By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:
Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.
These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.
How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.
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The unfathomed complexity inherent in a ‘simple’ cell cannot be overstated. The folding of a single protein, out of the billion proteins present in a cell*, clearly gets this point across.
It is known that proteins do not find their final folded form by random processes:
That no one really has a firm clue how proteins are finding their final folded form is made clear by the immense time (a few weeks) it takes for a few hundred thousand computers, which are linked together, to find the final folded form of a single protein:
The reason why finding the final form of a folded protein is so hard for super-computers is that it is like the ‘traveling salesman’ puzzle, which are ‘Just about the meanest problems you can set a computer (on) ‘.
of note: protein folding is found to be ‘NP-complete’
Yet it is exactly this type of ‘traveling salesman problem’ that quantum computers excel at:
Thus we have evidence that proteins are very likely finding their final folded form by some method of quantum computation. ,,,, If so, this far exceeds anything man has yet accomplished in regards to quantum computation although billions have been spent trying!
Here is the paper that proved that protein folding belongs to the physics of the quantum world and that protein folding does not belong to the physics of the classical world:
And here is a paper outlining that quantum computation is indeed possible in proteins:
* A given cell may make more than 10,000 different proteins, and typically contains more than a billion protein molecules at any one time.
http://www.netfuture.org/2012/May1012_184.html#2
‘ The cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture.’
Sounds like my Catholic Church, though Francis seems to have some work on his hands making it ‘fantastically’ efficient. At least, as regards the Curia and the Vatican bank.
Yes, you can say they are like a city or like a factory or whatever the current analogy is but it’s still an analogy. They are also very different from human cities and factories in so many ways. Do the similarities outweigh the differences or vice versa and by what measure?
This is still the “I can’t believe it’s not butter” style of argument, it’s so complex I can’t believe it wasn’t designed. But our instinctive reaction to perceived complexity proves nothing, one way or the other.
No argument, there are still mysteries at the heart of the cell but we still aren’t any closer to deciding if there was some intelligence involved.
as to: “but we still aren’t any closer to deciding if there was some intelligence involved.”
But WE are very decided that unguided processes were not involved! 🙂
Multiple Overlapping Genetic Codes Profoundly Reduce the Probability of Beneficial Mutation George Montañez 1, Robert J. Marks II 2, Jorge Fernandez 3 and John C. Sanford 4 – published online May 2013
Excerpt: In the last decade, we have discovered still another aspect of the multi- dimensional genome. We now know that DNA sequences are typically “ poly-functional” [38]. Trifanov previously had described at least 12 genetic codes that any given nucleotide can contribute to [39,40], and showed that a given base-pair can contribute to multiple overlapping codes simultaneously. The first evidence of overlapping protein-coding sequences in viruses caused quite a stir, but since then it has become recognized as typical. According to Kapronov et al., “it is not unusual that a single base-pair can be part of an intricate network of multiple isoforms of overlapping sense and antisense transcripts, the majority of which are unannotated” [41]. The ENCODE project [42] has confirmed that this phenomenon is ubiquitous in higher genomes, wherein a given DNA sequence routinely encodes multiple overlapping messages, meaning that a single nucleotide can contribute to two or more genetic codes. Most recently, Itzkovitz et al. analyzed protein coding regions of 700 species, and showed that virtually all forms of life have extensive overlapping information in their genomes [43].
38. Sanford J (2008) Genetic Entropy and the Mystery of the Genome. FMS Publications, NY. Pages 131–142.
39. Trifonov EN (1989) Multiple codes of nucleotide sequences. Bull of Mathematical Biology 51:417–432.
40. Trifanov EN (1997) Genetic sequences as products of compression by inclusive superposition of many codes. Mol Biol 31:647–654.
41. Kapranov P, et al (2005) Examples of complex architecture of the human transcriptome revealed by RACE and high density tiling arrays. Genome Res 15:987–997.
42. Birney E, et al (2007) Encode Project Consortium: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816.
43. Itzkovitz S, Hodis E, Sega E (2010) Overlapping codes within protein-coding sequences. Genome Res. 20:1582–1589.
http://www.worldscientific.com.....08728_0006
Multiple Overlapping Genetic Codes Profoundly Reduce the Probability of Beneficial Mutation George Montañez 1, Robert J. Marks II 2, Jorge Fernandez 3 and John C. Sanford 4 – May 2013
Conclusions: Our analysis confirms mathematically what would seem intuitively obvious – multiple overlapping codes within the genome must radically change our expectations regarding the rate of beneficial mutations. As the number of overlapping codes increases, the rate of potential beneficial mutation decreases exponentially, quickly approaching zero. Therefore the new evidence for ubiquitous overlapping codes in higher genomes strongly indicates that beneficial mutations should be extremely rare. This evidence combined with increasing evidence that biological systems are highly optimized, and evidence that only relatively high-impact beneficial mutations can be effectively amplified by natural selection, lead us to conclude that mutations which are both selectable and unambiguously beneficial must be vanishingly rare. This conclusion raises serious questions. How might such vanishingly rare beneficial mutations ever be sufficient for genome building? How might genetic degeneration ever be averted, given the continuous accumulation of low impact deleterious mutations?
