hair follicle morphogenesis.
Glover JD1, Wells KL1, Matthäus F2, Painter KJ3, Ho W1, Riddell J1, Johansson JA1,4, Ford MJ4, Jahoda CAB5, Klika V6, Mort RL7, Headon DJ1.
PLoS Biol. 15(7):e2002117.
doi: 10.1371/journal.pbio.2002117.

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DionisioOctober 3, 2017 at 3:46 am

The control of organ size presents a fundamental open problem in biology.

Since, as we show, a fit to the available experimental growth kinetics is insufficient to define the underlying mechanism of growth control, future experimental studies must focus on the molecular mechanisms to define the mechanism of growth control.

A fascinating aspect of embryonic development is how the growth of organ rudiments is globally coordinated such that all organs, tissues and the paired appendages grow to the correct (relative) size, even when final sizes differ between isogenic offspring because of external factors such as nutrition or temperature1.

The mechanism by which growth is terminated has remained elusive.

[…] we emphasize the need to explore a wider range of growth limiting mechanisms and to carefully check the consistency of any proposed mechanism with additional experimental data – the ability to recapitulate the growth kinetics alone provides insufficient support for any mechanism.

An Unbiased Analysis of Candidate Mechanisms for the Regulation of Drosophila Wing Disc Growth
Jannik Vollmer1,2 and Dagmar Ibera
Sci Rep. 2016; 6: 39228.
doi: 10.1038/srep39228

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DionisioOctober 3, 2017 at 3:54 am

How such positional differences would be measured by cells is not known.

[…] it has remained unclear whether the Fat-dependent growth limitation is central to growth.

[…] it remains unclear how the positional identity would scale when tissues grow to different final sizes, […]

[…] it remains unclear how wing discs would achieve this on the molecular level in a disc-autonomous way and how disc size could then vary in response to changes in external conditions (nutrients, temperature etc.).

[…] there could be other growth laws that also reproduce the data and that we have not yet identified.

An Unbiased Analysis of Candidate Mechanisms for the Regulation of Drosophila Wing Disc Growth
Jannik Vollmer1,2 and Dagmar Ibera
Sci Rep. 2016; 6: 39228.
doi: 10.1038/srep39228

Work in progress… stay tuned.

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DionisioOctober 3, 2017 at 6:14 am

[…] the mechanisms of the aging process, remain a fundamental and fascinating problem in biology.

[…] a small RNA-based gene regulatory machinery, the Piwi-piRNA pathway, represents a shared feature of nonaging (potentially immortal) biological systems, […]

The pathway primarily functions to repress the activity of mobile genetic elements, also called transposable elements (TEs) or ‘jumping genes’, which are capable of moving from one genomic locus to another, thereby causing insertional mutations.

TEs become increasingly active and multiply in the genomes of somatic cells as the organism ages.

These characteristics of TEs highlight their decisive mutagenic role in the progressive disintegration of genetic information, a molecular hallmark associated with aging.

Hence, TE-mediated genomic instability may substantially contribute to the aging process.

The Piwi-piRNA pathway: road to immortality.
Sturm Á1, Perczel A2, Ivics Z3, Vellai T1,4.
Aging Cell. 16(5):906-911.
doi: 10.1111/acel.12630.

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DionisioOctober 10, 2017 at 5:40 am

[…] the spatially different tissue-scale diffusivity is a core mechanism for AN3 gradient formation.

This provides evidence that the pure diffusion process establishes the formation of the long-range signaling gradient in leaf development.

Spatially Different Tissue-Scale Diffusivity Shapes ANGUSTIFOLIA3 Gradient in Growing Leaves
Kensuke Kawade, Hirokazu Tanimoto, Gorou Horiguchi, Hirokazu Tsukaya
DOI: http://dx.doi.org/10.1016/j.bpj.2017.06.072
Volume 113, Issue 5, p1109–1120
Biophysical Journal

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DionisioOctober 10, 2017 at 6:07 am

[…] tissue-scale diffusivity, but not cellular-scale diffusivity, is spatially varied along the proximal-to-distal axis.

[…] tissue-scale molecular mobility can be described as a diffusion process if position-dependent cell size is appropriately considered.

[…] the simplest mechanism of diffusion could be a core determinant for the AN3 gradient formation.

[…] the diffusion equation fulfills the dynamic formation of a signaling gradient […]

[…] the concentration gradient of AN3 plays an important role in regulating cell-proliferation dynamics along the leaf proximal-to-distal axis.

Spatially Different Tissue-Scale Diffusivity Shapes ANGUSTIFOLIA3 Gradient in Growing Leaves
Kensuke Kawade, Hirokazu Tanimoto, Gorou Horiguchi, Hirokazu Tsukaya
DOI: http://dx.doi.org/10.1016/j.bpj.2017.06.072
Volume 113, Issue 5, p1109–1120
Biophysical Journal

Did somebody say ‘preferable strategy’?

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DionisioOctober 10, 2017 at 6:22 am

[…] spatial difference of tissue-scale diffusivity along the leaf proximal-to-distal axis might help to maintain the higher AN3 concentration in the leaf proximal part for vigorous proliferation, and also to form long-range distribution toward the leaf distal part for lower, but detectable, proliferation activity.

[…] a developmental mechanism using the spatial gradient of a signaling molecule to regulate determinate tissue growth might be a preferable strategy across kingdoms.

[…] mechanical stress due to tissue growth induces feedback regulation on cell-proliferation activity in Arabidopsis petals and Drosophila wing discs […]

It would be interesting to test this cross talk in future work using a more complex model than our one-dimensional one that incorporates this inter-cell-layer movement and also mechanical feedback in three-dimensional geometry.

Implementing the kinetics of AN3 mobility in this future model will also be helpful for further investigation of AN3 gradient formation.

Spatially Different Tissue-Scale Diffusivity Shapes ANGUSTIFOLIA3 Gradient in Growing Leaves
Kensuke Kawade, Hirokazu Tanimoto, Gorou Horiguchi, Hirokazu Tsukaya
DOI: http://dx.doi.org/10.1016/j.bpj.2017.06.072
Volume 113, Issue 5, p1109–1120
Biophysical Journal

Did somebody say ‘preferable strategy’?

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DionisioOctober 10, 2017 at 6:50 am

@236-238 the referenced paper apparently deals with plant leaves, which are relatively simpler organs.
The morphogenesis of other more complex organs is a different story, as we have seen described in a number of recent papers, where the diffusion-reaction mechanisms by themselves can’t make the morphogen gradients. Other transport mechanisms have been described in those cases.
240

DionisioOctober 10, 2017 at 11:15 am

According to morphogen gradient theory, extracellular ligands produced from a localized source convey positional information to receiving cells by signaling in a concentration-dependent manner.

How do morphogens create concentration gradients to establish positional information in developing tissues?

Surprisingly, the answer to this central question remains largely unknown. During development, a relatively small number of morphogens are reiteratively deployed to ensure normal embryogenesis and organogenesis.

Thus, the intracellular processing and extracellular transport of morphogens are tightly regulated in a tissue-specific manner.

Over the past few decades, diverse experimental and theoretical approaches have led to numerous conflicting models for gradient formation.

Morphogen transport: theoretical and experimental controversies.
Akiyama T1, Gibson MC.
Wiley Interdiscip Rev Dev Biol. 4(2):99-112.
doi: 10.1002/wdev.167.

Did somebody say ‘Surprisingly’?

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DionisioOctober 10, 2017 at 1:25 pm

The role of protein localization along the apical-basal axis of polarized cells is difficult to investigate in vivo, partially due to lack of suitable tools.

[…] the Dpp gradient forming in the lateral plane of the Drosophila wing disc epithelium is essential for patterning of the wing imaginal disc.

Despite of its importance, the role of protein localization and the effects of forced protein mislocalization have not been studied extensively and hence remain in many cases not well understood.

[…] the functional Dpp morphogen gradient forms in the lateral plane of the wing disc epithelium.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila.
Harmansa S1, Alborelli I1, Bieli D1, Caussinus E1,2, Affolter M1.
Elife. 6. pii: e22549.
doi: 10.7554/eLife.22549.

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DionisioOctober 10, 2017 at 1:36 pm

[…] the functional implication and the necessity of proper localization, as well as the consequences of distinct mislocalization of a given protein, are less well understood.

In future studies, the GrabFP system will help to better understand the requirements for polarized distribution of signaling pathway components in different developmental contexts.

Dpp gradient formation in the Drosophila wing disc remains a paradigm to study morphogen dispersal and several mechanisms for morphogen gradient formation have been suggested, operating in different extracellular environments […]

[…] future studies will need to investigate the localization and the effect of forced mislocalization of Dpp receptors and interaction partners on Dpp dispersal and gradient formation.

A nanobody-based toolset to investigate the role of protein localization and dispersal in Drosophila.
Harmansa S1, Alborelli I1, Bieli D1, Caussinus E1,2, Affolter M1.
Elife. 6. pii: e22549.
doi: 10.7554/eLife.22549.

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DionisioOctober 10, 2017 at 1:59 pm

Dpp, a member of the BMP family, is a morphogen that specifies positional information in Drosophila wing precursors.

[…] the stripe of Dpp ensures that signalling remains above a pro-growth threshold, while at the same time generating a gradient that patterns cell fates.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action.
Bosch PS1, Ziukaite R2, Alexandre C2, Basler K1, Vincent JP2.
Elife. 6. pii: e22546.
doi: 10.7554/eLife.22546.

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DionisioOctober 10, 2017 at 2:01 pm

From the wings of a butterfly to the fingers of a human hand, living tissues often have complex and intricate patterns.

Developmental biologists have long been fascinated by the signals – called morphogens – that guide how these kinds of pattern develop.

Morphogens are substances that are produced by groups of cells and spread to the rest of the tissue to form a gradient.

Depending on where they sit along this gradient, cells in the tissue activate different sets of genes, and the resulting pattern of gene activity ultimately defines the position of the different parts of the tissue.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action.
Bosch PS1, Ziukaite R2, Alexandre C2, Basler K1, Vincent JP2.
Elife. 6. pii: e22546.
doi: 10.7554/eLife.22546.

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DionisioOctober 10, 2017 at 2:10 pm

Further work will be needed to explain how the Dpp signal regulates the growth of the wing.

The answer to this question will contribute to a better understanding of the role of morphogens in regulating the size of human organs and how a failure to do so might cause developmental disorders.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action.
Bosch PS1, Ziukaite R2, Alexandre C2, Basler K1, Vincent JP2.
Elife. 6. pii: e22546.
doi: 10.7554/eLife.22546.

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DionisioOctober 11, 2017 at 9:38 am

[…] the homeodomain transcription factors Dlx3b and Dlx4b are essential for proper induction of the otic-epibranchial progenitor domain (OEPD), as well as subsequent formation of sensory hair cells in the developing zebrafish inner ear.

[…] the Dlx3b/4b-dependent pathway has been either acquired newly in the fish lineage or lost in other vertebrate species during evolution, and that the events during early inner ear development are remarkably similar in fish and amniotes in the absence of this pathway.

Dlx3b/4b is required for early-born but not later-forming sensory hair cells during zebrafish inner ear development
Simone Schwarzer, Sandra Spieß, Michael Brand, and Stefan Hans
Biol Open. 6(9): 1270–1278.
doi: 10.1242/bio.026211

Where’s the beef? 🙂

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DionisioOctober 11, 2017 at 9:57 am

The vertebrate inner ear is a sensory organ mediating hearing and balance.

It derives from the otic placode, a transient ectodermal thickening adjacent to the developing hindbrain, and contains a complex arrangement of mechanosensory hair cells, nonsensory supporting cells and sensory neurons […]

Inner ear formation is a multistep process initiated by the establishment of the preplacodal region, a zone of ectoderm running around the anterior border of the neural plate containing precursors for all sensory placodes […]

[…] the Dlx3b/4b-dependent pathway has either been acquired in the fish lineage or lost in other vertebrate lineages and that inner ear development is highly similar in amniotes and fish in the absence of this pathway.

Dlx3b/4b is required for early-born but not later-forming sensory hair cells during zebrafish inner ear development
Simone Schwarzer, Sandra Spieß, Michael Brand, and Stefan Hans
Biol Open. 6(9): 1270–1278.
doi: 10.1242/bio.026211

Where’s the beef?

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DionisioOctober 11, 2017 at 5:08 pm

During development cell commitment is regulated by inductive signals that are tightly controlled in time and space.

In response, cells activate specific programmes, but the transcriptional circuits that maintain cell identity in a changing signalling environment are often poorly understood.

Specification of inner ear progenitors is initiated by FGF signalling.

[…] we reveal the regulatory logic that initiates ear formation and highlight the hierarchical organisation of the otic gene network.

A gene network regulated by FGF signalling during ear development
Maryam Anwar,#1,2 Monica Tambalo,#1,3 Ramya Ranganathan,1 Timothy Grocott,1,4 and Andrea Street
Sci Rep. 2017; 7: 6162.
doi: 10.1038/s41598-017-05472-0

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DionisioOctober 12, 2017 at 6:09 am

Unravelling the structure of regulatory circuits that control development provides mechanistic insight into the assembly of a body plan and functional organs.

The vesicle gradually acquires the architecture of the adult inner ear through morphogenetic changes accompanied by the differentiation of a large number of specialised cell types.

[…] complex signalling events gradually commit sensory progenitors to the otic lineage.

A gene network regulated by FGF signalling during ear development
Maryam Anwar,#1,2 Monica Tambalo,#1,3 Ramya Ranganathan,1 Timothy Grocott,1,4 and Andrea Street
Sci Rep. 2017; 7: 6162.
doi: 10.1038/s41598-017-05472-0

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DionisioOctober 12, 2017 at 6:12 am

The vertebrate inner ear arises from a pool of sensory progenitor cells that are initially competent to contribute to all sense organs and sensory ganglia in the head.

Over time their potential is restricted, and cells next to the hindbrain become committed to the ear lineage.

Rather than involving a single molecular switch ear commitment is achieved gradually as cells are exposed to different sequential signals

A gene network regulated by FGF signalling during ear development
Maryam Anwar,#1,2 Monica Tambalo,#1,3 Ramya Ranganathan,1 Timothy Grocott,1,4 and Andrea Street
Sci Rep. 2017; 7: 6162.
doi: 10.1038/s41598-017-05472-0

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DionisioOctober 12, 2017 at 6:15 am

[…] the major role of FGF signalling during otic placode initiation is to activate a small sub-circuit of genes, whose role is to stabilise the OEP programme before additional signals commit cells to inner ear or epibranchial identity.

FGFs are critical to activate the OEP programme.

[…] FGF signalling may be tightly controlled and this may occur on multiple levels.

A gene network regulated by FGF signalling during ear development
Maryam Anwar,#1,2 Monica Tambalo,#1,3 Ramya Ranganathan,1 Timothy Grocott,1,4 and Andrea Street
Sci Rep. 2017; 7: 6162.
doi: 10.1038/s41598-017-05472-0

Did somebody say ‘programme’?

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DionisioOctober 12, 2017 at 6:22 am

[…] repressive loops are critical to ensure the progression of OEPs towards otic commitment, while simultaneously preventing alternative fates.

[…] downstream of FGF signalling a few transcription factors form a circuit of positive feedback loops that is sufficient to maintain OEP identity and thus keeps cells competent to respond to the next signalling input.

A gene network regulated by FGF signalling during ear development
Maryam Anwar,#1,2 Monica Tambalo,#1,3 Ramya Ranganathan,1 Timothy Grocott,1,4 and Andrea Street
Sci Rep. 2017; 7: 6162.
doi: 10.1038/s41598-017-05472-0

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DionisioOctober 12, 2017 at 3:08 pm

The sensory organs of the vertebrate head originate from simple ectodermal structures known as cranial placodes.

All cranial placodes derive from a common domain adjacent to the neural plate, the pre-placodal region, which is induced at the border of neural and non-neural ectoderm during gastrulation.

Induction and specification of the pre-placodal region is regulated by the FGF, BMP, WNT and retinoic acid signaling pathways, and characterized by expression of the EYA and SIX family of transcriptional regulators.

The Molecular Basis of Craniofacial Placode Development
Sunita Singh and Andrew K. Groves
Wiley Interdiscip Rev Dev Biol. 5(3): 363–376.
doi: 10.1002/wdev.226

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DionisioOctober 12, 2017 at 3:35 pm

Placode development is a multi-step process, with each of these steps being regulated by distinct signaling pathways and transcription factors.

These signaling molecules create a local environment of differential expression of various transcription factors which first establish a non-neural and neural boundary followed by formation of the neural border which forms the neural crest and placodes.

The Molecular Basis of Craniofacial Placode Development
Sunita Singh and Andrew K. Groves
Wiley Interdiscip Rev Dev Biol. 5(3): 363–376.
doi: 10.1002/wdev.226

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DionisioOctober 12, 2017 at 3:38 pm

It remains unclear how the common pre-placodal region becomes competent to respond to similar inductive signaling and still be able to form different placode derivatives during embryonic development

It remains unclear how the common pre-placodal region becomes competent to respond to similar inductive signaling and still be able to form different placode derivatives during embryonic development

The Molecular Basis of Craniofacial Placode Development
Sunita Singh and Andrew K. Groves
Wiley Interdiscip Rev Dev Biol. 5(3): 363–376.
doi: 10.1002/wdev.226

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DionisioOctober 13, 2017 at 12:42 am

Embryonic mammalian craniofacial development is a complex process involving the growth, morphogenesis, and fusion of distinct facial prominences into a functional whole.

Gene expression profile data for mouse facial development
Author links open overlay panel Sonia M. Leach a, Weiguo Feng b, c, Trevor Williams
Data in Brief
Volume 13, Pages 242-247
DOI: https://doi.org/10.1016/j.dib.2017.05.003
ScienceDirect

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DionisioOctober 13, 2017 at 12:53 am

[…] different levels of expression and subsequent activation of Smad signaling differentially contribute each BMP type I receptor to BMP-Smad signaling and craniofacial development.

BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development
Author links open overlay panel Haichun Pan a, Honghao Zhang a, Ponnu Abraham a, Yoshihiro Komatsu a, c, Karen Lyons b, Vesa Kaartinen a, Yuji Mishina a
Developmental Biology
Volume 429, Issue 1, Pages 260-270

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DionisioOctober 13, 2017 at 1:07 am

Here’s an example of the fundamental evo-devo problem which has been formulated thus:

Dev(d) = Dev(a) + Delta(a,d)
Where
‘a’ is an ancestor biological system,
‘d’ is a descendant biological system,
Dev(x) is the entire developmental process of the biological system ‘x’
Delta(x,y) is the entire set of spatiotemporal changes required in Dev(x) in order to have Dev(y)

The apparent evolvability of the vertebrate head skeleton has allowed a diverse array of shapes, sizes, and compositions of the head in order to better adapt species to their environments. This encompasses feeding, breathing, sensing, and communicating: the head skeleton somehow participated in the evolution of all these critical processes for the last 500 million years. Through evolution, present head diversity was made possible via developmental modifications to the first head skeletal genetic program. Understanding the development of the vertebrate common ancestor’s head skeleton is thus an important step in identifying how different lineages have respectively achieved their many innovations in the head. To this end, cyclostomes (jawless vertebrates) are extremely useful, having diverged from jawed vertebrates approximately 400 million years ago, at the deepest node within living vertebrates. From this ancestral vantage point (that is, the node connecting cyclostomes and gnathostomes) we can best identify the earliest major differences in development between vertebrate classes, and start to address how these might translate onto morphology. In this review we survey what is currently known about the cell biology and gene expression during head development in modern vertebrates, allowing us to better characterize the developmental genetics driving head skeleton formation in the most recent common ancestor of all living vertebrates. By pairing this vertebrate composite with information from fossil chordates, we can also deduce how gene regulatory modules might have been arranged in the ancestral vertebrate head. Together, we can immediately begin to understand which aspects of head skeletal development are the most conserved, and which are divergent, informing us as to when the first differences appear during development, and thus which pathways or cell types might be involved in generating lineage specific shape and structure.

The origin and diversification of the developmental mechanisms that pattern the vertebrate head skeleton
Author links open overlay panel Tyler Square a, David Jandzik a, b, c, Marek Romášek a, c, Robert Cerny c, Daniel Meulemans Medeiros
Developmental Biology
Volume 427, Issue 2, Pages 219-229
DOI: https://doi.org/10.1016/j.ydbio.2016.11.014

Where’s the beef?

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DionisioOctober 13, 2017 at 3:16 pm

CS is the most abundant GAG in the CNS matrix.

Its diverse pattern of sulfation and epimerization pattern allows precise controls of various physiological processes including the proper development of the CNS and the maintenance of neuronal homeostasis.

[…] a better understanding of CS structure, their organization within the matrix, the mode of interaction with different types of proteins, are essential for targeting the important ECM component in the CNS.

Chondroitin sulfates and their binding molecules in the central nervous system.
Djerbal L1, Lortat-Jacob H2, Kwok J3.
Glycoconj J. 34(3):363-376.
doi: 10.1007/s10719-017-9761-z.

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DionisioOctober 14, 2017 at 5:24 am

The vertebrate inner ear is a precision sensory organ, acting as both a microphone to receive sound and an accelerometer to detect gravity and motion.

It consists of a series of interlinked, fluid-filled chambers containing patches of sensory epithelia, each with a specialised function.

The ear contains many different differentiated cell types with distinct morphologies, from the flask-shaped hair cells found in thickened sensory epithelium, to the thin squamous cells that contribute to non-sensory structures, such as the semicircular canal ducts.

Nearly all cell types of the inner ear, including the afferent neurons that innervate it, are derived from the otic placode, a region of cranial ectoderm that develops adjacent to the embryonic hindbrain.

As the ear develops, the otic epithelia grow, fold, fuse and rearrange to form the complex three-dimensional shape of the membranous labyrinth.

Sculpting the labyrinth: Morphogenesis of the developing inner ear
Author links open overlay panel Berta Alsina, Tanya T. Whitfield
DOI: https://doi.org/10.1016/j.semcdb.2016.09.015
Seminars in Cell & Developmental Biology
Volume 65, Pages 47-59

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DionisioOctober 14, 2017 at 8:03 am

In any study of organogenesis, it is important to gain an appreciation not only of the genetic control of patterning but also of the morphogenetic events that give rise to the three-dimensional form of the mature organ system.

Understanding the coupling of signalling pathways and transcription factor network activity to the cell behaviours and physical forces that effect these morphogenetic events is thus one of the major challenges in the field.

Sculpting the labyrinth: Morphogenesis of the developing inner ear
Author links open overlay panel Berta Alsina, Tanya T. Whitfield
DOI: https://doi.org/10.1016/j.semcdb.2016.09.015
Seminars in Cell & Developmental Biology
Volume 65, Pages 47-59

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DionisioOctober 16, 2017 at 1:14 am

We have omitted discussion of a number of other important processes, including formation of the endolymphatic duct and sac, establishment of the precise cytoarchitecture of the mammalian organ of Corti, the role of surrounding tissues (including hindbrain and periotic mesenchyme), and the morphogenesis of ancillary structures, each of which would justify a separate review in its own right.

Sculpting the labyrinth: Morphogenesis of the developing inner ear
Author links open overlay panel Berta Alsina, Tanya T. Whitfield
DOI: https://doi.org/10.1016/j.semcdb.2016.09.015
Seminars in Cell & Developmental Biology
Volume 65, Pages 47-59

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DionisioOctober 16, 2017 at 2:07 am

Human PrimPol is a primase belonging to the AEP superfamily with the unique ability to synthesize DNA primers de novo, and a non-processive DNA polymerase able to bypass certain DNA lesions.

PrimPol facilitates both mitochondrial and nuclear replication fork progression either acting as a conventional TLS polymerase, or repriming downstream of blocking lesions.

These new findings supports the existence of a functional PrimPol/RPA association that allows repriming at the exposed ssDNA regions formed in the leading strand upon replicase stalling.

Human PrimPol activity is enhanced by RPA
María I. Martínez-Jiménez, Antonio Lahera & Luis Blanco
Scientific Reports 7, Article number: 783 (2017)
doi:10.1038/s41598-017-00958-3

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DionisioOctober 16, 2017 at 6:11 am

DNA polymerases are the enzymes responsible for making and repairing the DNA to ensure cell viability.

Strikingly, although PrimPol recruitment to stalled forks seems to be mediated by RPA, it was proposed that RPA elicits an inhibitory effect on PrimPol activities in order to limit error-prone synthesis

Human PrimPol activity is enhanced by RPA
María I. Martínez-Jiménez, Antonio Lahera & Luis Blanco
Scientific Reports 7, Article number: 783 (2017)
doi:10.1038/s41598-017-00958-3

Did somebody say ‘Strikingly’?

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DionisioOctober 16, 2017 at 6:13 am

[…] it is likely that RPA binds the template strands used in our polymerases assays (14 and 49?nt, respectively) with a higher affinity than PrimPol.

It is also possible that the unwinding activity of RPA melts the primer, precluding PrimPol extension.

Human PrimPol activity is enhanced by RPA
María I. Martínez-Jiménez, Antonio Lahera & Luis Blanco
Scientific Reports 7, Article number: 783 (2017)
doi:10.1038/s41598-017-00958-3

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DionisioOctober 16, 2017 at 11:15 pm

The enhancement of PrimPol polymerase activity by RPA on a long ssDNA template may be due to different reasons […]

[…] PrimPol finds the opportunity to bind in proximity to the stalling site, probably by an specific interaction with RPA that reinforces its avidity for ssDNA, synthesizing a new primer to restart leading strand synthesis and re-establishing normal fork progression […]

Human PrimPol activity is enhanced by RPA
María I. Martínez-Jiménez, Antonio Lahera & Luis Blanco
Scientific Reports 7, Article number: 783 (2017)
doi:10.1038/s41598-017-00958-3

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DionisioOctober 16, 2017 at 11:23 pm

DNA damage tolerance (DDT) enables bypassing of DNA lesions during replication, thereby preventing fork stalling, replication stress, and secondary DNA damage related to fork stalling.

Three modes of DDT have been documented: translesion synthesis (TLS), template switching (TS), and repriming. TLS and TS depend on site-specific PCNA K164 monoubiquitination and polyubiquitination, respectively.

DNA damage tolerance in hematopoietic stem and progenitor cells in mice
Bas Pilzeckera,1, Olimpia Alessandra Buoninfantea,1, Paul van den Berka,1, Cesare Lancinib, Ji-Ying Songc, Elisabetta Citteriob, and Heinz Jacobs
PNAS vol. 114 no. 33 E6875–E6883,
doi: 10.1073/pnas.1706508114

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DionisioOctober 16, 2017 at 11:30 pm

Human PrimPol is a DNA primase/polymerase involved in DNA damage tolerance and prevents nuclear genome instability. PrimPol is also localized to the mitochondria, but its precise function in mitochondrial DNA maintenance has remained elusive.

PrimPol from human cell lines might be preferred for more complex studies including analysis of its interactions with various partner proteins.

Boldinova EO, Stojkovi? G, Khairullin R, Wanrooij S, Makarova AV (2017) Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol. PLoS ONE12(9): e0184489. https://doi.org/10.1371/journal.pone.0184489

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DionisioOctober 16, 2017 at 11:39 pm

Eukaryotic PrimPol is a recently discovered DNA-dependent DNA primase and translesion synthesis DNA polymerase found in the nucleus and mitochondria.

Although PrimPol has been shown to be required for repriming of stalled replication forks in the nucleus, its role in mitochondria has remained unresolved.

Our results not only help in the understanding of how mitochondria cope with replicative stress but can also explain some controversial features of the lagging-strand replication.

PrimPol is required for replication reinitiation after mtDNA damage
Rubén Torregrosa-Muñumera,1,
Josefin M. E. Forslundb,1,
Steffi Goffarta,
Annika Pfeifferb,
Gorazd Stojkovi?b,
Gustavo Carvalhoc,
Natalie Al-Furoukhb,
Luis Blancoc,
Sjoerd Wanrooijb,2,3, and
Jaakko L. O. Pohjoismäki
doi: 10.1073/pnas.1705367114
PNAS

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DionisioOctober 17, 2017 at 11:06 pm

During development, extracellular cues guiding cell fate determination are provided by morphogens.

One mechanism by which morphogens are proposed to traverse extracellular space is by traveling along specialized filopodia called cytonemes.

These cellular highways extend between signal-producing and -receiving cells to enable direct morphogen delivery.

Although genetic studies support cytoneme involvement in morphogen transport, mechanistic insight into how they are regulated is limited owing to technical challenges associated with performing cell biological analysis of the delicate filopodial structures.

A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport
William J. Bodeen, Suresh Marada, Ashley Truong, Stacey K. Ogden
Development 2017 144: 3612-3624;
doi: 10.1242/dev.152736

The authors of this paper should have consulted a biochemistry professor who a couple of years ago in this website claimed to know exactly how to cook the whole enchilada. 🙂

But they should have asked “honest questions” (whatever that means) lest he won’t share his secret recipe. 🙂

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DionisioOctober 17, 2017 at 11:11 pm

[…] Hedgehog and Dispatched colocalize in cytonemes […]

[…] cholesterol-modified Hedgehog acts through Dispatched to increase cytoneme occurrence.

[…] this occurs through Dispatched-mediated slowing of cytoneme retraction rates.

A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport
William J. Bodeen, Suresh Marada, Ashley Truong, Stacey K. Ogden
Development 2017 144: 3612-3624;
doi: 10.1242/dev.152736

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DionisioOctober 17, 2017 at 11:17 pm

During development, tissue patterning occurs as a consequence of morphogenetic signaling.

Morphogens are produced in and deployed from cells localized to discrete domains of developing tissues, and spread from their source to provide instructional cues to signal-receiving cells.

Morphogens signal short-range to adjacent cells, and long-range to targets situated at significant distances from the source (Tabata and Takei, 2004).

The exact processes facilitating morphogen transport and distribution are not yet fully established.

However, several models have been proposed, including free or hindered diffusion, transcytosis, exovesicle shuttling and direct delivery through specialized filopodia called cytonemes (Muller et al., 2013).

A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport
William J. Bodeen, Suresh Marada, Ashley Truong, Stacey K. Ogden
Development 2017 144: 3612-3624;
doi: 10.1242/dev.152736

The authors of this paper should have consulted a biochemistry professor who a couple of years ago in this website claimed to know exactly how to cook the whole enchilada. 🙂

But they should have asked “honest questions” (whatever that means) lest he won’t share his secret recipe. 🙂

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DionisioOctober 17, 2017 at 11:25 pm

Elucidation of the precise mechanism by which Disp expression alters cytoneme behavior to increase occurrence rates requires further study.

It is unlikely that Disp functions in isolation to modulate cytoneme behavior.

[…] multiple signals sent and received between neighboring cells probably converge to direct cytoneme function during tissue development.

Future mechanistic studies using cultured cell cytonemes will be directed at defining this biology, and identifying mechanisms by which Disp might help to integrate such signals and promote function of Hh-containing cytonemes.

A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport
William J. Bodeen, Suresh Marada, Ashley Truong, Stacey K. Ogden
Development 2017 144: 3612-3624;
doi: 10.1242/dev.152736

Work in progress… stay tuned.

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DionisioOctober 17, 2017 at 11:30 pm

Cell culture systems have the potential to accelerate studies addressing provocative questions about cytoneme biology, including how morphogens are gated into cytonemes, how cytoneme-localized proteins are appropriately trafficked within the structures, and how cytoneme directionality and length are controlled to assure morphogens reach their desired targets.

Answering such questions will be essential to advance our understanding of how morphogen gradients are generated and reinforced during tissue development.

A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport
William J. Bodeen, Suresh Marada, Ashley Truong, Stacey K. Ogden
Development 2017 144: 3612-3624;
doi: 10.1242/dev.152736

Work in progress… stay tuned.

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DionisioOctober 18, 2017 at 12:02 am

Morphogen concentration gradients that extend across developmental fields form by dispersion from source cells.

In the Drosophila wing disc, Hedgehog (Hh) produced by posterior compartment cells distributes in a concentration gradient to adjacent cells of the anterior compartment.

[…] in the wing disc, Hh distributions and signaling are dependent upon basal release and uptake, and on cytoneme-mediated movement.

Essential basal cytonemes take up Hedgehog in the Drosophila wing imaginal disc
Weitao Chen, Hai Huang, Ryo Hatori, Thomas B. Kornberg
Development 2017 144: 3134-3144;
doi: 10.1242/dev.149856

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DionisioOctober 18, 2017 at 5:21 am

Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation.

In addition, differential regulation of the DNA replication program during development can change gene copy number to influence cell size and gene expression.

The ability to identify ORC binding sites in a variety of differentiated cell types has revealed a high degree of tissue specificity of origin positioning within the genome.

Both the mechanism that dictates when origins become active and the biological significance of replication timing remain to be determined […]

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua and Terry L. Orr-Weaver
Genetics vol. 207 no. 1 29-47; https://doi.org/10.1534/genetics.115.186627

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DionisioOctober 19, 2017 at 1:11 am

A key future direction will be to decipher the chromatin configurations and chromosome conformation that designate origin and ORC positioning.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua and Terry L. Orr-Weaver
Genetics vol. 207 no. 1 29-47; https://doi.org/10.1534/genetics.115.186627

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DionisioOctober 19, 2017 at 1:24 am

The ability to track the activation of specific origins during gene amplification revealed at least three distinct mechanisms of origin activation, including the possibility of ORC-independent initiation.

Analyzing whether these mechanisms operate at origins during a canonical S phase and whether the other amplicon origins utilize additional activation mechanisms will be important.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua and Terry L. Orr-Weaver
Genetics vol. 207 no. 1 29-47; https://doi.org/10.1534/genetics.115.186627

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DionisioOctober 19, 2017 at 1:43 am

The tools in Drosophila will permit identification of the state of chromatin modifications and associated proteins at origins and correlation with origin activity as well as contacts between origins and other chromosomal sequences.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua and Terry L. Orr-Weaver
Genetics vol. 207 no. 1 29-47; https://doi.org/10.1534/genetics.115.186627

Work in progress… stay tuned.

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DionisioOctober 19, 2017 at 1:50 am

A crucial question to be solved is how genomic regions are established that lack ORC binding.

Another is whether genomic rearrangements resulting from underreplication serve biological functions.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua and Terry L. Orr-Weaver
Genetics vol. 207 no. 1 29-47; https://doi.org/10.1534/genetics.115.186627

Work in progress… stay tuned.

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DionisioOctober 19, 2017 at 1:53 am

Further insights into the tissue specificity of underreplicated domains and the mechanisms of their designation will be critical to our understanding of how chromatin configuration can affect the elongation phase of DNA replication.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua and Terry L. Orr-Weaver
Genetics vol. 207 no. 1 29-47; https://doi.org/10.1534/genetics.115.186627

Work in progress… stay tuned.

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DionisioOctober 19, 2017 at 2:21 am

Morphogens regulate tissue patterning through their distribution in concentration gradients.

Emerging research establishes a role for specialized signalling filopodia, or cytonemes, in morphogen dispersion and signalling.

Hedgehog (Hh) morphogen is transported via vesicles along cytonemes emanating from signal-producing cells to form a gradient in Drosophila epithelia.

However, the mechanisms for signal reception and transfer are still undefined.

Cytoneme-mediated cell-cell contacts for Hedgehog reception.
González-Méndez L1, Seijo-Barandiarán I1, Guerrero I1.
Elife. 6. pii: e24045.
doi: 10.7554/eLife.24045.

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DionisioOctober 20, 2017 at 10:38 pm

In eukaryotic cells, RNA binding proteins (RBPs) play critical roles in regulating almost every aspect of gene expression, often shuttling between the nucleus and the cytoplasm.

They are also key determinants in cell fate via controlling the target mRNAs under the regulation of various signaling pathways in response to environmental stresses.

Therefore, understanding the mechanisms that couple the location of mRNA and RBPs is a major challenge in the field of gene expression and signal responses.

Rae1-mediated nuclear export of Rnc1 is an important determinant in controlling MAPK signaling
Ryosuke Satoh, Kanako Hagihara, Reiko Sugiura
Curr Genet (2017). https://doi.org/10.1007/s00294-017-0732-5

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DionisioOctober 20, 2017 at 11:01 pm

Cell differentiation programs require dynamic regulation of gene expression.

During meiotic prophase in Saccharomyces cerevisiae, expression of the kinetochore complex subunit Ndc80 is downregulated by a 5′ extended long undecoded NDC80 transcript isoform.