http://www.worldscientific.com.....08728_0006
Biological Information – Overlapping Codes 10-25-2014 by Paul Giem – video
https://www.youtube.com/watch?v=OytcYD5791k&index=4&list=PLHDSWJBW3DNUUhiC9VwPnhl-ymuObyTWJ
Overlapping Genetic Codes 12-6-2014 by Paul Giem – video
https://www.youtube.com/watch?v=3WZy0n60_ZU
1. Marks, R. J. II et al. 2013. Biological Information: New Perspectives. Hackensack, NJ: World Scientific Publishing Co. Pte. Ltd. – Book available in sections at http://www.worldscientific.com.....8818#t=toc
2. Kapranov P., et al. 2005. Examples of complex architecture of the human transcriptome revealed by RACE and high density tiling arrays. Genome Res 15:987–997. Available at
http://www.ncbi.nlm.nih.gov/pm.....MC1172043/
3. Birney E., et al. (Encode Project Consortium) 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816. Available at http://www.nature.com/nature/j.....05874.html
4. Itzkovitz S., Hodis E., Sega E. 2010. Overlapping codes within protein-coding sequences. Genome Res. 20:1582–1589. Available at http://www.ncbi.nlm.nih.gov/pubmed/20841429
5. He H., et al. 2007. Mapping the C. elegant noncoding transcriptome with a whole genome tiling microarray. Genome Res 17:1471-1477. Available at http://www.ncbi.nlm.nih.gov/pubmed/17785534
6. http://www.mcld.co.uk/hiv/?q=HIV%20genome
7. http://nsmn1.uh.edu/dgraur/niv.....thesis.pdf
The thing about folding proteins is that 2 cells consistently fold them the SAME way. That is, it can’t be computationally hard to randomly fold a protein at Point A into Position B. The fact that this random fold is NOT useful requires that there be “assembly instructions”. You can start with a bag containing all of the pieces of a tent, but if you do NOT: 1) assemble them is something real close to the right order, and 2) emplace the pieces in SPECIFIC places, what you get is NOT a “tent”. Especially if you throw the fabric on the ground and pound the stakes through the middle of it. The fact that 2 isolated cells (isolated in time is probably more instructive than isolated in space) perform the assembly EXACTLY the same way argues strongly against any random process.
#3 Seversky
Well, there are some folks out there who have decided for everybody else to tell our kids in public school textbooks that it’s a known fact that it all happened by the power of the magic formula RV+NS+T=E!
As you well said, there are still mysteries at the heart of the biological systems.
#6 Mauna
Yes, and sometimes even using the same chaperones!
Now, where is the instructions manual for those procedures?
Let’s ask gpuccio! 🙂
Close Encounter of the Third Kind: The ER Meets Endosomes at Fission Suites
DOI: http://dx.doi.org/10.1016/j.devcel.2014.12.008
The endoplasmic reticulum (ER) forms functional contacts with several cellular organelles and regulates processes such as mitochondrial fission.
In a recent issue of Cell, Rowland et al. (2014) extend these findings to endosomes, showing that the ER contacts endosomes at sites containing the WASH subunit FAM21, where it forecasts fission events.
http://www.cell.com/developmen.....ll%20Press
The biological functions of miRNAs
DOI: http://dx.doi.org/10.1016/j.tcb.2014.11.004
Despite their clear importance as a class of regulatory molecules, pinpointing the relevance of individual miRNAs has been challenging.
Studies querying miRNA functions by overexpressing or silencing specific miRNAs have yielded data that are often at odds with those collected from loss-of-functions models.
In addition, knockout studies suggest that many conserved miRNAs are dispensable for animal development or viability.
In this review, we discuss these observations in the context of our current knowledge of miRNA biology and review the evidence implicating miRNA-mediated gene regulation in the mechanisms that ensure biological robustness.
http://www.cell.com/trends/cel.....14)00197-4
Networking galore: intermediate filaments and cell migration.
doi: 10.1016/j.ceb.2013.06.008.
Intermediate filaments (IFs) are assembled from a diverse group of evolutionarily conserved proteins and are specified in a tissue-dependent, cell type-dependent, and context-dependent fashion in the body.
IFs are involved in multiple cellular processes that are crucial for the maintenance of cell and tissue integrity and the response and adaptation to various stresses, as conveyed by the broad array of crippling clinical disorders caused by inherited mutations in IF coding sequences.
Accordingly, the expression, assembly, and organization of IFs are tightly regulated.
Migration is a fitting example of a cell-based phenomenon in which IFs participate as both effectors and regulators.
With a particular focus on vimentin and keratin, we here review how the contributions of IFs to the cell’s mechanical properties, to cytoarchitecture and adhesion, and to regulatory pathways collectively exert a significant impact on cell migration.
http://www.ncbi.nlm.nih.gov/pubmed/23886476
Has anyone checked this out yet?
http://www.newscientist.com/ar.....ng-37.html
#12 PeterJ
Interesting. Thanks.
Didn’t know weed smoking was legal in K-tan 🙂
DnaK Functions as a Central Hub in the E. coli Chaperone Network
DOI: http://dx.doi.org/10.1016/j.celrep.2011.12.007
Cellular chaperone networks prevent potentially toxic protein aggregation and ensure proteome integrity.
Here, we used Escherichia coli as a model to understand the organization of these networks, focusing on the cooperation of the DnaK system with the upstream chaperone Trigger factor (TF) and the downstream GroEL.
Quantitative proteomics revealed that DnaK interacts with at least ?700 mostly cytosolic proteins, including ?180 relatively aggregation-prone proteins that utilize DnaK extensively during and after initial folding.
Upon deletion of TF, DnaK interacts increasingly with ribosomal and other small, basic proteins, while its association with large multidomain proteins is reduced.
DnaK also functions prominently in stabilizing proteins for subsequent folding by GroEL.
These proteins accumulate on DnaK upon GroEL depletion and are then degraded, thus defining DnaK as a central organizer of the chaperone network.
Combined loss of DnaK and TF causes proteostasis collapse with disruption of GroEL function, defective ribosomal biogenesis, and extensive aggregation of large proteins.
http://www.cell.com/cell-repor.....all%3Dtrue
Polyphosphate Is a Primordial Chaperone
DOI: http://dx.doi.org/10.1016/j.molcel.2014.01.012
Composed of up to 1,000 phospho-anhydride bond-linked phosphate monomers, inorganic polyphosphate (polyP) is one of the most ancient, conserved, and enigmatic molecules in biology.
Here we demonstrate that polyP functions as a hitherto unrecognized chaperone.
We show that polyP stabilizes proteins in vivo, diminishes the need for other chaperone systems to survive proteotoxic stress conditions, and protects a wide variety of proteins against stress-induced unfolding and aggregation.
In vitro studies reveal that polyP has protein-like chaperone qualities, binds to unfolding proteins with high affinity in an ATP-independent manner, and supports their productive refolding once nonstress conditions are restored.
Our results uncover a universally important function for polyP and suggest that these long chains of inorganic phosphate may have served as one of nature’s first chaperones, a role that continues to the present day. [?]
http://www.cell.com/molecular-.....14)00073-2
Unraveling the Mechanism of Chaperone-Mediated Protein Folding
Chaperones are special proteins that aid the folding, unfolding, assembly and disassembly of other proteins. Chaperones rely on a large and diverse set of co-chaperones that regulate their specificity and function.
How these co-chaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown.
http://www.rochester.edu/data-.....lding.html
Molecular Chaperones in Cellular Protein Folding: The Birth of a Field
DOI: http://dx.doi.org/10.1016/j.cell.2014.03.029
Protein Folding and the Role of Chaperone Proteins in Neurodegenerative Disease
doi:10.1016/B978-008045046-9.00524-6
Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation, and intra- or extraneuronal accumulation of amyloid fibrils.
Molecular chaperones provide a first line of defense against misfolded, aggregation-prone proteins, and are among the most potent suppressors of neurodegeneration known for animal models of human disease.
We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades.
A detailed understanding of the molecular basis of protection by chaperones against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
http://www.sciencedirect.com/s.....0469005246
Molecular chaperones in protein folding and proteostasis
doi:10.1038/nature10317
Most proteins must fold into defined three-dimensional structures to gain functional activity.
But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species.
To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding.
Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis).
Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer’s disease and Parkinson’s disease.
Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
http://www.nature.com/nature/j.....10317.html
Structural characterization of the substrate transfer mechanism in Hsp70/?Hsp90 folding machinery mediated by ?Hop
doi:10.1038/ncomms6484
In eukarya, chaperones Hsp70 and ?Hsp90 act coordinately in the folding and maturation of a range of key proteins with the help of several co-chaperones, especially ?Hop.
Although biochemical data define the ?Hop-mediated Hsp70–?Hsp90 substrate transfer mechanism, the intrinsic flexibility of these proteins and the dynamic nature of their complexes have limited the structural studies of this mechanism.
http://www.nature.com/ncomms/2.....s6484.html
GroEL/ES Chaperonin Modulates the Mechanism and Accelerates the Rate of TIM-Barrel Domain Folding
DOI: http://dx.doi.org/10.1016/j.cell.2014.03.038
The GroEL/ES chaperonin system functions as a protein folding cage.
Many obligate substrates of GroEL share the (??)8 TIM-barrel fold, but how the chaperonin promotes folding of these proteins is not known.
http://www.cell.com/cell/abstr.....14)00413-9
Orchestration of secretory protein folding by ER chaperones.
doi: 10.1016/j.bbamcr.2013.03.007
The endoplasmic reticulum is a major compartment of protein biogenesis in the cell, dedicated to production of secretory, membrane and organelle proteins.
The secretome has distinct structural and post-translational characteristics, since folding in the ER occurs in an environment that is distinct in terms of its ionic composition, dynamics and requirements for quality control.
The folding machinery in the ER therefore includes chaperones and folding enzymes that introduce, monitor and react to disulfide bonds, glycans, and fluctuations of luminal calcium.
We describe the major chaperone networks in the lumen and discuss how they have distinct modes of operation that enable cells to accomplish highly efficient production of the secretome.
This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
http://www.ncbi.nlm.nih.gov/pubmed/23507200
Endoplasmic reticulum chaperones and oxidoreductases
doi: 10.3389/fonc.2014.00291.
Endoplasmic reticulum (ER) chaperones and oxidoreductases are abundant enzymes that mediate the production of fully folded secretory and transmembrane proteins.
http://www.ncbi.nlm.nih.gov/pubmed/25386408
A dynamic study of protein secretion and aggregation in the secretory pathway
doi: 10.1371/journal.pone.0108496
Precise coordination of protein biogenesis, traffic and homeostasis within the early secretory compartment (ESC) is key for cell physiology.
http://www.ncbi.nlm.nih.gov/pubmed/25279560
YidC protein, a molecular chaperone for LacY protein folding via the SecYEG protein machinery.
doi: 10.1074/jbc.M113.491613.
http://www.ncbi.nlm.nih.gov/pubmed/23928306
Chaperone machines for protein folding, unfolding and disaggregation
doi:10.1038/nrm3658
http://www.nature.com/nrm/jour.....m3658.html
Getting Folded: Chaperone Proteins in Muscle Development, Maintenance and Disease
DOI: 10.1002/ar.22980
http://onlinelibrary.wiley.com.....0/abstract
bornagain77 @ 4
YOU may be. The rest of us aren’t so sure.