Transcription from a distal NDC80 promoter directs Set1-dependent histone H3K4 dimethylation and Set2-dependent H3K36 trimethylation to establish a repressive chromatin state in the downstream canonical NDC80 promoter.

As a consequence, NDC80 expression is repressed during meiotic prophase.

The transcriptional mechanism described here is rapidly reversible, adaptable to fine-tune gene expression, and relies on Set2 and the Set3 histone deacetylase complex.

Thus, expression of a 5′ extended mRNA isoform causes transcriptional interference at the downstream promoter.

[…] this is an effective mechanism to promote dynamic changes in gene expression during cell differentiation.

Transcription of a 5′ extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter
Minghao Chia, Amy Tresenrider, Jingxun Chen, Gianpiero Spedale, Victoria Jorgensen, Elçin Ünal, Folkert Jacobus van Werven
eLife 2017;6:e27420
doi: 10.7554/eLife.27420

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DionisioOctober 21, 2017 at 3:21 am

Differentiation programs such as meiosis depend on extensive gene regulation to mediate cellular morphogenesis.

Meiosis requires transient removal of the outer kinetochore, the complex that connects microtubules to chromosomes.

How the meiotic gene expression program temporally restricts kinetochore function is unknown.

Kinetochore inactivation by expression of a repressive mRNA
Jingxun Chen, Amy Tresenrider, Minghao Chia, David T McSwiggen, Gianpiero Spedale, Victoria Jorgensen, Hanna Liao, Folkert Jacobus van Werven, Elcin Unal
eLife 2017;6:e27417
doi: 10.7554/eLife.27417

Did somebody say ‘programs’?

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DionisioOctober 21, 2017 at 3:24 am

We discovered that in budding yeast, kinetochore inactivation occurs by reducing the abundance of a limiting subunit, Ndc80.

Furthermore, we uncovered an integrated mechanism that acts at the transcriptional and translational level to repress NDC80 expression.

Central to this mechanism is the developmentally controlled transcription of an alternate NDC80 mRNA isoform, which itself cannot produce protein due to regulatory upstream ORFs in its extended 5′ leader.

Instead, transcription of this isoform represses the canonical NDC80 mRNA expression in cis, thereby inhibiting Ndc80 protein synthesis.

This model of gene regulation raises the intriguing notion that transcription of an mRNA, despite carrying a canonical coding sequence, can directly cause gene repression.

Kinetochore inactivation by expression of a repressive mRNA
Jingxun Chen, Amy Tresenrider, Minghao Chia, David T McSwiggen, Gianpiero Spedale, Victoria Jorgensen, Hanna Liao, Folkert Jacobus van Werven, Elcin Unal
eLife 2017;6:e27417
doi: 10.7554/eLife.27417

Did somebody say ‘intriguing’?

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DionisioOctober 21, 2017 at 5:54 am

GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding of GPCR conformational regulation by different ligands.

Yet there is no experimental evidence for how sidechain dynamics control allosteric transitions between GPCR conformations.

To address this deficit, we generated samples of a wild-type GPCR (A2AR) that are deuterated apart from (1)H/(13)C NMR probes at isoleucine ?1 methyl groups, which facilitated (1)H/(13)C methyl TROSY NMR measurements with opposing ligands.

Our data indicate that low [Na(+)] is required to allow large agonist-induced structural changes in A2AR, and that patterns of sidechain dynamics substantially differ between agonist (NECA) and inverse agonist (ZM241385) bound receptors, with the inverse agonist suppressing fast ps-ns timescale motions at the G protein binding site.

Our approach to GPCR NMR creates a framework for exploring how different regions of a receptor respond to different ligands or signaling proteins through modulation of fast ps-ns sidechain dynamics.

Ligand modulation of sidechain dynamics in a wild-type human GPCR
Lindsay D Clark, Igor Dikiy, Karen Chapman, Karin EJ Rödström, James Aramini, Michael V LeVine, George Khelashvili, Søren GF Rasmussen, Kevin H Gardner, Daniel M Rosenbaum
eLife 2017;6:e28505
doi: 10.7554/eLife.28505

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DionisioOctober 21, 2017 at 6:36 am

Almost every aspect of the human body – from our senses to our moods – depends, in one way or another, on a large family of proteins called G-protein-coupled receptors.

These receptor proteins, known as GPCRs for short, detect signals from outside the cell and trigger activity within the cell.

This allows cells to gather information from their surroundings and to communicate with each other.

Like all proteins, GPCRs are long chain-like molecules with a repetitive backbone and short branches called sidechains.

Each sidechain has its own chemical properties and electrical charge, which can affect how different parts of the chain interact with each other and what shape the protein can adopt.

Ligand modulation of sidechain dynamics in a wild-type human GPCR
Lindsay D Clark, Igor Dikiy, Karen Chapman, Karin EJ Rödström, James Aramini, Michael V LeVine, George Khelashvili, Søren GF Rasmussen, Kevin H Gardner, Daniel M Rosenbaum
eLife 2017;6:e28505
doi: 10.7554/eLife.28505

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DionisioOctober 21, 2017 at 6:41 am

Our understanding of the molecular underpinnings of GPCR function has been greatly advanced over the past two decades through a combination of X-ray crystal structures, computational simulations, and spectroscopic studies of protein dynamics.

How these diverse ligands activate signaling by a small number of G proteins and arrestins through a common structural scaffold remains a central problem for the GPCR field.

Ligand modulation of sidechain dynamics in a wild-type human GPCR
Lindsay D Clark, Igor Dikiy, Karen Chapman, Karin EJ Rödström, James Aramini, Michael V LeVine, George Khelashvili, Søren GF Rasmussen, Kevin H Gardner, Daniel M Rosenbaum
eLife 2017;6:e28505
doi: 10.7554/eLife.28505

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DionisioOctober 21, 2017 at 6:46 am

[…] ligand-activated GPCRs are weakly coupled allosteric systems in which multiple energetic inputs (i.e. agonist and G protein binding) are required to predominantly populate the active conformation.

[…] a set of loosely coupled microswitches connecting the orthosteric pocket and G protein binding site are activated by agonists in a non-concerted fashion, and stabilizing subsets of these rearrangements can lead to alternate overall conformations that have different signaling properties.

These data represent an important first step towards understanding how agonists can activate the fast motions of specific sidechains to facilitate conformational changes of a GPCR.

Ligand modulation of sidechain dynamics in a wild-type human GPCR
Lindsay D Clark, Igor Dikiy, Karen Chapman, Karin EJ Rödström, James Aramini, Michael V LeVine, George Khelashvili, Søren GF Rasmussen, Kevin H Gardner, Daniel M Rosenbaum
eLife 2017;6:e28505
doi: 10.7554/eLife.28505

Did somebody say “microswitches”?

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DionisioOctober 21, 2017 at 6:49 am

Sidechain dynamics represent an important functional component of protein behavior.

Changes in ? for other peaks in our dataset may provide further insights into the regulation of different regions of the receptor by ligands, depending on assignment of the other Ile residues in our spectra.

Ligand modulation of sidechain dynamics in a wild-type human GPCR
Lindsay D Clark, Igor Dikiy, Karen Chapman, Karin EJ Rödström, James Aramini, Michael V LeVine, George Khelashvili, Søren GF Rasmussen, Kevin H Gardner, Daniel M Rosenbaum
eLife 2017;6:e28505
doi: 10.7554/eLife.28505

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DionisioOctober 21, 2017 at 7:36 am

Bacteria frequently need to adapt to altered environmental conditions.

Adaptation requires changes in gene expression, often mediated by global regulators of transcription.

The nucleoid-associated protein H-NS is a key global regulator in Gram-negative bacteria and is believed to be a crucial player in bacterial chromatin organization via its DNA-bridging activity.

H-NS activity in vivo is modulated by physico-chemical factors (osmolarity, pH, temperature) and interaction partners.

Mechanistically, it is unclear how functional modulation of H-NS by such factors is achieved.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

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DionisioOctober 21, 2017 at 7:38 am

[…] a diverse spectrum of H-NS modulators alter the DNA-bridging activity of H-NS.

Changes in monovalent and divalent ion concentrations drive an abrupt switch between a bridging and non-bridging DNA-binding mode.

Similarly, synergistic and antagonistic co-regulators modulate the DNA-bridging efficiency.

Structural studies suggest a conserved mechanism: H-NS switches between a ‘closed’ and an ‘open’, bridging competent, conformation driven by environmental cues and interaction partners.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

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DionisioOctober 21, 2017 at 7:40 am

The genetic information every cell needs to work properly is encoded in molecules of DNA that are much longer than the cell itself.

A key challenge in biology is to understand how DNA is organized to fit inside each cell, whilst still providing access to the information that it contains.

Since the way DNA is organized can influence which genes are active, rearranging DNA plays an important role in controlling how cells behave.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

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DionisioOctober 21, 2017 at 7:42 am

[…] changes in the environment cause structural changes to H-NS, altering its ability to form DNA loops.

A previously unnoticed region of the protein acts as a switch to control these structural changes, and ultimately affects which genes are active in the cell.

These findings shed new light on how bacteria organize their DNA and the strategies they have developed to adapt to different environments.

The new protein region identified in H-NS may also be present in similar proteins found in other organisms.

In the future, this knowledge may ultimately help to develop new antibiotic drugs that target H-NS proteins in bacteria.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

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DionisioOctober 21, 2017 at 10:24 am

Molecular Dynamics (MD) simulations reveal that ions and interacting proteins directly alter H-NS structure from a ‘closed’ bridging incapable to an ‘open’ bridging capable conformation, thus providing a molecular understanding of the modulation of H-NS function.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

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DionisioOctober 21, 2017 at 10:26 am

What are the implications of our observations?

Our observations add to the large body of evidence showing that regulation of transcription via H-NS is complex, and that it does not proceed via a single, simple, well-defined mechanism.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

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DionisioOctober 21, 2017 at 10:29 am

What are the implications of our observations?

[…] different H-NS repressed genes are expected to be subject to different types of modulation, providing a key to a coordinated response in gene expression to altered conditions and selectivity for the interplay with specific co-regulators at specific target regions.

Mechanism of environmentally driven conformational changes that modulate H-NS DNA-bridging activity
Ramon A van der Valk, Jocelyne Vreede, Liang Qin, Geri F Moolenaar, Andreas Hofmann, Nora Goosen, Remus T Dame
Biophysics and Structural BiologyGenes and Chromosomes
eLife 2017;6:e27369
doi: 10.7554/eLife.27369

Did somebody say “coordinated”?

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DionisioOctober 22, 2017 at 3:09 pm

Bromodomain and Extra-terminal motif (BET) proteins play a central role in transcription regulation and chromatin signalling pathways.

Taken together, our results unveil a new role for Bdf1 –working independently from its predominant protein partners Bdf2 and the SWR1 complex–as a regulator of meiosis-specific genes.

Bdf1 Bromodomains Are Essential for Meiosis and the Expression of Meiotic-Specific Genes
Encar García-Oliver, Claire Ramus, Jonathan Perot, Marie Arlotto, Morgane Champleboux, Flore Mietton, Christophe Battail, Anne Boland, Jean-François Deleuze, Myriam Ferro, Yohann Couté, Jérôme Govin
PLOS Genetics
https://doi.org/10.1371/journal.pgen.1006541

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DionisioOctober 22, 2017 at 3:11 pm

Chromatin modifying proteins play a central role in transcription regulation and chromatin signalling.

[…] Bdf1 is a new regulator of the meiotic transcription program and of the expression of the master regulator NDT80.

Bdf1 Bromodomains Are Essential for Meiosis and the Expression of Meiotic-Specific Genes
Encar García-Oliver, Claire Ramus, Jonathan Perot, Marie Arlotto, Morgane Champleboux, Flore Mietton, Christophe Battail, Anne Boland, Jean-François Deleuze, Myriam Ferro, Yohann Couté, Jérôme Govin
PLOS Genetics
https://doi.org/10.1371/journal.pgen.1006541

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DionisioOctober 22, 2017 at 3:18 pm

Further studies will be required to explore its precise mode of action and whether these molecular mechanisms are conserved during the mammalian cell cycle in somatic cells and during meiosis and gamete differentiation.

Bdf1 Bromodomains Are Essential for Meiosis and the Expression of Meiotic-Specific Genes
Encar García-Oliver, Claire Ramus, Jonathan Perot, Marie Arlotto, Morgane Champleboux, Flore Mietton, Christophe Battail, Anne Boland, Jean-François Deleuze, Myriam Ferro, Yohann Couté, Jérôme Govin
PLOS Genetics
https://doi.org/10.1371/journal.pgen.1006541

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DionisioOctober 24, 2017 at 4:32 pm

Bacterial adaptation is accelerated by the acquisition of novel traits through horizontal gene transfer, but the integration of these genes affects genome organization.

[…] homologous recombination and horizontal gene transfer are tightly linked in genome evolution.

The chromosomal organization of horizontal gene transfer in bacteria
Pedro H. Oliveira, Marie Touchon, Jean Cury & Eduardo P. C. Rocha
Nature Communications 8, Article number: 841 (2017
doi:10.1038/s41467-017-00808-w
http://www.nature.com/articles.....0808-w.pdf
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DionisioOctober 24, 2017 at 4:51 pm

A rigorous statistical assessment of the ecological traits affecting the organization of HTgenes will require the analysis of a larger panel of species representative of the different prokaryotic lifestyles.

A rigorous statistical assessment of the ecological traits affecting the organization of HTgenes will require the analysis of a larger panel of species representative of the different prokaryotic lifestyles.

[…] our study focused on the dynamics of hotspots and how they contribute to genome diversification, but left unanswered the questions related to their origin and fate.

The chromosomal organization of horizontal gene transfer in bacteria
Pedro H. Oliveira, Marie Touchon, Jean Cury & Eduardo P. C. Rocha
Nature Communications 8, Article number: 841 (2017
doi:10.1038/s41467-017-00808-w
http://www.nature.com/articles.....0808-w.pdf
304

DionisioOctober 25, 2017 at 10:32 am

A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral embryonic axis of vertebrates and invertebrates.

The prevailing view in vertebrates for BMP gradient formation is through a counter-gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels.

Surprisingly, rather than supporting a counter-gradient mechanism, our analyses support a fourth model, a source-sink mechanism, which relies on a restricted BMP antagonist distribution acting as a sink that drives BMP flux dorsally and gradient formation.

We measured Bmp2 diffusion and found that it supports the source-sink model, suggesting a new mechanism to shape BMP gradients during development.

Systems biology derived source-sink mechanism of BMP gradient formation.
Zinski J1, Bu Y2, Wang X2, Dou W2, Umulis D2,3, Mullins MC
Elife. 2017 Aug 9;6. pii: e22199.
doi: 10.7554/eLife.22199.

a new mechanism? another one?

Did somebody say “Surprisingly”?

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DionisioOctober 25, 2017 at 10:35 am

Before an animal is born, a protein called BMP plays a key role in establishing the difference between the front and the back of the animal.

Cells nearer the front of the embryo contain higher amounts of the BMP protein, whilst cells nearer the back have progressively lower levels of BMP.

This gradient of BMP ‘concentration’ affects the identity of the cells, with the level of BMP in each cell dictating what parts of the body are made where.

Systems biology derived source-sink mechanism of BMP gradient formation.
Zinski J1, Bu Y2, Wang X2, Dou W2, Umulis D2,3, Mullins MC
Elife. 2017 Aug 9;6. pii: e22199.
doi: 10.7554/eLife.22199.

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DionisioOctober 25, 2017 at 10:39 am

Morphogen gradients pattern axonal pathways, the neural tube, the dorsal-ventral (DV) and anterior-posterior (AP) embryonic axes, as well as multiple organ systems […]

Morphogens are defined as factors that form a spatially non-uniform distribution spanning multiple cell-lengths that instructs different cell fates at distinct levels.

Their importance in specifying multiple cell fates in a gradient has spurred decades of research deciphering how they work.

[…] the mechanisms by which morphogen gradients are established are diverse and complex, and that understanding these mechanisms is paramount to understanding developmental biology […]

Systems biology derived source-sink mechanism of BMP gradient formation.
Zinski J1, Bu Y2, Wang X2, Dou W2, Umulis D2,3, Mullins MC
Elife. 2017 Aug 9;6. pii: e22199.
doi: 10.7554/eLife.22199.

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DionisioOctober 25, 2017 at 10:53 am

[…] the source-sink mechanism is more robust to changes in biophysical parameters than the counter-gradient mechanism […]

[…] the shape of the bmp expression domain contributes to BMP gradient formation even if it does not entirely account for it […]

[…] our studies here, intriguingly, suggest that an alternate source-sink mechanism may prevail.

Future studies will be required to definitively determine the mechanism and further test the source-sink and counter gradient models of BMP gradient formation.

Systems biology derived source-sink mechanism of BMP gradient formation.
Zinski J1, Bu Y2, Wang X2, Dou W2, Umulis D2,3, Mullins MC
Elife. 2017 Aug 9;6. pii: e22199.
doi: 10.7554/eLife.22199.

The authors of this research paper may want to consult someone who -at least momentarily- claimed -two years ago- to know exactly how morphogen gradients form. 🙂

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DionisioOctober 25, 2017 at 11:11 am

During vertebrate embryogenesis, dorsal-ventral patterning is controlled by the BMP/Chordin activator/inhibitor system.

BMP induces ventral fates, whereas Chordin inhibits BMP signaling on the dorsal side.

Several theories can explain how the distributions of BMP and Chordin are regulated to achieve patterning, but the assumptions regarding activator/inhibitor diffusion and stability differ between models.

Our findings challenge current self-regulating reaction-diffusion and shuttling models and provide support for a graded source-sink mechanism underlying zebrafish dorsal-ventral patterning.

Dynamics of BMP signaling and distribution during zebrafish dorsal-ventral patterning
Autumn P Pomreinke, Gary H Soh, Katherine W Rogers, Jennifer K Bergmann, Alexander J Bläßle, Patrick Müller
eLife 2017;6:e25861
doi: 10.7554/eLife.25861

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DionisioOctober 25, 2017 at 11:33 am

The dorsal-ventral axis is one of the earliest coordinate systems established during animal development and divides the embryo into dorsal (back) and ventral (belly) territories.

[…] the necessity of signal diffusion for developmental patterning has recently been challenged by several studies […]

It will be interesting to determine whether BMP diffusion is indeed required for proper patterning […]

Dynamics of BMP signaling and distribution during zebrafish dorsal-ventral patterning
Autumn P Pomreinke, Gary H Soh, Katherine W Rogers, Jennifer K Bergmann, Alexander J Bläßle, Patrick Müller
eLife 2017;6:e25861
doi: 10.7554/eLife.25861

Work in progress… stay tuned.

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DionisioOctober 28, 2017 at 11:37 am

The gene encoding the secreted protein Sonic hedgehog (Shh) is expressed in the polarizing region (or zone of polarizing activity), a small group of mesenchyme cells at the posterior margin of the vertebrate limb bud.

[…] Shh has the properties of the long sought after polarizing region morphogen that specifies positional values across the antero-posterior axis (e.g., thumb to little finger axis) of the limb.

[…] it remains unclear how antero-posterior positional values are encoded and then interpreted to give the particular structure appropriate to that position, for example, the type of digit.

Sonic Hedgehog Signaling in Limb Development.
Tickle C1, Towers M2
Front Cell Dev Biol. 5:14.
doi: 10.3389/fcell.2017.00014.

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DionisioOctober 28, 2017 at 11:42 am

[…] further studies are required to understand how positional values are specified by Shh signaling in mammals and lizards […]

Sonic Hedgehog Signaling in Limb Development.
Tickle C1, Towers M2
Front Cell Dev Biol. 5:14.
doi: 10.3389/fcell.2017.00014.

I thought they knew exactly how morphogen gradients are formed. I must have read the wrong memo. 🙂

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DionisioOctober 28, 2017 at 11:44 am

It is now established that Shh has a pivotal function in vertebrate limb development and many details have been uncovered.

Surprisingly however, there is still no consensus about how Shh specifies antero-posterior positional values in the limb.

It remains possible that different combinations of transcription factors govern antero-posterior positional values, but it has been difficult to identify them because all the digits are made up of the same differentiated cell types

Sonic Hedgehog Signaling in Limb Development.
Tickle C1, Towers M2
Front Cell Dev Biol. 5:14.
doi: 10.3389/fcell.2017.00014.

Did somebody say “surprisingly”? Why?

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DionisioOctober 28, 2017 at 11:50 am

[…] since the cells that give rise to all the other digits express Hoxd12 and Hoxd13, a simple Hox code is unlikely to specify the digits, and perhaps timing of expression is the important determinant.

Sonic Hedgehog Signaling in Limb Development.
Tickle C1, Towers M2
Front Cell Dev Biol. 5:14.
doi: 10.3389/fcell.2017.00014.

Did somebody say ‘timing’?

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DionisioOctober 28, 2017 at 11:52 am

Another challenge is to understand how the positional information conferred by Shh signaling is remembered and then interpreted so that digits with different identities arise in the proper places in the limb.

Sonic Hedgehog Signaling in Limb Development.
Tickle C1, Towers M2
Front Cell Dev Biol. 5:14.
doi: 10.3389/fcell.2017.00014.

Did somebody say ‘information remembered’?
Did somebody say ‘information interpreted’?

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DionisioOctober 28, 2017 at 11:58 am

It will be important to fill this gap in knowledge […]

An issue of general relevance is the mode of Shh transport in the limb and how a graded distribution of Shh is established.

[…] the timing of Shh expression is another critical parameter that still needs to be addressed.

Disentangling the relationship between autoregulatory mechanisms of intrinsic timing of Shh expression and extrinsic mechanisms could shed light on processes that ensure robustness of limb development and pattern scaling between different species.

Sonic Hedgehog Signaling in Limb Development.
Tickle C1, Towers M2
Front Cell Dev Biol. 5:14.
doi: 10.3389/fcell.2017.00014.

The more we know, more is there for us to learn.

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DionisioOctober 28, 2017 at 12:28 pm

[…] broader speculations will be made regarding what the antero-posterior patterning of chick limbs can tell us about the evolution of other digit patterns, including those that were found in the limbs of the earliest tetrapods.

[…] speculations will be made about how such a patterning mechanism could have arisen and then how it could have been subsequently adapted in different tetrapod lineages.

The difficulty lies in that mechanisms of limb evolution are only based on conjecture and that many parameters are likely to remain unknown.

The challenge is to establish new model species with diverse digit patterns in their limbs, in order to gain further insights into the mechanisms of antero-posterior patterning […]

[…] a major gap in our understanding resides in our lack of knowledge of the molecular mechanisms that result in the formation of particular type of digit in a particular position.

Evolution of antero-posterior patterning of the limb: insights from the chick.
Towers M
Genesis.
doi: 10.1002/dvg.23047.

Did somebody say ‘speculations ‘?

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DionisioOctober 28, 2017 at 4:26 pm

Nonhomologous end joining (NHEJ) must adapt to diverse end structures during repair of chromosome breaks.

Data presented here identify a much more sophisticated function.

DNA ligase IV guides end-processing choice during nonhomologous end joining
Michael P. Conlin,1,4 Dylan A. Reid,2,4 George W. Small,1 Howard H. Chang,3 Go Watanabe,3 Michael R. Lieber,3 Dale A. Ramsden,1,5 and Eli Rothenberg
Cell Rep.; 20(12): 2810–2819.
doi: 10.1016/j.celrep.2017.08.091

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rvb8October 28, 2017 at 11:01 pm

Dionisio, of to the races as of @1.

Write a book. No one will read it as your style lacks grace; “Compex fuctionally specified informational complexity.” Heh:)

Me thinks thou hast supped too much of the teat of Kairos; anon.
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DionisioOctober 29, 2017 at 4:23 am

DNA holds the cellular information essential for life, but is constantly being damaged.

To maintain genetic homeostasis, cells must continually repair DNA: a process that relies on the redundant information in the DNA double helix and efficient DNA damage signaling and repair (DR) processes known collectively as the DNA damage response (DDR).

What Combined Measurements From Structures and Imaging Tell Us About DNA Damage Responses
Chris A. Brosey,* Zamal Ahmed,* Susan P. Lees-Miller,†,1 and John A. Tanner
Methods Enzymol. 2017; 592: 417–455.
doi: 10.1016/bs.mie.2017.04.005

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DionisioOctober 29, 2017 at 11:03 am

Although biology is written at the level of sequences, we suggest that it is read in the context of dynamic molecular shapes and assemblies, particularly for the DDR.

There is much to learn about these NER complexes which are also providing new insights into possible charge transfer through DNA […]

There are also largely unexplored levels of interactions beyond the level of specific assemblies. It would be useful to follow DNA or protein conformations in reconstituted multiprotein DR pathways […]

[…] do unstructured regions allow long-range localizations of repair factors and is controlling these localizations one function of PTMs to these regions?

Perhaps, fluorescence methods plus X-ray scattering with X-ray tomography in cells (Hammel, Amlanjyoti, et al., 2016) will address this issue and help with other gaps in knowledge at the transition from nanoscale DDR complexes to mesoscale subcellular structures.

What Combined Measurements From Structures and Imaging Tell Us About DNA Damage Responses
Chris A. Brosey,* Zamal Ahmed,* Susan P. Lees-Miller,†,1 and John A. Tanner
Methods Enzymol. 2017; 592: 417–455.
doi: 10.1016/bs.mie.2017.04.005

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DionisioOctober 29, 2017 at 11:31 am

The bacterial cell wall is essential for survival, and proteins that participate in its biosynthesis have been the targets of antibiotic development efforts for decades.

The biosynthesis of its main component, the peptidoglycan, involves the coordinated action of proteins that are involved in multi-member complexes which are essential for cell division (the “divisome”) and/or cell wall elongation (the “elongasome”), in the case of rod-shaped cells.

Structural Insights into Protein-Protein Interactions Involved in Bacterial Cell Wall Biogenesis
Federica Laddomada, Mayara M. Miyachiro and Andréa Dessen
Antibiotics 5(2), 14;
doi:10.3390/antibiotics5020014

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DionisioOctober 29, 2017 at 2:13 pm

Peptidoglycan (PG) is a key component of the bacterial cell wall, and plays an important role in bacterial shape, as well as division and elongation processes.

In rod-shaped bacteria, the orchestration of cellular morphogenesis occurs in two phases: cell division, which generates two daughter cells, and elongation, where cellular growth occurs along the longitudinal axis of the cell.

Both phases require synthesis, modification, and recycling of PG.

Structural Insights into Protein-Protein Interactions Involved in Bacterial Cell Wall Biogenesis
Federica Laddomada, Mayara M. Miyachiro and Andréa Dessen
Antibiotics 5(2), 14;
doi:10.3390/antibiotics5020014

Did somebody say ‘orchestration’?

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DionisioOctober 29, 2017 at 2:26 pm

The sheer complexity of the bacterial cell wall biosynthetic pathway has created significant challenges for the characterization of proteins that are involved in the different aspects of the process.

[…] the near future should allow many more details of protein interactions involved in these complex machineries to come into view.

Structural Insights into Protein-Protein Interactions Involved in Bacterial Cell Wall Biogenesis
Federica Laddomada, Mayara M. Miyachiro and Andréa Dessen
Antibiotics 5(2), 14;
doi:10.3390/antibiotics5020014

Did somebody say ‘complexity’?

Did somebody say ‘complex machineries’?

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DionisioOctober 29, 2017 at 2:44 pm

Bacterial morphology is extremely diverse.

Specific shapes are the consequence of adaptive pressures optimizing bacterial fitness.

Shape affects critical biological functions, including nutrient acquisition, motility, dispersion, stress resistance and interactions with other organisms.

Determinants of Bacterial Morphology: From Fundamentals to Possibilities for Antimicrobial Targeting
Muriel C. F. van Teeseling1†, Miguel A. de Pedro2 and Felipe Cava1*
Front. Microbiol.,
https://doi.org/10.3389/fmicb.2017.01264

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DionisioOctober 29, 2017 at 3:02 pm

The characteristic morphology of a bacterial species is maintained through countless generations but is periodically modified within set limits during bacterial division and life cycles […]

Much more research is also needed to identify additional morphological determinants and molecular mechanisms underlying cell shape […]

[…] more research is needed on existing inhibitors.

Morphological determination continues to be an important field of fundamental research in which many open questions remain.

Determinants of Bacterial Morphology: From Fundamentals to Possibilities for Antimicrobial Targeting
Muriel C. F. van Teeseling1†, Miguel A. de Pedro2 and Felipe Cava1*
Front. Microbiol.,
https://doi.org/10.3389/fmicb.2017.01264

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DionisioOctober 30, 2017 at 3:50 am

In S. suis the ComX-inducing peptide (XIP) pheromone regulates ComR-dependent transcriptional activation of comX (or sigX) the regulator of the late competence regulon.

The genes associated with natural competence are widely distributed throughout the bacterial kingdom […]

[…] fluctuation in comX expression could be due to an oscillation of the positive and negative feedback loops controlling its transcription […]

[…] ComR is required for competence induction in S. suis […]

[…] ComR interacts with the mature ComS pheromone to induce comX and comS […]

Temporal Regulation of the Transformasome and Competence Development in Streptococcus suis
Edoardo Zaccaria, Michiel Wels, Peter van Baarlen and Jerry M. Wells
Front. Microbiol.,
DOI: https://doi.org/10.3389/fmicb.2016.01922

Did somebody say “oscillation of […] feedback loops”?
Is this about biology or electronic circuits?

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DionisioOctober 30, 2017 at 3:52 am

The operon SSU0038-45, comprises three putative membrane proteins, one CAAX amino terminal protease and two ABC transporters with ATPase activity.

OppA encoding the binding subunit of the general oligopeptide transporter was required for competence development suggesting it transports XIP into the bacteria where it binds to ComR.

The transient nature of competence development is assumed to avoid potentially adverse effects of genetic recombination on genome integrity during cell division and is associated with a suppression of basal metabolism […]

[…] further studies are needed to elucidate the mechanisms involved.

Temporal Regulation of the Transformasome and Competence Development in Streptococcus suis
Edoardo Zaccaria, Michiel Wels, Peter van Baarlen and Jerry M. Wells
Front. Microbiol.,
DOI: https://doi.org/10.3389/fmicb.2016.01922

Work in progress… stay tuned.

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DionisioOctober 30, 2017 at 4:09 am

Natural genetic transformation is a transient, rapidly progressing energy-consuming process characterized by expression of the transformasome and competence-associated regulatory genes.

This transient state is tightly controlled to avoid potentially adverse effects of genetic recombination on genome integrity during cell division.

[…] competence development is associated with a suppression of basal metabolism, which may have consequences for the microbe’s resilience to fluctuations in the environment, as competence is costly in terms of use of energy and protein translation.

[…] several basal metabolic pathways are incompatible with activation of competence in S. suis.

[…] targeting specific pathways during the development of competence, might render S. suis more vulnerable toward novel antibiotic therapies.

Zaccaria E, Wells JM, van Baarlen P (2016) Metabolic Context of the Competence-Induced Checkpoint for Cell Replication in Streptococcus suis. PLoS ONE11(5): e0153571. https://doi.org/10.1371/journal.pone.0153571

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DionisioOctober 30, 2017 at 4:21 am

Natural genetic transformation is associated with internalization and chromosomal recombination of exogenous DNA with the genome, enabling bacteria to obtain new genetic traits that may improve fitness in changing environmental conditions, including those involving avoidance of host immune defences.

Zaccaria E, Wells JM, van Baarlen P (2016) Metabolic Context of the Competence-Induced Checkpoint for Cell Replication in Streptococcus suis. PLoS ONE11(5): e0153571. https://doi.org/10.1371/journal.pone.0153571

Reshuffling existing functionality?

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DionisioOctober 30, 2017 at 5:16 am

[…] induction of competence and energy depletion might render bacteria more vulnerable to antimicrobial therapy and the host immune defences.

[…] upon competence activation, S. suis is characterised by an unfavourable energy balance and not well suited to control its redox balance since key antioxidant genes as thioredoxin and superoxide dismutase are hardly expressed during the competence state.

[…] it is possible that competent bacteria are more susceptible to reactive oxygen species which are produced by neutrophils and macrophages following bacterial contact.

[…] it might be of interest to investigate if induction of competence of S. suis could render the bacteria less virulent during infection.

Blocking essential pathways, rather than blocking individual genes, might decrease the incidence of resistance, since chances of developing resistance in all the pathway genes, at the same time keeping the pathway functional, are low.

Zaccaria E, Wells JM, van Baarlen P (2016) Metabolic Context of the Competence-Induced Checkpoint for Cell Replication in Streptococcus suis. PLoS ONE11(5): e0153571. https://doi.org/10.1371/journal.pone.0153571

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DionisioOctober 30, 2017 at 11:57 am

Functional tags are extremely valuable tools.

Currently, the use of the methods summarized here allows the determination of expression and the functional manipulation of ?2500 individual genes based on available fly strains.

This number is likely to significantly increase in the near future as both CRIMIC, FlyFos, and FlyORF stocks are being created.

Gene Tagging Strategies To Assess Protein Expression, Localization, and Function in Drosophila.
Kanca O1,2, Bellen HJ3,2,4,5,6, Schnorrer F7
Genetics. 207(2):389-412.
doi: 10.1534/genetics.117.199968.
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DionisioOctober 30, 2017 at 12:03 pm

The Dpp morphogen gradient derived from the anterior stripe of cells is thought to control growth and patterning of the Drosophila wing disc.

However, the spatial-temporal requirement of dpp for growth and patterning remained largely unknown.

[…] growth control by the Dpp morphogen gradient remains under debate.

[…] the dpp stripe source is indeed required for wing disc growth, also during third instar larval stages.

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc.
Matsuda S1, Affolter M1
Elife. ;6. pii: e22319.
doi: 10.7554/eLife.22319.

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DionisioOctober 30, 2017 at 12:06 pm

From the wings of a butterfly to the fingers of a human hand, living tissues often have complex and intricate patterns.

Developmental biologists have long been fascinated by the signals – called morphogens – that guide how these kinds of pattern develop.

Morphogens are substances that are produced by groups of cells and spread to the rest of the tissue to form a gradient.

Depending on where they sit along this gradient, cells in the tissue activate different sets of genes, and the resulting pattern of gene activity ultimately defines the position of the different parts of the tissue.

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc.
Matsuda S1, Affolter M1
Elife. ;6. pii: e22319.
doi: 10.7554/eLife.22319.

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DionisioOctober 30, 2017 at 12:07 pm

Further work will be needed to explain how the Dpp signal regulates the growth of the wing.

The answer to this question will contribute to a better understanding of the role of morphogens in regulating the size of human organs […]

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc.
Matsuda S1, Affolter M1
Elife. ;6. pii: e22319.
doi: 10.7554/eLife.22319.

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DionisioOctober 30, 2017 at 12:20 pm

Morphogens are thought to disperse and form concentration gradients to control tissue patterning and growth […]

decapentagplegic (dpp), a homologue of vertebrate bone morphogenetic protein 2/4 (BMP2/4), is expressed in a stripe of cells in the anterior compartment along the anterior-posterior compartmental boundary of the wing imaginal disc.

From this source, Dpp protein is thought to spread and form a concentration gradient to control patterning and growth of the wing imaginal disc […]

[…] a not-yet identified anterior dpp source outside the stripe of cells is required for wing disc growth […]

[…] the anterior dpp stripe is critical for growth as well as patterning of the wing imaginal disc.

[…] it remains an open question whether the requirement of the dpp stripe on wing disc growth changes over time.

Dpp from the anterior stripe of cells is crucial for the growth of the Drosophila wing disc.
Matsuda S1, Affolter M1
Elife. ;6. pii: e22319.
doi: 10.7554/eLife.22319.

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DionisioOctober 30, 2017 at 12:24 pm

Dpp, a member of the BMP family, is a morphogen that specifies positional information in Drosophila wing precursors.

In this tissue, Dpp expressed along the anterior-posterior boundary forms a concentration gradient that controls the expression domains of target genes, which in turn specify the position of wing veins.

Dpp also promotes growth in this tissue.

The relationship between the spatio-temporal profile of Dpp signalling and growth has been the subject of debate […]

[…] the stripe of Dpp ensures that signalling remains above a pro-growth threshold, while at the same time generating a gradient that patterns cell fates.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action
Pablo Sanchez Bosch,1,† Ruta Ziukaite,2,† Cyrille Alexandre,2,† Konrad Basler,1 and Jean-Paul Vincent
eLife. 6: e22546.
doi: 10.7554/eLife.22546

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DionisioOctober 30, 2017 at 12:31 pm

It remains to be determined how the two processes – growth and patterning – are coordinated to ensure the reproducible formation of the adult wing.