Dionisio @ 7
Then you’ll be happy to know that there are a few so-called science teachers who are failing in their duty to their students by teaching them in the science classroom that the theory of evolution is wrong and Christian creationism is right, the world was created by God out of nothing in six days flat. Which is the more magical? And what happened to the Christian duty not to bear false witness?
#28 Seversky
Can you provide the source of that information?
BTW, how do you know I’ll be happy to know that?
#28 Seversky
Who is “the rest of us”?
designed?
Was this paper peer-reviewed?
How could they miss that politically incorrect term twice?
Seversky, besides people being paid by government funds to try to find the slightest hint that life might come from non-life, and dogmatic atheists/Neo-Darwinists, such as yourself who will deny even their very own mind before they will ever admit to any evidence for God, who exactly is this ‘we’ you are talking about?
Suzan Mazur: Origin of life shifting to “nonmaterial events”? – December 15, 2013
Excerpt: The first paradox is the tendency of organic matter to devolve and to give tar. If you can avoid that, you can start to try to assemble things that are not tarry, but then you encounter the water problem, which is related to the fact that every interesting bond that you want to make is unstable, thermodynamically, with respect to water. If you can solve that problem, you have the problem of entropy, that any of the building blocks are going to be present in a low concentration; therefore, to assemble a large number of those building blocks, you get a gene-like RNA — 100 nucleotides long — that fights entropy. And the fourth problem is that even if you can solve the entropy problem, you have a paradox that RNA enzymes, which are maybe catalytically active, are more likely to be active in the sense that destroys RNA rather than creates RNA.
http://www.uncommondescent.com.....al-events/
Chemistry by Chance: A Formula for Non-Life by Charles McCombs, Ph.D.
Excerpt: The following eight obstacles in chemistry ensure that life by chance is untenable.
1. The Problem of Unreactivity
2. The Problem of Ionization
3. The Problem of Mass Action
4. The Problem of Reactivity
5. The Problem of Selectivity
6. The Problem of Solubility
7. The Problem of Sugar
8. The Problem of Chirality
The chemical control needed for the formation of a specific sequence in a polymer chain is just not possible through random chance. The synthesis of proteins and DNA/RNA in the laboratory requires the chemist to control the reaction conditions, to thoroughly understand the reactivity and selectivity of each component, and to carefully control the order of addition of the components as the chain is building in size.
http://www.icr.org/article/che.....-non-life/
Tissue-Resident Memory T Cells
DOI: http://dx.doi.org/10.1016/j.immuni.2014.12.007
Tissue-resident memory T (Trm) cells constitute a recently identified lymphocyte lineage that occupies tissues without recirculating.
They provide a first response against infections reencountered at body surfaces, where they accelerate pathogen clearance.
Because Trm cells are not present within peripheral blood, they have not yet been well characterized, but are transcriptionally, phenotypically, and functionally distinct from recirculating central and effector memory T cells.
http://www.cell.com/immunity/a.....14)00449-X
Dionisio @ 30
Those of us who aren’t “WE”
bornagain77 @ 32
See previous comment re “WE”
As for government funding of origins of life research, who else is going to put money into it? Not private enterprise because they will only put money into research that offers the prospect of a good return on their investment. This means that the pharmaceutical industry will only conduct research into diseases that afflict enough people to provide a lucrative market for any theraprutic agent they might develop. People who suffer from rarer ailments generally have to go without – unless the government stumps up some research funding.
What’s a “nonmaterial event”?
Any atheist who believes that life can come from non-life does so on pure blind faith in spite of a mountain of evidence against it EVER happening.
Modern research has only further highlighted how impossible it is.
The law of biogenesis, i.e. life comes only from life, remains as solid as ever!
as to:
That would be anything that cannot be reduced to a material basis, such as mind and information!
Verse and Music:
Protein folding and chaperones
https://www.youtube.com/embed/jOhNyVjkChM
https://www.youtube.com/embed/4GYOmosYerQ
Protein folding
https://www.youtube.com/embed/zm-3kovWpNQ
Chaperones for protein folding – unfolding and disassembling
https://www.youtube.com/embed/7BfThtnXLY0
RNA interference
https://www.youtube.com/embed/nRuefh6OO-E
Provided by William Orfanos in:
https://www.youtube.com/channel/UCbFS2uVI4xvFGg-MDq9WuXg/about
Microtubules and chromosome segregation
https://www.youtube.com/embed/KV03282vHP4
Mitosis
https://www.youtube.com/embed/DwAFZb8juMQ
unexpectedly revealed ?
What did they expect to find?
Orchestrated Intron Retention Regulates Normal Granulocyte Differentiation
DOI: http://dx.doi.org/10.1016/j.cell.2013.06.052
Intron retention (IR) is widely recognized as a consequence of mis-splicing that leads to failed excision of intronic sequences from pre-messenger RNAs.
Our bioinformatic analyses of transcriptomic and proteomic data of normal white blood cell differentiation reveal IR as a physiological mechanism of gene expression control.
IR regulates the expression of 86 functionally related genes, including those that determine the nuclear shape that is unique to granulocytes.