Dpp controls growth and patterning in Drosophila wing precursors through distinct modes of action
Pablo Sanchez Bosch,1,† Ruta Ziukaite,2,† Cyrille Alexandre,2,† Konrad Basler,1 and Jean-Paul Vincent
eLife. 6: e22546.
doi: 10.7554/eLife.22546

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DionisioOctober 31, 2017 at 1:49 am

The range of biological outcomes generated by many signalling proteins in development and homeostasis is increased by their interactions with glycosaminoglycans, particularly heparan sulfate (HS).

This interaction controls the localization and movement of these signalling proteins, but whether such control depends on the specificity of the interactions is not known.

[…] the specificity of the interactions of proteins with glycosaminoglycans controls their binding and diffusion. Moreover, cells regulate the spatial distribution of different protein-binding sites in glycosaminoglycans independently of each other, implying that the extracellular matrix has long-range structure.

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix.
Sun C1, Marcello M2, Li Y1, Mason D2, Lévy R1, Fernig DG
Open Biol. 6(3). pii: 150277.
doi: 10.1098/rsob.150277.

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DionisioOctober 31, 2017 at 1:58 am

[…] protein-binding sites in HS (and chondroitin sulfate/dermatan sulfate for FGF10) of pericellular matrix are not homogeneously distributed.

A number of different mechanisms are likely to regulate the distribution of these binding sites, including the biosynthesis of the HS chains, the localization of core proteins in membrane microdomains and the interactions of the polysaccharide chains with endogenous HS-binding proteins.

The high multiplicity of interactions, both between proteins and polysaccharide and between the polysaccharide-binding proteins themselves [4] (reviewed in [1,2]), is likely to produce a dynamic network of interlinked molecules.

[…] although extracellular matrix in cartilage is specialized, in other tissues, an analogous situation may exist, where pericellular, extracellular and basement membrane matrices may exhibit different types of supramolecular structure and consequently have different functions.

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix.
Sun C1, Marcello M2, Li Y1, Mason D2, Lévy R1, Fernig DG
Open Biol. 6(3). pii: 150277.
doi: 10.1098/rsob.150277.

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DionisioOctober 31, 2017 at 5:34 am

Human plasma kallikrein-kinin system proteins are related to inflammation through bradykinin.

In the proximity of its target cells, high molecular weight kininogen (H-kininogen) is the substrate of plasma kallikrein, which releases bradykinin from H-kininogen.

Heparan sulfate proteoglycans (HSPGs) play a critical role in either recruiting kinin precursors from the plasma, or in the assembly of kallikrein-kinin system components on the cell surface.

Modulation of the Plasma Kallikrein-Kinin System Proteins Performed by Heparan Sulfate Proteoglycans.
Motta G1, Tersariol ILS
Front Physiol. 8:481.
doi: 10.3389/fphys.2017.00481.

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DionisioOctober 31, 2017 at 8:26 am

Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche.

Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion.

However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

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DionisioOctober 31, 2017 at 8:28 am

[…] the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion.

Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix.

In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes.

However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

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DionisioOctober 31, 2017 at 8:30 am

The transport of morphogens within the renal stem/progenitor cell niche was in the past more simplified described than it really seems to be […]

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

Why? Based on what?

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DionisioOctober 31, 2017 at 8:33 am

[…] more morphological details about illustrated tunneling nanotubes, extension at the contact site, molecular construction, colocalization with other proteins and individual transport features within the renal niche wait to be generated.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

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DionisioOctober 31, 2017 at 8:35 am

[…] it is also imaginable that all involved morphogens and independently from their biophysical properties are comfortably transported via tunneling nanotubes.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

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DionisioOctober 31, 2017 at 8:39 am

Theoretically and independent from mentioned routes, transport of morphogens may also occur by vesicles such as exosomes (40–100?nm) or microvesicles (100–1000?nm).

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

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DionisioOctober 31, 2017 at 8:42 am

Previously it was assumed that mesenchymal and epithelial cells in the renal stem/progenitor cell niche have an intimate contact and that the reciprocal transport of morphogens during induction of a nephron is based exclusively on diffusion.

However, recent morphological findings illustrate that mesenchymal and epithelial cell bodies are separated by a striking interface consisting of textural extracellular matrix.

Further on, projections of mesenchymal cells cross the interface to establish an intercellular communication with epithelial cells via tunneling nanotubes.

Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.
Minuth WW1, Denk L
Biores Open Access. 5(1):49-60.
doi: 10.1089/biores.2015.0039

Wrong assumption?

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DionisioOctober 31, 2017 at 11:20 pm

A key protein involved in the segregation of meiotic chromosomes is produced ‘just in time’ by the regulated expression of two mRNA isoforms.

A transcriptional switch controls meiosis.
Hildreth AE, Arndt KM
Elife. ;6. pii: e31911.
doi: 10.7554/eLife.31911

Did somebody say ‘just in time’?

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DionisioOctober 31, 2017 at 11:26 pm

To grow and develop properly, cells must control the timing of critical events.

This means that the proteins that drive these events need to be active at specific times and, in many cases, this is achieved by precisely regulating when the genes that encode these proteins are transcribed.

A transcriptional switch controls meiosis.
Hildreth AE, Arndt KM
Elife. ;6. pii: e31911.
doi: 10.7554/eLife.31911

Did somebody say ‘control the timing’?

Did somebody say ‘precisely regulating’?

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DionisioOctober 31, 2017 at 11:32 pm

Meiosis is the specialized form of cell division that produces new cells with half as many chromosomes as the parent cell.

This process must be precise because too many or too few chromosomes in the new cells can lead to problems.

A transcriptional switch controls meiosis.
Hildreth AE, Arndt KM
Elife. ;6. pii: e31911.
doi: 10.7554/eLife.31911

Did somebody say ‘precise’?

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DionisioOctober 31, 2017 at 11:52 pm

[…] observations raise the question of how cells eliminate the existing pools of Ndc80 as they enter prophase in meiosis.

Future studies will now need to determine if and how protein degradation contributes to rapid depletion of Ndc80.

A transcriptional switch controls meiosis.
Hildreth AE, Arndt KM
Elife. ;6. pii: e31911.
doi: 10.7554/eLife.31911

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DionisioOctober 31, 2017 at 11:53 pm

A goal for the future will be to characterize the expression of these genes, which might confirm that interfering with transcription and translation are general regulatory trends in the tuning of gene expression during meiosis.

A transcriptional switch controls meiosis.
Hildreth AE, Arndt KM
Elife. ;6. pii: e31911.
doi: 10.7554/eLife.31911

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DionisioNovember 1, 2017 at 12:07 am

Chromosomes reorganize in early meiotic prophase to form the so-called telomere bouquet.

[…] the intrinsic negative charge of Rap1 is important for forming interactions with its binding partners.

Thus, Rap1 is able to retain bouquet formation under heavily phosphorylated status.

Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation
Hanna Amelina, Shaan Subramaniam, Vera Moiseeva, Christine Anne Armstrong, Siân Rosanna Pearson and Kazunori Tomita
BMC Biology 13:37
https://doi.org/10.1186/s12915-015-0149-x

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DionisioNovember 1, 2017 at 12:10 am

Telomeres are specialized nucleoprotein structures that form the natural ends of linear chromosomes.

While telomeres are mostly known for their essential function in chromosome maintenance, they also play an important role in meiotic progression […]

[…] the molecular mechanisms that govern dissociation of telomeres from the SPB remain elusive.

Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation
Hanna Amelina, Shaan Subramaniam, Vera Moiseeva, Christine Anne Armstrong, Siân Rosanna Pearson and Kazunori Tomita
BMC Biology 13:37
https://doi.org/10.1186/s12915-015-0149-x

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DionisioNovember 1, 2017 at 12:14 am

[…] rap1-5D and rap1-5E mutants do not have any sporulation defects [15], which suggests that the bouquet is intact.

This is surprising since the Rap1-Bqt4 interaction is required for telomere clustering in meiosis [8], and raises the possibility that telomeres remain associated with Bqt4 and the SPB via different mechanisms.

Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation
Hanna Amelina, Shaan Subramaniam, Vera Moiseeva, Christine Anne Armstrong, Siân Rosanna Pearson and Kazunori Tomita
BMC Biology 13:37
https://doi.org/10.1186/s12915-015-0149-x

Did somebody say ‘surprising’?

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DionisioNovember 1, 2017 at 12:29 am

The role of the conserved meiotic telomere bouquet has been enigmatic for over a century.

Surprisingly, bouquet-deficient meiocytes with functional spindles harbour chromosomes that fail to achieve spindle attachment.

These results reveal an unanticipated level of control of centromeres by telomeres.

The telomere bouquet regulates meiotic centromere assembly.
Klutstein M, Fennell A, Fernández-Álvarez A, Cooper JP.
Nat Cell Biol. 17(4):458-69.
doi: 10.1038/ncb3132.

Did somebody say ‘Surprisingly’?

Did somebody say ‘unanticipated level of control’?

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DionisioNovember 1, 2017 at 8:39 am

The mammalian nuclear division cycle is coordinated with nuclear envelope breakdown (NEBD), in which the entire nuclear envelope (NE) is dissolved to allow chromosomes to access their segregation vehicle, the spindle.

In other eukaryotes, complete NEBD is replaced by localized disassembly or remodeling of the NE.

[…] the molecular mechanisms controlling NE disassembly are incompletely understood, coordinated cycles of modification of specific NE components drive breakdown.

Chromosomes Orchestrate Their Own Liberation: Nuclear Envelope Disassembly
Alfonso Fernández-Álvarez 1, Julia Promisel Cooper
Volume 27, Issue 4, Pages 255-265
Trends in Cell Biology

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DionisioNovember 1, 2017 at 9:51 am

Despite its ubiquity in interphase eukaryotic nuclei, the functional significance of the RabI configuration, in which interphase centromeres are clustered at the nuclear envelope (NE) near the centrosome and telomeres localize at the opposite end of the nucleus, has remained mysterious.

The functionally elusive RabI chromosome configuration directly regulates nuclear membrane remodeling at mitotic onset
Alfonso Fernández-Álvarez & Julia Promisel Cooper
Journal Cell Cycle ?
Volume 16, 2017 – Issue 15, Pages 1392-1396
http://dx.doi.org/10.1080/15384101.2017.1338986

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DionisioNovember 1, 2017 at 2:29 pm

The centromere is a critical genomic region that enables faithful chromosome segregation during mitosis, and must be distinguishable from other genomic regions to facilitate establishment of the kinetochore.

The centromere-specific histone H3-variant CENP-A forms a special nucleosome that functions as a marker for centromere specification.

In addition to the CENP-A nucleosomes, there are additional H3 nucleosomes that have been identified in centromeres, both of which are predicted to exhibit specific features.

It is likely that the composite organization of CENP-A and H3 nucleosomes contributes to the formation of centromere-specific chromatin, termed ‘centrochromatin’.

Recent studies suggest that centrochromatin has specific histone modifications that mediate centromere specification and kinetochore assembly.

Critical histone post-translational modifications for centromere function and propagation
Tatsuo Fukagawa
Journal Cell Cycle ?
Volume 16, 2017 – Issue 13
http://dx.doi.org/10.1080/15384101.2017.1325044

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DionisioNovember 1, 2017 at 2:48 pm

Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation.

In addition, differential regulation of the DNA replication program during development can change gene copy number to influence cell size and gene expression.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua1 and Terry L. Orr-Weaver
Genetics. 207(1): 29–47.
doi: 10.1534/genetics.115.186627

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DionisioNovember 1, 2017 at 2:52 pm

Before cell division, the genome must be completely and accurately replicated to maintain the integrity of genetic information across cell generations.

[…] it is clear that the mechanisms that regulate origin activity and replication fork progression are diverse and complex, particularly in the context of development.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua1 and Terry L. Orr-Weaver
Genetics. 207(1): 29–47.
doi: 10.1534/genetics.115.186627

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DionisioNovember 1, 2017 at 2:58 pm

DNA replication initiation requires the sequential recruitment and activation of a large number of replication protein components.

Despite the conservation of the proteins governing initiation of DNA replication in eukaryotes, there are complexities in the control of metazoan DNA replication.

At the most fundamental level, it remains to be determined what dictates a replication origin and where ORC will bind in metazoans […]

[…] how developmental signals modulate the activity of replication origins and forks remains to be elucidated.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua1 and Terry L. Orr-Weaver
Genetics. 207(1): 29–47.
doi: 10.1534/genetics.115.186627

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DionisioNovember 1, 2017 at 3:04 pm

Both the mechanism that dictates when origins become active and the biological significance of replication timing remain to be determined […]

A crucial question to be solved is how genomic regions are established that lack ORC binding.

Another is whether genomic rearrangements resulting from underreplication serve biological functions.

Further insights into the tissue specificity of underreplicated domains and the mechanisms of their designation will be critical to our understanding of how chromatin configuration can affect the elongation phase of DNA replication.

DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression
Brian L. Hua1 and Terry L. Orr-Weaver
Genetics. 207(1): 29–47.
doi: 10.1534/genetics.115.186627

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DionisioNovember 1, 2017 at 11:37 pm

Microtubule-organizing centers (MTOCs), known as centrosomes in animals and spindle pole bodies (SPBs) in fungi, are important for the faithful distribution of chromosomes between daughter cells during mitosis as well as for other cellular functions.

The cytoplasmic duplication cycle and regulation of the Schizosaccharomyces pombe SPB is analogous to centrosomes, making it an ideal model to study MTOC assembly.

Molecular model of fission yeast centrosome assembly determined by superresolution imaging.
Bestul AJ1, Yu Z1, Unruh JR1, Jaspersen S
J Cell Biol. 216(8):2409-2424.
doi: 10.1083/jcb.201701041.

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DionisioNovember 1, 2017 at 11:44 pm

The fission yeast scaffold molecule Sid4 anchors the septum initiation network to the spindle pole body (SPB, centrosome equivalent) to control mitotic exit events.

A second SPB-associated scaffold, Cut12, promotes SPB-associated Cdk1–cyclin B to drive mitotic commitment.

[…] signals from Sid4 contribute to the Cut12 mitotic commitment switch.

Such integration of signals emanating from neighboring scaffolds shows how centrosomes/SPBs can integrate inputs from multiple pathways to control cell fate.

Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment.
Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4.
J Cell Biol. 216(9):2795-2812.
doi: 10.1083/jcb.201702172.

Did somebody say ‘dialogue’?

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DionisioNovember 1, 2017 at 11:50 pm

In some systems, engagement of Polo feedback control influences the rate of mitotic commitment, whereas in others, Polo activity sets its timing […]

[…] the incorporation of the DNA replication checkpoint kinase Chk2Cds1 offers further potential for signals emanating from Sid4 to integrate inputs from replication/repair pathways into cell cycle control as reported for DNA checkpoint control by human centrosome components […]

Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment.
Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4.
J Cell Biol. 216(9):2795-2812.
doi: 10.1083/jcb.201702172.

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DionisioNovember 1, 2017 at 11:57 pm

This dialog between two independent scaffolds reinforces the robustness of the mitotic switch.

The concept of dialog between scaffolding proteins on the SPB addresses the longstanding question as to why mitotic entry and exit should be regulated from the spindle pole.

Centrosomal scaffold dialog can integrate inputs from diverse signaling networks with a limited number of neighboring molecules in order to generate a single coherent output that can then be amplified throughout the cell.

Alongside centrosomal signaling in cell cycle and DNA checkpoint controls, the overriding impact of the spindle assembly checkpoint signal emanating from a single kinetochore provides another example of the dramatic impact that coordinated singling from a single center can have […]

Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment.
Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4.
J Cell Biol. 216(9):2795-2812.
doi: 10.1083/jcb.201702172.

Did somebody say ‘dialogue’?
Did somebody say ‘coherent’?

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DionisioNovember 2, 2017 at 12:04 am

[…] further studies will reveal similar networks in mitotic controls in other systems as both CK1? and Chk2 are recruited to human centrosomes […]

[…] it remains to be established whether it is this centrosomal pool of CK1? that mediates these controls.

Such extensive similarities between fission yeast and human centrosomal CK1?/Chk2/Aurora A/Polo signaling define some simple dependency relationships that can be probed in higher systems to unravel the complex usage of the spindle pole as a hub at which to coordinate signaling events that determine cell fate.

Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment.
Chan KY1, Alonso-Nuñez M2, Grallert A2, Tanaka K2, Connolly Y3, Smith DL3, Hagan IM4.
J Cell Biol. 216(9):2795-2812.
doi: 10.1083/jcb.201702172.

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DionisioNovember 2, 2017 at 12:08 am

The spindle pole body (SPB) of budding yeast duplicates once per cell cycle.

In G1, the satellite, an SPB precursor, assembles next to the mother SPB (mSPB) on the cytoplasmic side of the nuclear envelope (NE).

How the growing satellite subsequently inserts into the NE is an open question.

Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes.
Rüthnick D1, Neuner A1, Dietrich F1, Kirrmaier D1, Engel U2, Knop M1, Schiebel E3.
J Cell Biol. 216(8):2425-2442.
doi: 10.1083/jcb.201612129

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DionisioNovember 2, 2017 at 12:20 am

[…] the bridge structure that separates the mSPB from the satellite is a distance holder that prevents deleterious fusion of both structures.

Binding of the ?-tubulin receptor Spc110 to the central plaque from within the nucleus is important for NE insertion of the new SPB.

[…] a nuclear pore complex associates with the duplicating SPB and helps to insert the SPB into the NE.

After SPB insertion, membrane-associated proteins including the conserved Ndc1 encircle the SPB and retain it within the NE.

Thus, uncoupling SPB growth from NE insertion unmasks functions of the duplication machinery.

Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes.
Rüthnick D1, Neuner A1, Dietrich F1, Kirrmaier D1, Engel U2, Knop M1, Schiebel E3.
J Cell Biol. 216(8):2425-2442.
doi: 10.1083/jcb.201612129

Did somebody say ‘machinery’?

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DionisioNovember 2, 2017 at 12:33 am

Centrosomes, or spindle pole bodies (SPBs) in yeast, are vital mechanical hubs that maintain load-bearing attachments to microtubules during mitotic spindle assembly, spindle positioning, and chromosome segregation.

However, the strength of microtubule-centrosome attachments is unknown, and the possibility that mechanical force might regulate centrosome function has scarcely been explored.

[…] calmodulin binding contributes to SPB mechanical integrity […]

[…] the very high strength of SPB-microtubule attachments may be important for spindle integrity in mitotic cells so that tensile forces generated at kinetochores do not cause microtubule detachment and delamination at SPBs.

Direct measurement of the strength of microtubule attachment to yeast centrosomes.
Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL
Mol Biol Cell. 28(14):1853-1861.
doi: 10.1091/mbc.E17-01-0034

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DionisioNovember 2, 2017 at 12:41 am

The centrosome is the microtubule-organizing center of the cell, responsible for nucleation of microtubules and organization of the bipolar mitotic spindle.

Centrosomes serve as mechanical hubs, subjected to force from interpolar microtubules […], kinetochore microtubules […], and astral microtubules […]

[…] the mechanical strength of centrosome–microtubule attachments is unknown, and the role of mechanical signals at centrosomes remains unclear.

The complexity and dynamics of pericentriolar material make it difficult to understand how forces are transmitted through the mammalian centrosome structure.

Direct measurement of the strength of microtubule attachment to yeast centrosomes.
Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL
Mol Biol Cell. 28(14):1853-1861.
doi: 10.1091/mbc.E17-01-0034

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DionisioNovember 2, 2017 at 12:49 am

The strength of SPB–microtubule attachment is very high, exceeding the strength of attachment between kinetochores and growing microtubule plus ends by approximately fourfold.

[…] this strong anchorage to SPBs might be important for spindle integrity in mitotic cells […]

[…] microtubule attachment strength depends on the tethering molecule, Spc110, and calmodulin.

[…] these mammalian proteins might also contribute mechanical strength to minus-end attachments at mammalian centrosomes.

Direct measurement of the strength of microtubule attachment to yeast centrosomes.
Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL
Mol Biol Cell. 28(14):1853-1861.
doi: 10.1091/mbc.E17-01-0034

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DionisioNovember 2, 2017 at 12:52 am

We anticipate that our in vitro mechanical approach to studying SPB–microtubule attachments will allow further dissection of the molecular basis for their very high strength.

Our work should also guide efforts to study the centrosomes of other eukaryotes and facilitate direct tests for whether forces control phosphoregulation or other signaling events at SPBs.

Direct measurement of the strength of microtubule attachment to yeast centrosomes.
Fong KK1, Sarangapani KK2, Yusko EC2, Riffle M1, Llauró A2, Graczyk B1, Davis TN1, Asbury CL
Mol Biol Cell. 28(14):1853-1861.
doi: 10.1091/mbc.E17-01-0034

There yet?

Work in progress… stay tuned.

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DionisioNovember 2, 2017 at 2:53 am

Faithful genome propagation requires coordination between nuclear envelope (NE) breakdown, spindle formation, and chromosomal events.

[…] interphase chromosome-LINC contacts constitute a cell-cycle control device linking nucleoplasmic and cytoplasmic events.

Mitotic Nuclear Envelope Breakdown and Spindle Nucleation Are Controlled by Interphase Contacts between Centromeres and the Nuclear Envelope.
Fernández-Álvarez A1, Bez C2, O’Toole ET3, Morphew M3, Cooper JP4
Dev Cell. 39(5):544-559.
doi: 10.1016/j.devcel.2016.10.021

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DionisioNovember 2, 2017 at 3:06 am

During meiosis, chromosomes undergo a homology search in order to locate their homolog to form stable pairs and exchange genetic material.

Early in prophase, chromosomes associate in mostly non-homologous pairs, tethered only at their centromeres.

This phenomenon, conserved through higher eukaryotes, is termed centromere coupling in budding yeast.

Both initiation of recombination and the presence of homologs are dispensable for centromere coupling (occurring in spo11 mutants and haploids induced to undergo meiosis) but the presence of the synaptonemal complex (SC) protein Zip1 is required.

The nature and mechanism of coupling have yet to be elucidated.

Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern.
Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M
PLoS Genet. 12(10):e1006347.
doi: 10.1371/journal.pgen.1006347.

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DionisioNovember 2, 2017 at 3:29 am

[…] a chromosome size preference for centromere coupling helps establish efficient homolog recognition.

Meiosis enables sexual reproduction in eukaryotes by producing gametes.

In the process, it increases genetic diversity through recombination of homologous chromosomes from the parents.

Prior to finding their unique pairing partner (homolog), chromosomes associate non-homologously with other chromosomes through their centromeres, a process termed centromere coupling.

Little is known about the nature and mechanism of centromere coupling.

Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern.
Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M
PLoS Genet. 12(10):e1006347.
doi: 10.1371/journal.pgen.1006347.

Reshuffling existing genetic/epigenetic information?

Embedded Variability Framework (EVF)?

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DionisioNovember 2, 2017 at 3:53 am

Processes in meiosis are geared to recombine homologous chromosomes to both increase genetic diversity, and segregate them efficiently thus producing viable gametes for sexual reproduction.

Homologous pairing and recombination between chromosomes favor the formation of stable pairs [2, 3], which are secured by the proteinaceous synaptonemal complex (SC), containing ZMM proteins such as Zip1 [4].

Two dynamic homology-independent events precede homolog pairing: the meiotic bouquet and non-homologous centromere coupling.

[…] centromere coupling, with its preference for chromosomes of similar size, helps chromosomes find their homolog.

Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern.
Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M
PLoS Genet. 12(10):e1006347.
doi: 10.1371/journal.pgen.1006347.

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DionisioNovember 2, 2017 at 4:39 am

The role of centromere coupling remains unknown.

Identification of additional functional requirements for centromere coupling will likely provide more clues into its role in early meiosis.

Multiple Pairwise Analysis of Non-homologous Centromere Coupling Reveals Preferential Chromosome Size-Dependent Interactions and a Role for Bouquet Formation in Establishing the Interaction Pattern.
Lefrançois P, Rockmill B, Xie P, Roeder GS, Snyder M
PLoS Genet. 12(10):e1006347.
doi: 10.1371/journal.pgen.1006347.

There yet?

Work in progress… stay tuned.

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DionisioNovember 2, 2017 at 5:17 am

In meiosis I, chromosomes become paired with their homologous partners and then are pulled toward opposite poles of the spindle.

In the budding yeast, Saccharomyces cerevisiae, in early meiotic prophase, centromeres are observed to associate in pairs in a homology-independent manner; a process called centromere coupling.

Later, as homologous chromosomes align, their centromeres associate in a process called centromere pairing.

The synaptonemal complex protein Zip1 is necessary for both types of centromere association.

[…] centromere pairing, which was previously shown to be necessary to ensure disjunction of achiasmate chromosomes, is not sufficient for ensuring their disjunction.

Meiotic Centromere Coupling and Pairing Function by Two Separate Mechanisms in Saccharomyces cerevisiae.
Kurdzo EL, Obeso D, Chuong H, Dawson DS
Genetics. 205(2):657-671.
doi: 10.1534/genetics.116.190264

Necessary but not sufficient?

Complex functionally specified informational complexity
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DionisioNovember 2, 2017 at 9:19 am

During meiotic prophase, telomeres cluster, forming the bouquet chromosome arrangement, and facilitate homologous chromosome pairing.

In fission yeast, bouquet formation requires switching of telomere and centromere positions.

Centromeres are located at the spindle pole body (SPB) during mitotic interphase, and upon entering meiosis, telomeres cluster at the SPB, followed by centromere detachment from the SPB.

Telomere clustering depends on the formation of the microtubule-organizing center at telomeres by the linker of nucleoskeleton and cytoskeleton complex (LINC), while centromere detachment depends on disassembly of kinetochores, which induces meiotic centromere formation.

However, how the switching of telomere and centromere positions occurs during bouquet formation is not fully understood.

A Taz1- and Microtubule-Dependent Regulatory Relationship between Telomere and Centromere Positions in Bouquet Formation Secures Proper Meiotic Divisions.
Katsumata K1, Hirayasu A1, Miyoshi J2, Nishi E1, Ichikawa K1, Tateho K1, Wakuda A2, Matsuhara H3, Yamamoto A
PLoS Genet. 12(9):e1006304.
doi: 10.1371/journal.pgen.1006304.

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DionisioNovember 2, 2017 at 9:30 am

These findings establish novel regulatory mechanisms, which prevent concurrent detachment of telomeres and centromeres from the SPB during bouquet formation and secure proper meiotic divisions.

Our findings reveal a hitherto unknown regulatory relationship between meiotic telomere and centromere positions in bouquet formation, which secures proper meiotic divisions.

A Taz1- and Microtubule-Dependent Regulatory Relationship between Telomere and Centromere Positions in Bouquet Formation Secures Proper Meiotic Divisions.
Katsumata K1, Hirayasu A1, Miyoshi J2, Nishi E1, Ichikawa K1, Tateho K1, Wakuda A2, Matsuhara H3, Yamamoto A
PLoS Genet. 12(9):e1006304.
doi: 10.1371/journal.pgen.1006304.

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DionisioNovember 2, 2017 at 9:38 am

The bouquet arrangement is highly conserved among eukaryotes [6, 7], and how it is formed and what functions it has are important questions in the field of meiosis.

[…] conservation of the regulatory mechanisms is currently unclear […]

[…] our findings may also be relevant for understanding the chromosome positioning-dependent mechanisms that regulate development and differentiation of other organisms.

A Taz1- and Microtubule-Dependent Regulatory Relationship between Telomere and Centromere Positions in Bouquet Formation Secures Proper Meiotic Divisions.
Katsumata K1, Hirayasu A1, Miyoshi J2, Nishi E1, Ichikawa K1, Tateho K1, Wakuda A2, Matsuhara H3, Yamamoto A
PLoS Genet. 12(9):e1006304.
doi: 10.1371/journal.pgen.1006304.

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DionisioNovember 3, 2017 at 2:57 pm

Transcription of a 5’ extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter
Minghao Chia, Amy Tresenrider, Jingxun Chen, Gianpiero Spedale, Victoria Jorgensen, Elçin Ünal, Folkert Jacobus van Werven
DOI: 10.7554/eLife.27420
eLife

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DionisioNovember 3, 2017 at 10:44 pm

In multicellular organisms, a stringent control of the transition between cell division and differentiation is crucial for correct tissue and organ development.

In the Arabidopsis root, the boundary between dividing and differentiating cells is positioned by the antagonistic interaction of the hormones auxin and cytokinin.

Cytokinin affects polar auxin transport, but how this impacts the positional information required to establish this tissue boundary, is still unknown.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

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DionisioNovember 3, 2017 at 10:50 pm

[…] boundary formation is dependent on cytokinin’s control on auxin polar transport and degradation.

The regulation of both processes shapes the auxin profile in a well-defined auxin minimum.

This auxin minimum positions the boundary between dividing and differentiating cells, acting as a trigger for this developmental transition, thus controlling meristem size.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

Complex functionally specified informational complexity
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DionisioNovember 3, 2017 at 11:03 pm

The maintenance of boundaries between neighboring groups of distinct cell types is vital during development of multicellular organisms, as groups of cells with distinct functions must be kept physically separated to guarantee correct control of organ and body growth and function.

[…] a well-defined and tightly controlled minimum of the hormone auxin acts as a signal to establish the position of the transition zone by controlling the developmental switch from cell division to cell differentiation.

[…] another hormone, cytokinin, controls and positions this auxin minimum, thus regulating root size.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

How is citokinin controlled?

Complex functionally specified informational complexity
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DionisioNovember 3, 2017 at 11:19 pm

Understanding how boundaries are maintained during organ growth is a fundamental question in developmental biology.

[…] auxin minimum acts as a positional signal that triggers the developmental switch from cell division to cell differentiation.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

Complex functionally specified informational complexity
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DionisioNovember 3, 2017 at 11:22 pm

The peculiar feature of this auxin minimum consists in having the lowest auxin level (dip) within each tissue aligned in a cell row.

This alignment of dips ensures the coordinated activity of the cells where the dip occurs, so that these cells will switch together to the differentiation program thus preserving the root structure and zonation.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

Did somebody say ‘coordinated’?

Did somebody say ‘program’?

Complex functionally specified informational complexity
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DionisioNovember 3, 2017 at 11:25 pm

It should be pointed out that the consistent correspondence between cytokinin-driven auxin minimum formation and root zonation reveals that auxin patterning guides the localization and stabilization of the TZ in a self-organizing manner where cytokinin may operate along with other inputs […]

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

Do they mean that this is not the end of the story?

Complex functionally specified informational complexity
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DionisioNovember 3, 2017 at 11:29 pm

Future challenge will be to understand how the position of the auxin minimum correlates with the programmed cell death of the LRC and how these two inputs are coordinated to control the dynamic of root growth and the entire root system organization.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

Complex functionally specified informational complexity
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DionisioNovember 3, 2017 at 11:42 pm

[…] it may be insightful to reconsider morphogenetic gradient theory in terms of context-dependent profile features, such as minima with an inherent curvature, instead of absolute thresholds only.

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
Di Mambro R1, De Ruvo M1,2,3, Pacifici E1, Salvi E1, Sozzani R4, Benfey PN5,6, Busch W7, Novak O8, Ljung K8, Di Paola L2, Marée AFM3, Costantino P1, Grieneisen VA9, Sabatini S10,11.
Proc Natl Acad Sci U S A. 114(36):E7641-E7649.
doi: 10.1073/pnas.1705833114.
http://www.pnas.org/content/114/36/E7641.full

Did somebody say “reconsider morphogenetic gradient theory” in 2017?

Didn’t a distinguished biochemistry professor claim two years ago, here in this website, that all is known about morphogen gradient formation?

Why reconsider it now?

Complex functionally specified informational complexity
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DionisioNovember 4, 2017 at 4:05 pm

Biogenesis of mammalian red blood cells requires nuclear expulsion by orthochromatic erythoblasts late in terminal differentiation (enucleation), but the mechanism is largely unexplained.

This novel structure, the “enucleosome,” may mediate common cytoskeletal mechanisms underlying erythroblast enucleation, notwithstanding the morphological heterogeneity of enucleation across species.

Tropomodulin 1 controls erythroblast enucleation via regulation of F-actin in the enucleosome.
Nowak RB1, Papoin J2, Gokhin DS1, Casu C3, Rivella S3, Lipton JM2,4,5, Blanc L2,4,5, Fowler VM1
Blood. 130(9):1144-1155.
doi: 10.1182/blood-2017-05-787051.

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DionisioNovember 4, 2017 at 4:20 pm

Transcription factors such as KLF1, along with epigenetic modifiers, play crucial roles in establishing the proper onset and progression of terminal differentiation events.

[…] the orthochromatic erythroblast stage is a critical nodal point for many of the effects on enucleation.

Orchestration of late events in erythropoiesis by KLF1/EKLF.
Gnanapragasam MN1, Bieker JJ.
Curr Opin Hematol. 24(3):183-190.
doi: 10.1097/MOH.0000000000000327

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DionisioNovember 4, 2017 at 4:52 pm

Erythroid enucleation is the process by which the future red blood cell disposes of its nucleus prior to entering the blood stream.

This key event during red blood cell development has been likened to an asymmetric cell division (ACD), by which the enucleating erythroblast divides into two very different daughter cells of alternate molecular composition, a nucleated cell that will be removed by associated macrophages, and the reticulocyte that will mature to the definitive erythrocyte.

Together our results put into question a role for cell polarity and asymmetric cell division in erythroid enucleation.

The Asymmetric Cell Division Regulators Par3, Scribble and Pins/Gpsm2 Are Not Essential for Erythroid Development or Enucleation.
Wölwer CB1,2, Gödde N1,2, Pase LB1, Elsum IA1, Lim KY2, Sacirbegovic F3,4, Walkley CR5,6, Ellis S3,4, Ohno S7, Matsuzaki F8, Russell SM4,9,10, Humbert PO1,2,4,9,11.
PLoS One. 12(1):e0170295.
doi: 10.1371/journal.pone.0170295

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DionisioNovember 4, 2017 at 4:56 pm

Erythroid enucleation embodies many features of an asymmetric cell division[1–10] and results in the generation of two unique daughter cells: the pyrenocyte containing the condensed nucleus and the anucleated reticulocyte that will further mature into the erythrocyte found in the peripheral blood.

The Asymmetric Cell Division Regulators Par3, Scribble and Pins/Gpsm2 Are Not Essential for Erythroid Development or Enucleation.
Wölwer CB1,2, Gödde N1,2, Pase LB1, Elsum IA1, Lim KY2, Sacirbegovic F3,4, Walkley CR5,6, Ellis S3,4, Ohno S7, Matsuzaki F8, Russell SM4,9,10, Humbert PO1,2,4,9,11.
PLoS One. 12(1):e0170295.
doi: 10.1371/journal.pone.0170295

Complex functionally specified informational complexity
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DionisioNovember 4, 2017 at 5:09 pm

The factors that control HSPC fate decision remain unclear.

[…] our data reveal what may be a novel function for TGF-? in HSC self-renewal activity as fate determinant to modulate HSC activity.

p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation
Ashwini Hinge,1 Juying Xu,1 Jose Javier,1 Eucabeth Mose,1 Sachin Kumar,1 Reuben Kapur,2 Edward F. Srour,2 Punam Malik,1 Bruce J. Aronow,3 and Marie-Dominique Filippi
Nat Commun. 2017; 8: 14382.
doi: 10.1038/ncomms14382

Complex functionally specified informational complexity
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DionisioNovember 5, 2017 at 11:20 pm

NODAL/Activin signaling orchestrates key processes during embryonic development via SMAD2.

How SMAD2 activates programs of gene expression that are modulated over time however, is not known.

Thus SMAD2 binding does not linearly equate with transcriptional kinetics […]

[…] SMAD2 recruits multiple co-factors during sustained signaling to shape the downstream transcriptional program.

Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling.
Coda DM1, Gaarenstroom T1, East P2, Patel H2, Miller DS1, Lobley A2, Matthews N3, Stewart A2, Hill CS1
Elife.;6. pii: e22474.
doi: 10.7554/eLife.22474.

Did somebody say ‘orchestrates’?
Did somebody say ‘programs’?