Retention of introns in specific genes is associated with downregulation of splicing factors and higher GC content.
IR, conserved between human and mouse, led to reduced mRNA and protein levels by triggering the nonsense-mediated decay (NMD) pathway.
In contrast to the prevalent view that NMD is limited to mRNAs encoding aberrant proteins, our data establish that IR coupled with NMD is a conserved mechanism in normal granulopoiesis.
Physiological IR may provide an energetically favorable level of dynamic gene expression control prior to sustained gene translation.
http://www.cell.com/cell/abstr.....13)00834-9
Seversky @ 34
Why did you answer my question posted @ 30 but did NOT answer my two questions posted @ 29 ?
#34 Seversky
Hmm…
Why did you answer my question posted @ 30 but did NOT answer my two questions posted @ 29 ?
You don’t have to answer any questions, but it is kind of
suspiciousinteresting that you answered the post 30 but did not answer post 29 which was also addressed to you.¡Feliz Año Nuevo!
http://1.bp.blogspot.com/-gKHu.....+mejor.jpg
In Vivo Single-Cell Detection of Metabolic Oscillations in Stem Cells
DOI: http://dx.doi.org/10.1016/j.celrep.2014.12.007
Through the use of bulk measurements in metabolic organs, the circadian clock was shown to play roles in organismal energy homeostasis.
However, the relationship between metabolic and circadian oscillations has not been studied in vivo at a single-cell level.
Also, it is unknown whether the circadian clock controls metabolism in stem cells.
We used a sensitive, noninvasive method to detect metabolic oscillations and circadian phase within epidermal stem cells in live mice at the single-cell level.
We observe a higher NADH/NAD+ ratio, reflecting an increased glycolysis/oxidative phosphorylation ratio during the night compared to the day.
Furthermore, we demonstrate that single-cell metabolic heterogeneity within the basal cell layer correlates with the circadian clock and that diurnal fluctuations in NADH/NAD+ ratio are Bmal1 dependent.
Our data show that, in proliferating stem cells, the circadian clock coordinates activities of oxidative phosphorylation and glycolysis with DNA synthesis, perhaps as a protective mechanism against genotoxicity.
http://www.cell.com/cell-repor.....14)01018-3
Erk Signaling Suppresses Embryonic Stem Cell Self-Renewal to Specify Endoderm
DOI: http://dx.doi.org/10.1016/j.celrep.2014.11.032
Fgf signaling via Erk activation has been associated with both neural induction and the generation of a primed state for the differentiation of embryonic stem cells (ESCs) to all somatic lineages.
To dissect the role of Erk in both ESC self-renewal and lineage specification, we explored the requirements for this pathway in various in vitro differentiation settings.
A combination of pharmacological inhibition of Erk signaling and genetic loss of function reveal a role for Erk signaling in endodermal, but not neural differentiation.
Neural differentiation occurs normally despite a complete block to Erk phosphorylation.
In support of this, Erk activation in ESCs derepresses primitive endoderm (PrE) gene expression as a consequence of inhibiting the pluripotent/epiblast network.
The early response to Erk activation correlates with functional PrE priming, whereas sustained Erk activity results in PrE differentiation.
Taken together, our results suggest that Erk signaling suppresses pluripotent gene expression to enable endodermal differentiation.
http://www.cell.com/cell-repor.....14)00998-X
Spatial regulation of the spindle assembly checkpoint and anaphase-promoting complex
DOI: 10.1111/mmi.12871
The spindle assembly checkpoint (SAC) plays a critical role in preventing mitotic errors by inhibiting anaphase until all kinetochores are correctly attached to spindle microtubules.
In spite of the economic and medical importance of filamentous fungi, relatively little is known about the behavior of SAC proteins in these organisms.
In our efforts to understand the role of ?-tubulin in cell cycle regulation, we have created functional fluorescent protein fusions of four SAC proteins in Aspergillus nidulans, the homologs of Mad2, Mps1, Bub1/BubR1 and Bub3.
Time-lapse imaging reveals that SAC proteins are in distinct compartments of the cell until early mitosis when they co-localize at the spindle pole body.
SAC activity is, thus, spatially regulated in A.?nidulans.
Likewise, Cdc20, an activator of the anaphase-promoting complex/cyclosome, is excluded from interphase nuclei, but enters nuclei at mitotic onset and accumulates to a higher level in mitotic nuclei than in the surrounding nucleoplasm before leaving in anaphase/telophase.
The activity of this critical cell cycle regulatory complex is likely regulated by the location of Cdc20.
Finally, the ?-tubulin mutation mipAD159 causes a nuclear-specific failure of nuclear localization of Mps1 and Bub1/R1 but not of Cdc20, Bub3 or Mad2.
http://onlinelibrary.wiley.com.....1/abstract
Translational Regulation of the Post-Translational Circadian Mechanism
•DOI: 10.1371/journal.pgen.1004628
http://www.plosgenetics.org/ar.....en.1004628
Inhibition of FOXO1/3 Promotes Vascular Calcification
doi: 10.1161/ATVBAHA.114.304786
…the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification.
http://atvb.ahajournals.org/co.....5.abstract
O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells*
doi: 10.1074/mcp.M114.040691
Runx2 is the master switch controlling osteoblast differentiation and formation of the mineralized skeleton.
The post-translational modification of Runx2 by phosphorylation, ubiquitinylation, and acetylation modulates its activity, stability, and interactions with transcriptional co-regulators and chromatin remodeling proteins downstream of osteogenic signals.
Altogether, these findings link O-GlcNAc cycling to the Runx2-dependent regulation of the early ALP marker under osteoblast differentiation conditions.
http://www.mcponline.org/conte.....1.abstract
Genomic Determinants of Gene Regulation by 1,25-Dihydroxyvitamin D3 during Osteoblast-lineage Cell Differentiation*?
doi: 10.1074/jbc.M114.578104
The biological effects of 1?,25-dihydroxyvitamin D3 (1,25 (OH)2D3) on osteoblast differentiation and function differ significantly depending upon the cellular state of maturation.
Continued novel regulation by 1,25(OH)2D3, however, suggested that factors in addition to the VDR might also be involved.
We conclude that each of these mechanisms may contribute to the diverse actions of 1,25(OH)2D3 on differentiating osteoblasts.
http://www.jbc.org/content/289/28/19539.abstract
What about the cell membrane…? Will DNA, RNA and proteins work together without it even if they are present and “active’ at the same time…? Or… will the cell continue to live and function if one of the components is removed from the living and active cell…?
The answer is obvious to all logically thinking people… except the blind followers of Darwin… They believe that the obvious can somehow be omitted… ignored… so that their blind beliefs can be kept alive… but only in their blinded minds due to their hardened hearts…
#58 Quest
Interesting observation. Thanks.
Kinetochore motors drive congression of peripheral polar chromosomes by overcoming random arm-ejection forces
doi:10.1038/ncb3060
Accurate chromosome segregation during cell division in metazoans relies on proper chromosome congression at the equator.
Chromosome congression is achieved after bi-orientation to both spindle poles shortly after nuclear envelope breakdown, or by the coordinated action of motor proteins that slide misaligned chromosomes along pre-existing spindle microtubules1.
These proteins include the minus-end-directed kinetochore motor dynein2, 3, 4, 5, and the plus-end-directed motors ?CENP-E at kinetochores6, 7 and chromokinesins on chromosome arms8, 9, 10, 11.
However, how these opposite and spatially distinct activities are coordinated to drive chromosome congression remains unknown.
Here we used RNAi, chemical inhibition, kinetochore tracking and laser microsurgery to uncover the functional hierarchy between kinetochore and arm-associated motors, exclusively required for congression of peripheral polar chromosomes in human cells.
We show that dynein poleward force counteracts chromokinesins to prevent stabilization of immature/incorrect end-on kinetochore–microtubule attachments and random ejection of polar chromosomes.
At the poles, ?CENP-E becomes dominant over dynein and chromokinesins to bias chromosome ejection towards the equator.
Thus, dynein and ?CENP-E at kinetochores drive congression of peripheral polar chromosomes by preventing arm-ejection forces mediated by chromokinesins from working in the wrong direction.
http://www.nature.com/ncb/jour.....b3060.html
DNA methylation changes during cell differentiation
overall perspective on the connections between DNA methylation and other epigenetic marks and the interplay with transcription factors
http://www.abcam.com/events/dn.....ee-webinar
A two-step mechanism for epigenetic specification of centromere identity and function
doi:10.1038/ncb2805
The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark.
Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely.
Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3.
Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively.
http://www.nature.com/ncb/jour.....b2805.html
Membranes Organize Cellular Complexity
http://learn.genetics.utah.edu.....membranes/
Fed up with so many boring references to research papers posted here lately?
Wanna try something lighter, more entertaining?
Considering that apparently the fiction genre has been more popular in literature history, here’s an amusing story, which I think was referred to in another post in this site in the last quarter of last year. (if this doesn’t make you laugh, perhaps nothing else will):
You may read more on this here: http://www.biomedcentral.com/1741-7007/12/76
Enjoy it! 🙂
#64 follow-up / important reminder:
https://www.youtube.com/embed/Ug75diEyiA0
Targeting the Cell’s ‘Biological Clock’ in Promising New Cancer Therapy
Cell biologists at UT Southwestern Medical Center have targeted telomeres with a small molecule called 6-thiodG that takes advantage of the cell’s “biological clock” to kill cancer cells and shrink tumor growth.
http://www.biosciencetechnolog.....cation=top
Sensors at Centrosomes Reveal Determinants of Local Separase Activity
http://www.ncbi.nlm.nih.gov/pm.....MC4191886/
CENP-W Plays a Role in Maintaining Bipolar Spindle Structure
http://www.ncbi.nlm.nih.gov/pm.....MC4198083/
Kinetochore-microtubule stability governs the metaphase requirement for Eg5
Although it is known that Kif15, a second mitotic kinesin, enforces spindle bipolarity in the absence of Eg5, how Kif15 functions in this capacity and/or whether other biochemical or physical properties of the spindle promote its bipolarity have been poorly studied.
http://www.ncbi.nlm.nih.gov/pm.....MC4072578/
The spindle and kinetochore-associated (Ska) complex enhances binding of the anaphase-promoting complex/cyclosome (APC/C) to chromosomes and promotes mitotic exit.
http://www.ncbi.nlm.nih.gov/pubmed/24403607
Molecular Characterization of an Intact p53 Pathway Subtype
http://www.ncbi.nlm.nih.gov/pubmed/25460179
STEM CELLS AND REGENERATION
Postnatal subventricular zone progenitors switch their fate to generate neurons with distinct synaptic input patterns
doi: 10.1242/dev.110767
It is unknown to what extent the distinct synaptic input patterns are already determined in SVZ progenitors and/or by the brain circuit into which neurons integrate.
http://dev.biologists.org/cont.....tract?etoc
Establishing neural crest identity: a gene regulatory recipe
doi: 10.1242/dev.105445
Neural crest development is thought to be controlled by a suite of transcriptional and epigenetic inputs arranged hierarchically in a gene regulatory network.
http://dev.biologists.org/content/142/2/242
When DNA gets sent to time-out
http://www.rdmag.com/news/2015.....cation=top
“Now we have a lot of interesting questions to answer about how different types of cells use this mechanism to regulate different sets of genes.”?