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 12:20 am

To allow a complex animal to develop from a small bundle of cells, the cells need to be able to communicate with each other to coordinate their activities.

[…] it is not clear how the detection of these signals at the surface of the cell leads to changes in the activity of genes inside the nucleus.

Two transforming growth factor beta signals called Activin and NODAL cause a transcription factor known as SMAD2 to move into the nucleus where it can alter gene activity.

[…] future experiments will investigate which other proteins help SMAD2 to change gene activity at later times.

Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling.
Coda DM1, Gaarenstroom T1, East P2, Patel H2, Miller DS1, Lobley A2, Matthews N3, Stewart A2, Hill CS1
Elife.;6. pii: e22474.
doi: 10.7554/eLife.22474.

Did somebody say ‘communicate’?
Did somebody say ‘coordinate’?

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 12:31 am

Patterning of tissues during embryonic development depends on the control of gene expression by extracellular signals.

The signaling molecules involved frequently act as morphogens to impart positional information […]

[…] we know little about the sequence of events that occur from TF binding to the induction of dynamic programs of gene expression.

We go on to define the sequence of events that occur from SMAD2 binding to transcriptional activation, and the mechanisms underlying them.

Our work establishes new paradigms for signal-dependent transcriptional regulation.

Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling.
Coda DM1, Gaarenstroom T1, East P2, Patel H2, Miller DS1, Lobley A2, Matthews N3, Stewart A2, Hill CS1
Elife.;6. pii: e22474.
doi: 10.7554/eLife.22474.

Did somebody say ‘new paradigms’?

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 1:16 am

[…] there is no single generic mechanism of SMAD2-mediated transcription, but rather it is gene specific and can occur in an acute or delayed fashion and can be activatory or repressive.

The initial transcriptional profile is modulated at later time points as a result of both delayed SMAD2 binding, and subsequent binding of repressors to already occupied SBSs.

Future work will aim to identify TFs and enzymes that collaborate with the SMADS to modulate the transcriptional response over time, allowing cells to correctly execute gene expression programs in response to TGF-? superfamily signaling.

Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling.
Coda DM1, Gaarenstroom T1, East P2, Patel H2, Miller DS1, Lobley A2, Matthews N3, Stewart A2, Hill CS1
Elife.;6. pii: e22474.
doi: 10.7554/eLife.22474.

Work in progress… stay tuned.

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 1:40 am

[…] the mechanism by which Shh patterns the limb, how it acts to instruct digit ‘identity’, nevertheless remains an enigma.

This review focuses on what has been learned about Shh function in the limb and the outstanding puzzles that remain to be solved.

John Saunders’ ZPA, Sonic hedgehog and digit identity – How does it really all work?
Zhu J1, Mackem S
Dev Biol. 429(2):391-400.
doi: 10.1016/j.ydbio.2017.02.001.

Did somebody say ‘instruct’?

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 3:13 am

Vertebrate limb development relies on the activity of signaling centers that promote growth and control patterning along three orthogonal axes of the limb bud.

The apical ectodermal ridge, at the distal rim of the limb bud ectoderm, produces WNT and FGF signals, which promote limb bud growth and progressive distalization.

The zone of polarizing activity, a discrete postero-distal mesenchymal domain, produces SHH, which stimulates growth and organizes patterning along the antero-posterior axis.

The dorsal and ventral ectoderms produce, respectively, WNT7A and BMPs, which induce dorso-ventral limb fates.

Interestingly, these signaling centers and the mechanisms they instruct interact with each other to coordinate events along the three axes.

Coordination of limb development by crosstalk among axial patterning pathways
Irene Delgado, Miguel Torres
ScienceDirect / Developmental Biology
Volume 429, Issue 2, Pages 382-386
https://doi.org/10.1016/j.ydbio.2017.03.006

Did somebody say ‘coordinate’?

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 4:05 am

Critical steps in forming the vertebrate limb include the positioning of digits and the positioning of joints within each digit.

Recent studies have proposed that the iterative series of digits is established by a Turing-like mechanism generating stripes of chondrogenic domains.

However, re-examination of available data suggest that digits are actually patterned as evenly spaced spots, not stripes, which then elongate into rod-shaped digit rays by incorporating new cells at their tips.

Moreover, extension of the digit rays and the patterning of the joints occur simultaneously at the distal tip, implying that an integrated model is required to fully understand these processes.

On the Formation of Digits and Joints during Limb Development
Tom W. Hiscock, Patrick Tschopp, Clifford J. Tabin
Volume 41, Issue 5, p459–465
Developmental Cell
DOI: http://dx.doi.org/10.1016/j.devcel.2017.04.021

A Turing-like mechanism doesn’t seem to explain the observed facts?

an integrated model is required to fully understand these processes?

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 7:16 am

Gut microbes can shape responses to cancer immunotherapy

Studies find that species diversity and antibiotics influence cutting-edge treatments.

http://www.nature.com/news/gut.....py-1.22938
406

DionisioNovember 6, 2017 at 11:54 am

Stem cells self-renew but also give rise to daughter cells that are committed to lineage-specific differentiation.

To achieve this remarkable task, they can undergo an intrinsically asymmetric cell division whereby they segregate cell fate determinants into only one of the two daughter cells.

Alternatively, they can orient their division plane so that only one of the two daughter cells maintains contact with the niche and stem cell identity.

Although the molecules involved are highly conserved in vertebrates, the way they act is tissue specific and sometimes very different from invertebrates.

Mechanisms of Asymmetric Stem Cell Division
Juergen A. Knoblich
DOI: http://dx.doi.org/10.1016/j.cell.2008.02.007
Cell
Volume 132, Issue 4, p583–597

Complex functionally specified informational complexity
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DionisioNovember 6, 2017 at 3:45 pm

Both oriented cell divisions and cell rearrangements are critical for proper embryogenesis and organogenesis.

However, little is known about how these two cellular events are integrated.

Our work provides new insights into the mechanisms generating appropriate tissue architecture of limb skeleton.

Planar cell polarity signaling coordinates oriented cell division and cell rearrangement in clonally expanding growth plate cartilage
Yuwei Li, Ang Li, Jason Junge, Marianne Bronner
eLife 2017;6:e23279
doi: 10.7554/eLife.23279

Complex functionally specified informational complexity
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DionisioNovember 7, 2017 at 10:24 am

The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood.

[…] cleavage furrow ingression initiates by contraction of an equatorial actin network with randomly oriented filaments.

The network subsequently gradually reoriented actin filaments along the cell equator.

[…] during cytokinesis progression, mechanical tension increased substantially along the direction of the cell equator, while the network contracted laterally along the pole-to-pole axis without a detectable increase in tension.

[…] an asymmetric increase in cortical tension promotes filament reorientation along the cytokinetic cleavage furrow, which might have implications for diverse other biological processes involving actomyosin rings.

Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments
Felix Spira, Sara Cuylen-Haering, Shalin Mehta, Matthias Samwer, Anne Reversat, Amitabh Verma, Rudolf Oldenbourg, Michael Sixt, Daniel W Gerlich
eLife 2017;6:e30867
doi: 10.7554/eLife.30867

Complex functionally specified informational complexity
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DionisioNovember 7, 2017 at 12:28 pm

A central question in modern biology is how cells build a complex tissue within a four dimensional (xyz and t) context.

This is particularly true in developing embryos, in which cells undergo intricate behaviors including proliferation, migration and differentiation, while interacting with similar as well as distinct cell types.

Two fundamental cellular processes, oriented cell divisions and cell rearrangements, play important roles during tissue growth […]

Planar cell polarity signaling coordinates oriented cell division and cell rearrangement in clonally expanding growth plate cartilage
Yuwei Li, Ang Li, Jason Junge, Marianne Bronner
eLife 2017;6:e23279
doi: 10.7554/eLife.23279

Complex functionally specified informational complexity
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DionisioNovember 7, 2017 at 12:48 pm

[…] clonally related chondrocytes become arranged in either single or multi-columns along the axis of tissue elongation.

These columnar morphologies are generated through two types of cell behaviors: cell pivoting resulting in single columns or cell intercalation resulting in complex columns.

The PCP pathway coordinates cell pivoting following mediolateral division.

In this way, chondrocytes increase their cell numbers while concomitantly undergoing stereotypical arrangements that result in tissue elongation.

[…] this highlights the importance of PCP signaling in shaping tissues via regulating polarized cell behaviors.

Planar cell polarity signaling coordinates oriented cell division and cell rearrangement in clonally expanding growth plate cartilage
Yuwei Li, Ang Li, Jason Junge, Marianne Bronner
eLife 2017;6:e23279
doi: 10.7554/eLife.23279

Complex functionally specified informational complexity
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DionisioNovember 7, 2017 at 12:55 pm

Afadin plays an essential role in regulating apical-basal polarity and adherens junction integrity of radial glial cells, and suggest that epithelial architecture plays an important role in radial glial identity by regulating mitotic orientation and preventing premature exit from the neurogenic niche.

Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia
Jennifer Rakotomamonjy, Molly Brunner, Christoph Jüschke, Keling Zang, Eric J. Huang, Louis F. Reichardt, Anjen Chen
Neural Dev (2017) 12: 7.
https://doi.org/10.1186/s13064-017-0085-2

Complex functionally specified informational complexity
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DionisioNovember 7, 2017 at 12:59 pm

[…] the regulation of asymmetric and symmetric cell divisions plays a fundamental role in the generation of cell diversity in the developing cortex […]

By orienting the angle of mitotic cleavage, cleavage furrows could segregate determinants symmetrically or asymmetrically to produce equal or unequal daughter cells […]

Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia
Jennifer Rakotomamonjy, Molly Brunner, Christoph Jüschke, Keling Zang, Eric J. Huang, Louis F. Reichardt, Anjen Chen
Neural Dev (2017) 12: 7.
https://doi.org/10.1186/s13064-017-0085-2

Complex functionally specified informational complexity
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DionisioNovember 7, 2017 at 11:58 pm

[…] Afadin regulates apical-basal polarity, adherens junctions, and mitotic spindle orientation in radial glial cells in the developing cerebral cortex.

[…] Afadin regulates mitotic division orientation of radial glial cells.

The relationships between Afadin, epithelial cell polarity, adherens junctions, and mitotic spindle orientation are complex.

Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia
Jennifer Rakotomamonjy, Molly Brunner, Christoph Jüschke, Keling Zang, Eric J. Huang, Louis F. Reichardt, Anjen Chen
Neural Dev (2017) 12: 7.
https://doi.org/10.1186/s13064-017-0085-2

Complex functionally specified informational complexity
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DionisioNovember 8, 2017 at 12:20 am

Developmental remodeling of the sensory epithelium of the cochlea is required for the formation of an elongated, tonotopically organized auditory organ, but the cellular processes that mediate these events are largely unknown.

[…] the cochlea extends through a combination of radial intercalation and cell growth.

[…] concomitant cellular intercalation results in a brief period of epithelial convergence, although subsequent changes in cell size lead to medial-lateral spreading.

Cell migration, intercalation and growth regulate mammalian cochlear extension
Elizabeth Carroll Driver, Amy Northrop, Matthew W. Kelley
Development 2017 144: 3766-3776;
doi: 10.1242/dev.151761

Complex functionally specified informational complexity
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DionisioNovember 8, 2017 at 12:22 am

Supporting cells, which retain contact with the basement membrane, exhibit biased protrusive activity and directed movement along the axis of extension.

By contrast, hair cells lose contact with the basement membrane, but contribute to continued outgrowth through increased cell size.

Regulation of cellular protrusions, movement and intercalation within the cochlea all require myosin II.

These results establish, for the first time, many of the cellular processes that drive the distribution of sensory cells along the tonotopic axis of the cochlea.

Cell migration, intercalation and growth regulate mammalian cochlear extension
Elizabeth Carroll Driver, Amy Northrop, Matthew W. Kelley
Development 2017 144: 3766-3776;
doi: 10.1242/dev.151761

Complex functionally specified informational complexity
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DionisioNovember 8, 2017 at 12:35 am

Development of the central nervous system requires orchestration of morphogenetic processes which drive elevation and apposition of the neural folds and their fusion into a neural tube.

Our results pinpoint a novel role of hmmr in anterior neural development and support the notion that RI is a major driving force for anterior neurulation and forebrain morphogenesis.

hmmr mediates anterior neural tube closure and morphogenesis in the frog Xenopus
Angela Prager, Cathrin Hagenlocher, Tim Ott, Alexandra Schambony, Kerstin Feistel
Developmental Biology
Volume 430, Issue 1, 1 October 2017, Pages 188–201

Did somebody say ‘orchestration’?

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DionisioNovember 8, 2017 at 12:40 am

Neurulation is the process in which a flat neural plate generates folds that elevate, converge medially and fuse in the midline, creating a closed neural tube.

Rostrally, the neural tube will go on to differentiate into the future brain while the caudal part continues to develop into the spinal cord.

The morphogenesis of neural tube closure (NTC) requires the concerted action of cell shape changes together with cell polarization, migration and intercalation

hmmr mediates anterior neural tube closure and morphogenesis in the frog Xenopus
Angela Prager, Cathrin Hagenlocher, Tim Ott, Alexandra Schambony, Kerstin Feistel
Developmental Biology
Volume 430, Issue 1, 1 October 2017, Pages 188–201

Did somebody say ‘concerted action’?

Complex functionally specified informational complexity
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DionisioNovember 8, 2017 at 1:10 am

[…] it is tempting to speculate that hmmr participates in neural morphogenesis by influencing the stability and / or dynamics of MTs.

It will be interesting to test whether the same holds true for mammalian embryos […]

In summary, our work has revealed a novel in vivo function of hmmr in anterior neural morphogenesis and NTC, that may have important implications for tissue integrity in the developing and adult human.

hmmr mediates anterior neural tube closure and morphogenesis in the frog Xenopus
Angela Prager, Cathrin Hagenlocher, Tim Ott, Alexandra Schambony, Kerstin Feistel
Developmental Biology
Volume 430, Issue 1, 1 October 2017, Pages 188–201

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DionisioNovember 8, 2017 at 1:21 am

The planar cell polarity (PCP) pathway is best known for its role in polarizing epithelial cells within the plane of a tissue but it also plays a role in a range of cell migration events during development.

The mechanism by which the PCP pathway polarizes stationary epithelial cells is well characterized, but how PCP signaling functions to regulate more dynamic cell behaviors during directed cell migration is much less understood.

Planar cell polarity in moving cells: think globally, act locally
Crystal F. Davey, Cecilia B. Moens
Development 2017 144: 187-200;
doi: 10.1242/dev.122804

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DionisioNovember 8, 2017 at 1:48 am

Indeed, the PCP pathway regulates a variety of processes during development, from the coordinated orientation of cells and cell divisions across an epithelium, and the orientation of multicellular epithelial structures such as the mammalian hair follicle or the fly eye, to the directional movements of motile cells across developing vertebrate embryos.

All of these processes require a core group of membrane-associated proteins that regulate each other’s localization and the organization of the cytoskeleton.

Planar cell polarity in moving cells: think globally, act locally
Crystal F. Davey, Cecilia B. Moens
Development 2017 144: 187-200;
doi: 10.1242/dev.122804

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DionisioNovember 8, 2017 at 2:30 am

Different directional cues in the embryo – a diffusible Wnt ligand for commissural axons versus local polarity cues on nearby neuroepithelial progenitors for migrating facial motor neurons – might determine how PCP signaling is transduced within cellular protrusions to influence migration.

Planar cell polarity in moving cells: think globally, act locally
Crystal F. Davey, Cecilia B. Moens
Development 2017 144: 187-200;
doi: 10.1242/dev.122804

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DionisioNovember 8, 2017 at 2:36 am

Differential recruitment of vertebrate-specific PCP-associated proteins such as Ptk7, Ror2, Knypek and others in specific cell movement contexts might also influence the activities of PCP core components in as-yet-undiscovered ways.

Planar cell polarity in moving cells: think globally, act locally
Crystal F. Davey, Cecilia B. Moens
Development 2017 144: 187-200;
doi: 10.1242/dev.122804

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DionisioNovember 8, 2017 at 2:42 am

[…] the effectors of PCP that regulate actomyosin contractility in collectively moving cells are frequently the same multifunctional effectors that regulate actin assembly downstream of PCP in individually migrating cells.

What determines how these conserved PCP effectors influence diverse migratory cell behaviors downstream of PCP signaling will be a topic of future research.

Planar cell polarity in moving cells: think globally, act locally
Crystal F. Davey, Cecilia B. Moens
Development 2017 144: 187-200;
doi: 10.1242/dev.122804

Work in progress… stay tuned.

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DionisioNovember 8, 2017 at 1:06 pm

[…] we have emphasized several principles common to PCP-mediated cell movements during development but there are clearly many open questions.

[…] it should be noted that many other cell movements and axon guidance events have been shown to involve some, but not other, core PCP components.

It thus remains to be determined whether any of the principles we have described here hold true in those contexts.

[…] it remains an important goal to validate these findings by studying endogenous PCP components.

Planar cell polarity in moving cells: think globally, act locally
Crystal F. Davey, Cecilia B. Moens
Development 2017 144: 187-200;
doi: 10.1242/dev.122804

Work in progress… stay tuned.

Complex functionally specified informational complexity
425

DionisioNovember 8, 2017 at 3:49 pm

One core PCP protein, VANGL2, is proposed to be a key molecule determining the direction of ameloblast movement.

Cytoskeleton, intercellular junctions, planar cell polarity, and cell movement in amelogenesis
Sumio Nishikawa
Journal of Oral Biosciences
Volume 59, Issue 4, Pages 197-204
https://doi.org/10.1016/j.job.2017.07.002

Complex functionally specified informational complexity
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DionisioNovember 13, 2017 at 6:07 am

A common path to the formation of complex 3D structures starts with an epithelial sheet that is patterned by inductive cues that control the spatiotemporal activities of transcription factors.

These activities are then interpreted by the cis-regulatory regions of the genes involved in cell differentiation and tissue morphogenesis.

[…] the range of experimental models in which each of the steps can be examined in detail and evaluated in its effect on the final structure remains very limited.

Studies of the Drosophila eggshell patterning provide unique insights into the multiscale mechanisms that connect gene regulation and 3D epithelial morphogenesis.