A new discovery, which may or may not have answered outstanding questions, has raised “a lot of interesting questions”! Doesn’t this seem like a never-ending story?
🙂
#71 addendum
Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction
doi: 10.1083/jcb.201409108
The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood.
http://jcb.rupress.org/content.....45dcec0140
Can’t wait to see the revelation of the unknown part. 🙂
Can’t wait to see the revelation of the unknown part. 🙂
Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair
doi: 10.1083/jcb.201405077
however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown.
http://jcb.rupress.org/content.....45dcec0140
Dionisio:
“Doesn’t this seem like a never-ending story?”
It does, indeed!
The problem is: we learn layer after layer of complexity in the regulation cascade, but we never get to the decisions. How are the decisions made? What determines the different decisions?
After all, different cells make different decisions, which activate different, unending layers of “differentiation” (yes, the word indeed comes from “different”, although we often forget it).
Where do those different decisions come into existence? What codes for them? And for the strict connection between the decisions and the following multiple, endless layers of regulation?
And why are there so many layers of regulation, parallel or sequential, and interconnected? The reasonable answer to that seems to be: to allow for more decisions, in the course of action: checkpoints, alternatives, meta-regulations, and so on.
How does the neo darwinist paradigm help in understanding all that?
Again, at least this answer is easy: it does not help at all.
Dionisio:
Just a quick read of the abstract of the last paper you linked will be enough to give a taste of what we are discussing here:
And this is only part of a repair mechanism!
Easy-peasy! Random chance and Co.
gpuccio @ 77
Would anyone else like to comment on this?
You may want to let all your interlocutors know that their comments are most welcome this time.
🙂
#78 gpuccio
Well, what else can I say? It tastes divinely! 🙂
Wow!
#79 Axel
Of course! That’s obvious! Glad to see you finally understood that!
Now see if you can convince our beloved friend gpuccio too.
🙂
Can’t wait to read newer reports about those ‘largely unknown’ mechanisms in the days ahead. 🙂
Pseudoscientific fiction or fictional pseudoscience ?
None of that. Just real science with bogus terminology scattered through the reports, to make it sound cool.
🙂
This took place last year, but still it’s interesting to read about it:
So let me get this straight Dio, you ask for explanations about how things evolved and then when presented with it, you just read the abstract and call it “pseudoscientific fiction or fictional pseudoscience?
Yeah sounds about right.
Thank you for making you and your friends look even more foolish than you already do.
#71 addendum
How DNA Wallflowers Miss the Epigenetic Dance
It seems likely that YY1 is involved in summoning the proteins that attach the molecular tags to the histones.
But whether YY1 has additional roles, like acting as a magnet to bring the DNA to the lamina, is unclear.
http://www.genengnews.com/gen-...../81250775/
#84 follow-up
I knew those ‘tricky’ comments will prompt certain folks to comment on that post.
The bait worked!
They react so abruptly to the ‘tricky’ question, that can’t even notice it was just a question. Then to make things even worse, they stop reading the rest of the post, hence they miss the last two sentences.
That makes me feel a little better about my proven poor reading comprehension… at least now I know I’m not alone. Although there’s a huge difference between not being good at reading and not wanting to read well intentionally. 🙂
Dio, you can say whatever you want but the fact that you try to belittle months of people’s work on something that you don’t even understand is all anybody needs to know to see how childish you are.
AVS,
Dorogoi, ty umnitsa, prosto molodets! 🙂
If only you spoke Biologese 1/1000 as well as any other language, Dio.
If only.
AVS,
Trying damage control? Well, too late now.
You swallowed the ‘tricky’ bait along with the hook!
You didn’t even noticed it was just a question. Then, to make things worse, didn’t read the rest of the post, which clarify the whole meaning of the comments. Instead, you abruptly overreacted and started your usual personal attacks. Too bad, buddy. Next time be more cautious. 🙂
Your comrades and fellow travelers may not like what you just did. 🙂
This was an easy experiment on human communications and reactions to different textual messages. I appreciate you volunteered to participate in the experiment. Sorry for any inconvenience this may have caused to you. But perhaps someday you’ll look back at this embarrassing moment you just experienced and will see that it was not that bad after all.
🙂
Why don’t you try and comment on gpuccio’s posts #77 better?
Don’t know what to say about it?
🙂
Don’t worry Dio, I’m already sorting through Pucci’s hogwash on another post.
And I’m glad to be of service. Whenever I see you talking out of your rear end, I’ll bring you back to planet Earth.
LoL! As if…
Transport by Populations of Fast and Slow Kinesins Uncovers Novel Family-Dependent Motor Characteristics Important for In Vivo Function
DOI: http://dx.doi.org/10.1016/j.bpj.2014.09.009
Intracellular cargo transport frequently involves multiple motor types, either having opposite directionality or having the same directionality but different speeds.