Gene regulation during Drosophila eggshell patterning
George Pyrowolakis, Ville Veikkolainen, Nir Yakoby, and Stanislav Y. Shvartsman
PNAS vol. 114 no. 23 5808–5813,
doi: 10.1073/pnas.1610619114

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DionisioNovember 13, 2017 at 6:28 am

It appears that cis-regulatory changes can account for only some aspects of the morphological diversity of Drosophila eggshells, such as the prominent differences in the number of the respiratory dorsal appendages.

Other changes, such as the appearance of the respiratory eggshell ridges, are caused by changes in the spatial distribution of inductive signals.

Both types of mechanisms are at play in this rapidly evolving system, which provides an excellent model of developmental patterning and morphogenesis.

Gene regulation during Drosophila eggshell patterning
George Pyrowolakis, Ville Veikkolainen, Nir Yakoby, and Stanislav Y. Shvartsman
PNAS vol. 114 no. 23 5808–5813,
doi: 10.1073/pnas.1610619114

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DionisioNovember 13, 2017 at 6:45 am

Much work remains to be done to characterize the regulatory sequences and their control by transcription factors.

Furthermore, some of the important players, most notably the activators, are yet to be identified and placed within the existing network.

[…] it will be very interesting to see whether a change in a single enhancer is sufficient to change both the expression pattern of BR and the number of dorsal appendages.

[…] it is important to keep in mind the mechanisms that rely on the intracellular modulation of inductive signals.

[…] GRK induces several negative feedback loops that modulate the signals sensed by the enhancers of the genes within the patterning network […]

One of the most exciting directions for future studies is related to the mechanistic analysis and experimental validation of the computational models that can explain the remarkable morphological diversity of eggshell structures.

In the future, we envision a unified model that accounts for multiple processes, from inductive signals to enhancers, and can generate all of the observed eggshell morphologies by variations of model parameters and sequence variations.

Gene regulation during Drosophila eggshell patterning
George Pyrowolakis, Ville Veikkolainen, Nir Yakoby, and Stanislav Y. Shvartsman
PNAS vol. 114 no. 23 5808–5813,
doi: 10.1073/pnas.1610619114

Work in progress… stay tuned.

Complex functionally specified informational complexity
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DionisioNovember 13, 2017 at 7:57 am

DNA regulatory regions represent an important part of the genome, where DNA binding Transcription Factors (TF) and a large number of co-regulators cooperate to convey cellular information and control gene activity.

Recent genome-wide analyses, conducted by ENCODE and other projects in a variety of cell lines and tissues, led to the unexpected observation that distant or proximal non-promotorial regulatory regions, defined as enhancers, outnumber gene promoters by a factor of ten1.

They appear to serve in a developmentally-regulated fashion, and only a fraction of them is poised or active in a defined cell type at any specific time.

Dissecting the genomic activity of a transcriptional regulator by the integrative analysis of omics data
Giulio Ferrero,1,2,3 Valentina Miano,1,3 Marco Beccuti,2 Gianfranco Balbo,1,2 Michele De Bortoli,corresponding author1,3 and Francesca Cordero1,2
Sci Rep. 2017; 7: 8564.
doi: 10.1038/s41598-017-08754-9

Did somebody say ‘unexpected’?

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DionisioNovember 13, 2017 at 8:04 am

Surprisingly though, there is no systematic analysis leading to definition of a reference cistrome and to identification of the differential activity of ER? in different experimental contexts and with different ligands or, notably, in absence of estrogen as we reported previously15 and that represents possibly one of the most puzzling activity of this TR.

Dissecting the genomic activity of a transcriptional regulator by the integrative analysis of omics data
Giulio Ferrero,1,2,3 Valentina Miano,1,3 Marco Beccuti,2 Gianfranco Balbo,1,2 Michele De Bortoli,corresponding author1,3 and Francesca Cordero1,2
Sci Rep. 2017; 7: 8564.
doi: 10.1038/s41598-017-08754-9

Did somebody say ‘Surprisingly’?

Did somebody say ‘puzzling’?

Complex functionally specified informational complexity
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DionisioNovember 13, 2017 at 9:25 am

Eggshell patterning has been extensively studied in Drosophila melanogaster.

However, the cis-regulatory modules (CRMs), which control spatiotemporal expression of these patterns, are vastly unexplored.

[…] complex gene patterns are assembled combinatorially by different CRMs controlling the expression of genes in simple domains.

Simple Expression Domains Are Regulated by Discrete CRMs During Drosophila Oogenesis
Nicole T. Revaitis, Robert A. Marmion, Maira Farhat, Vesile Ekiz, Wei Wang and Nir Yakoby
G3: Genes, Genomes, Genetics August 1, 2017 vol. 7 no. 8 2705-2718; https://doi.org/10.1534/g3.117.043810

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DionisioNovember 13, 2017 at 10:19 am

The spatiotemporal control of gene expression is a fundamental requirement for animal development […]

[…] our understanding of how genes are regulated in time and space is still limited […]

Further analysis is needed to determine whether brU functions during br expression in the genomic context.

Further analysis is required to determine the repression mechanism(s) of brRF in the dorsal midline and anterior domains.

Understanding the regulatory mechanisms of br may shed light on the evolution of eggshell morphologies (Pyrowolakis et al. 2017).

Simple Expression Domains Are Regulated by Discrete CRMs During Drosophila Oogenesis
Nicole T. Revaitis, Robert A. Marmion, Maira Farhat, Vesile Ekiz, Wei Wang and Nir Yakoby
G3: Genes, Genomes, Genetics August 1, 2017 vol. 7 no. 8 2705-2718; https://doi.org/10.1534/g3.117.043810

What they have to understand is the fundamental evo-devo problem formulated thus:

Dev(d) = Dev(a) + Delta(a,d)

Where,
Dev(a) is the entire developmental process of the ancestor ‘a’
Dev(d) is the entire developmental process of the descendant ‘d’
Delta(a,d) is the collection of all the required spatiotemporal changes in Dev(a) in order to get Dev(d).

Note that entire developmental process includes the whole enchilada, i.e. all the ingredients and cooking recipes.

Complex functionally specified informational complexity
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DionisioNovember 13, 2017 at 10:58 am

[…] different mechanisms pattern the anterior domain of the follicle cells.

[…] dad and dpp are regulated by BMP and EGFR signaling, respectively.

[…] the two anterior CRMs are regulated by different signaling pathways […]

[…] the dpp driver is expressed earlier than the dad driver […]

[…] a follow-up study on the activation/repression of these drivers is needed […]

In the future, it will be interesting to determine whether each gene’s endogenous promoter and 3? UTR play a role in the patterning of the corresponding genes.

Simple Expression Domains Are Regulated by Discrete CRMs During Drosophila Oogenesis
Nicole T. Revaitis, Robert A. Marmion, Maira Farhat, Vesile Ekiz, Wei Wang and Nir Yakoby
G3: Genes, Genomes, Genetics August 1, 2017 vol. 7 no. 8 2705-2718; https://doi.org/10.1534/g3.117.043810

Complex functionally specified informational complexity
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DionisioNovember 14, 2017 at 6:06 pm

It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis.

But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR).

This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome.

Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation.

In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis.

We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals.

Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.

The double life of the ribosome: When its protein folding activity supports prion propagation.
Voisset C1, Blondel M1, Jones GW2, Friocourt G1, Stahl G3, Chédin S4, Béringue V5, Gillet R6.
Prion. 11(2):89-97.
doi: 10.1080/19336896.2017.1303587.

Complex functionally specified informational complexity
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DionisioNovember 16, 2017 at 3:12 am

@385-392: juicy

Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root.
436

DionisioJanuary 31, 2018 at 7:57 am

Proteins in the form of transcription factors (TFs) bind to specific DNA sites that regulate cell growth, differentiation, and cell development. The interactions between proteins and DNA are important toward maintaining and expressing genetic information. Without knowing TFs structures and DNA-binding properties, it is difficult to completely understand the mechanisms by which genetic information is transferred between DNA and proteins. The increasing availability of structural data on protein-DNA complexes and recognition mechanisms provides deeper insights into the nature of protein-DNA interactions and therefore, allows their manipulation. TFs utilize different mechanisms to recognize their cognate DNA (direct and indirect readouts). In this review, we focus on these recognition mechanisms as well as on the analysis of the DNA-binding domains of stem cell TFs, discussing the relative role of various amino acids toward facilitating such interactions. Unveiling such mechanisms will improve our understanding of the molecular pathways through which TFs are involved in repressing and activating gene expression.

Yesudhas, Dhanusha & Batool, Maria & Anwar, Muhammad Ayaz & Panneerselvam, Suresh & Choi, Sangdun. (2017). Proteins Recognizing DNA: Structural Uniqueness and Versatility of DNA-Binding Domains in Stem Cell Transcription Factors. Genes. 8. . 10.3390/genes8080192.
437

DionisioJanuary 31, 2018 at 8:18 am

Background
Enhancers are DNA regulatory elements that influence gene expression. There is substantial diversity in enhancers’ activity patterns: some enhancers drive expression in a single cellular context, while others are active across many. Sequence characteristics, such as transcription factor (TF) binding motifs, influence the activity patterns of regulatory sequences; however, the regulatory logic through which specific sequences drive enhancer activity patterns is poorly understood. Recent analysis of Drosophila enhancers suggested that short dinucleotide repeat motifs (DRMs) are general enhancer sequence features that drive broad regulatory activity. However, it is not known whether the regulatory role of DRMs is conserved across species.

Results
We performed a comprehensive analysis of the relationship between short DNA sequence patterns, including DRMs, and human enhancer activity in 38,538 enhancers across 411 different contexts. In a machine-learning framework, the occurrence patterns of short sequence motifs accurately predicted broadly active human enhancers. However, DRMs alone were weakly predictive of broad enhancer activity in humans and showed different enrichment patterns than in Drosophila. In general, GC-rich sequence motifs were significantly associated with broad enhancer activity, and consistent with this enrichment, broadly active human TFs recognize GC-rich motifs.

Conclusions
Our results reveal the importance of specific sequence motifs in broadly active human enhancers, demonstrate the lack of evolutionary conservation of the role of DRMs, and provide a computational framework for investigating the logic of enhancer sequences.

Electronic supplementary material
The online version of this article (doi:10.1186/s12864-017-3934-9) contains supplementary material, which is available to authorized users.

L. Colbran, Laura & Chen, Ling & A. Capra, John. (2017). Short DNA sequence patterns accurately identify broadly active human enhancers. BMC Genomics. 18. . 10.1186/s12864-017-3934-9.
438

DionisioJanuary 31, 2018 at 8:22 am

Convolutionary neural networks (CNN) has been widely used for DNA motif discovery due to its high accuracy. To employ CNN for DNA motif discovery task, the input DNA sequences are required to be encoded as numerical values and represented as either vector or multi-dimensional matrix. This paper evaluates the simple and more compact ordinal encoding method versus the popular one-hot encoding for DNA sequences. We compare the performances of both encoding methods using three sets of datasets enriched with DNA motifs. We found that the ordinal encoding performs comparable to the one-hot encoding method but with significant reduction in training time. In addition, the one-hot encoding performance is quite consistent across various datasets but would require suitable CNN configuration to perform well. The ordinal encoding with matrix representation performs best in some of the evaluated datasets. This study implies that the performance of CNN for DNA motif discovery depends on the suitable design of the sequence encoding and representation. In addition, the CNN architecture and configuration require some tuning to suit different encoding methods.

Choong, Allen & Lee, Nung Kion. (2017). Evaluation of Convolutionary Neural Networks Modeling of DNA Sequences using Ordinal versus one-hot Encoding Method. BIORXIV/2017/186965. . 10.1101/186965.
439

DionisioJanuary 31, 2018 at 8:28 am

For identifying the genes that are regulated by a transcription factor (TF), we have established an analytical pipeline that combines genomic systematic evolution of ligands by exponential enrichment (gSELEX)-Seq and RNA-Seq. Here, SELEX was used to select DNA fragments from an Aspergillus nidulans genomic library that bound specifically to AmyR, a TF from A. nidulans. High-throughput sequencing data were obtained for the DNAs enriched through the selection, following which various in silico analyses were performed. Mapping reads to the genome revealed the binding motifs including the canonical AmyR-binding motif, CGGN8CGG, as well as the candidate promoters controlled by AmyR. In parallel, differentially expressed genes related to AmyR were identified by using RNA-Seq analysis with samples from A. nidulans WT and amyR deletant. By obtaining the intersecting set of genes detected using both gSELEX-Seq and RNA-Seq, the genes directly regulated by AmyR in A. nidulans can be identified with high reliability. This analytical pipeline is a robust platform for comprehensive genome-wide identification of the genes that are regulated by a target TF.

Kojima, Takaaki & Kunitake, Emi & Ihara, Kunio & Kobayashi, Tetsuo & Nakano, Hideo. (2016). A Robust Analytical Pipeline for Genome-Wide Identification of the Genes Regulated by a Transcription Factor: Combinatorial Analysis Performed Using gSELEX-Seq and RNA-Seq. PLOS ONE. 11. e0159011. 10.1371/journal.pone.0159011.
440

DionisioJanuary 31, 2018 at 8:29 am

In the past decade, various transcriptional activators of cellulolytic enzyme genes have been identified in Ascomycete fungi. The regulatory system of cellulolytic enzymes is not only partially conserved, but also significantly diverse. For example, Trichoderma reesei has a system distinct from those of Aspergillus and Neurospora crassa—the former utilizes Xyr1 (the Aspergillus XlnR ortholog) as the major regulator of cellulolytic enzyme genes, while the latter uses CLR-2/ClrB/ManR orthologs. XlnR/Xyr1 and CLR-2/ClrB/ManR are evolutionarily distant from each other. Regulatory mechanisms that are controlled by CLR-2, ClrB, and ManR are also significantly different, although they are orthologous factors. Expression of clr-2 requires the activation of another transcription factor, CLR-1, by cellobiose, while CLR-2 is constitutively active for transactivation. By contrast, ClrB activation requires cellobiose. While ClrB mainly regulates cellulolytic genes, ManR is essential for the activation of not only cellulolytic but also mannanolytic enzyme genes. In this review, we summarize XlnR/Xyr1- and CLR-2/ClrB/ManR-dependent regulation in N. crassa, A. nidulans, A. oryzae, and T. reesei and emphasize the conservation and diversity of the regulatory systems for cellulolytic enzyme genes in these Ascomycete fungi. In addition, we discuss the role of McmA, another transcription factor that plays an important role in recruiting ClrB to the promoters in A. nidulans.

Kunitake, Emi & Kobayashi, Tetsuo. (2017). Conservation and diversity of the regulators of cellulolytic enzyme genes in Ascomycete fungi. Current Genetics. 63. . 10.1007/s00294-017-0695-6.
441

DionisioJanuary 31, 2018 at 8:31 am

Background
Genome and transcriptome sequencing has greatly facilitated the understanding of biomass-degrading mechanisms in a number of fungal species. The information obtained enables the investigation and discovery of genes encoding proteins involved in plant cell wall degradation, which are crucial for saccharification of lignocellulosic biomass in second-generation biorefinery applications. The thermophilic fungus Malbranchea cinnamomea is an efficient producer of many industrially relevant enzymes and a detailed analysis of its genomic content will considerably enhance our understanding of its lignocellulolytic system and promote the discovery of novel proteins. ResultsThe 25-million-base-pair genome of M. cinnamomea FCH 10.5 was sequenced with 225× coverage. A total of 9437 protein-coding genes were predicted and annotated, among which 301 carbohydrate-active enzyme (CAZyme) domains were found. The putative CAZymes of M. cinnamomea cover cellulases, hemicellulases, chitinases and pectinases, equipping the fungus with the ability to grow on a wide variety of biomass types. Upregulation of 438 and 150 genes during growth on wheat bran and xylan, respectively, in comparison to growth on glucose was revealed. Among the most highly upregulated CAZymes on xylan were glycoside hydrolase family GH10 and GH11 xylanases, as well as a putative glucuronoyl esterase and a putative lytic polysaccharide monooxygenase (LPMO). AA9-domain-containing proteins were also found to be upregulated on wheat bran, as well as a putative cutinase and a protein harbouring a CBM9 domain. Several genes encoding secreted proteins of unknown function were also more abundant on wheat bran and xylan than on glucose. Conclusions
The comprehensive combined genome and transcriptome analysis of M. cinnamomea provides a detailed insight into its response to growth on different types of biomass. In addition, the study facilitates the further exploration and exploitation of the repertoire of industrially relevant lignocellulolytic enzymes of this fungus.

Hüttner, Silvia & Thuy Nguyen, Thanh & Granchi, Zoraide & Chin-A-Woeng, Thomas & Ahrén, Dag & Larsbrink, Johan & Thanh, Vu & Olsson, Lisbeth. (2017). Combined genome and transcriptome sequencing to investigate the plant cell wall degrading enzyme system in the thermophilic fungus Malbranchea cinnamomea. Biotechnology for Biofuels. 10. . 10.1186/s13068-017-0956-0.
442

DionisioJanuary 31, 2018 at 8:34 am

The spinal cord (SC) is the part of the central nervous system (CNS) that is responsible for the motor, somato-sensory, and visceral innervation of the extremities, trunk, and large parts of the neck as well as all inner organs. Spinal nerves of the peripheral nervous system (PNS) serve as connections between the CNS and distal receptors and organs. And just as the SC controls many aspects of locomotion and visceral function, it also serves as an important relay station for incoming, afferent information from the periphery to central brain regions. It thus constitutes the major coordination hub for how humans unconsciously perceive their periphery and how our bodies react to this information, often involuntarily and without involvement of higher brain functions. And while the topography and cytoarchitecture of the human spinal cord is fairly well understood, the functional implications of some well-described structures remain elusive. Because of the central role the spinal cord plays in many forms of CNS impairment, a better understanding of the functional neuroanatomy of this structure is a prerequisite for addressing potential therapeutic approaches. This chapter gives an overview of spinal cord development, topography, cytoarchitecture, and functional assembly with a special focus on two aspects often compromised during spinal cord injury, namely, the control of micturition and the propriospinal neuron networks that hold great promise for the future improvement of therapies for patients suffering from spinal cord injury.

Engelhardt, Maren & Sobotzik, Jürgen-Markus. (2017). Functional Neuroanatomy of the Spinal Cord. Neurological Aspects of Spinal Cord Injury. 19-60. 10.1007/978-3-319-46293-6_2.

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The “beautiful mechanism” by which an egg becomes an embryo

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