Although significant progress has been made in characterizing kinesin motors at the single-molecule level, predicting their ensemble behavior is challenging and requires tight coupling between experiments and modeling to uncover the underlying motor behavior.
http://www.cell.com/biophysj/a.....14)00947-3
Genomic Perspectives of Transcriptional Regulation in Forebrain Development
DOI: http://dx.doi.org/10.1016/j.neuron.2014.11.021
The activity of neurons in the primate lateral prefrontal cortex (LPFC) is strongly modulated by visual attention.
Such a modulation has mostly been documented by averaging the activity of independently recorded neurons over repeated experimental trials.
However, in realistic settings, ensembles of simultaneously active LPFC neurons must generate attentional signals on a single-trial basis, despite the individual and correlated variability of neuronal responses.
Whether, under these circumstances, the LPFC can reliably generate attentional signals is unclear.
http://www.cell.com/neuron/abs.....14)01073-3
Visual Areas Exert Feedforward and Feedback Influences through Distinct Frequency Channels
DOI: http://dx.doi.org/10.1016/j.neuron.2014.12.018
Visual cortical areas subserve cognitive functions by interacting in both feedforward and feedback directions.
While feedforward influences convey sensory signals, feedback influences modulate feedforward signaling according to the current behavioral context.
http://www.cell.com/neuron/abs.....14)01099-X
The drosophila Chmp1 protein determines wing cell fate through regulation of epidermal growth factor receptor signaling
DOI: 10.1002/dvdy.24140
Receptor down-regulation by the multivesicular body (MVB) pathway is critical for many cellular signaling events.
MVB generation is mediated by the highly conserved ESCRT (0, I, II, and III) protein complexes.
Chmp1 is an ESCRT-III component and a putative tumor suppressor in humans.
However, published data on Chmp1 activity are conflicting and its role during tissue development is not well defined.
http://onlinelibrary.wiley.com.....0/abstract
The condensin component ?NCAPG2 regulates microtubule–kinetochore attachment through recruitment of ?Polo-like kinase 1 to kinetochores
doi:10.1038/ncomms5588
http://www.nature.com/ncomms/2.....s5588.html
The outer kinetochore protein KNL-1 contains a defined oligomerization domain in nematodes
Citable URI: http://hdl.handle.net/1721.1/92587
The kinetochore is a large, macromolecular assembly that is essential for connecting chromosomes to microtubules during mitosis.
Despite the recent identification of multiple kinetochore components, the nature and organization of the higher order kinetochore structure remain unknown.
http://dspace.mit.edu/handle/1721.1/92587
Dionisio:
Please, behave yourself! Our kind interlocutor AVS is already busy sorting through my hogwash on another post. Don’t distract him. He needs his full concentration… 🙂
A Protective Chaperone for the Kinetochore Adaptor Bub3
DOI: http://dx.doi.org/10.1016/j.devcel.2014.01.024
BuGZ Is Required for Bub3 Stability, Bub1 Kinetochore Function, and Chromosome Alignment
DOI: http://dx.doi.org/10.1016/j.devcel.2013.12.014
During mitosis, the spindle assembly checkpoint (SAC) monitors the attachment of kinetochores (KTs) to the plus ends of spindle microtubules (MTs) and prevents anaphase onset until chromosomes are aligned and KTs are under proper tension.
http://www.cell.com/developmen.....13)00761-2
A Microtubule-Associated Zinc Finger Protein, BuGZ, Regulates Mitotic Chromosome Alignment by Ensuring Bub3 Stability and Kinetochore Targeting
DOI: http://dx.doi.org/10.1016/j.devcel.2013.12.013
Equal chromosome segregation requires proper assembly of many proteins, including Bub3, onto kinetochores to promote kinetochore-microtubule interactions.
BuGZ not only serves as a molecular chaperone for Bub3 but also enhances its loading onto kinetochores during prometaphase in a microtubule-dependent manner to promote chromosome alignment.
http://www.cell.com/developmen.....13)00760-0
#101 gpuccio
Sorry, but I did not realize our kind interlocutors needed so much time to understand what you wrote so clearly.
Ok, I’ll try not to distract their attention away from that task that seems so difficult for them to do.
🙂
Here’s a case where an outstanding question has been answered. 🙂
Extracellular matrix assembly: a multiscale deconstruction
doi:10.1038/nrm3902
The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour.
The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM.
The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.
http://www.nature.com/nrm/jour.....m3902.html
Remodelling the extracellular matrix in development and disease
doi:10.1038/nrm3904
The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling.
This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases.
The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation.
ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands.
Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer.
A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.
http://www.nature.com/nrm/jour.....m3904.html
Mechanotransduction and extracellular matrix homeostasis
doi:10.1038/nrm3896
Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health.
The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function.
Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.
http://www.nature.com/nrm/jour.....m3896.html
Role of the extracellular matrix in regulating stem cell fate
doi:10.1038/nrm3620
The field of stem cells and regenerative medicine offers considerable promise as a means of delivering new treatments for a wide range of diseases.
In order to maximize the effectiveness of cell-based therapies — whether stimulating expansion of endogenous cells or transplanting cells into patients — it is essential to understand the environmental (niche) signals that regulate stem cell behaviour.
One of those signals is from the extracellular matrix (ECM).
New technologies have offered insights into how stem cells sense signals from the ECM and how they respond to these signals at the molecular level, which ultimately regulate their fate.
http://www.nature.com/nrm/jour.....m3620.html
More examples of deleterious mutations?
Mutation of the kinetochore protein, CENPF, linked to major health issues.
doi:10.1136/jmedgenet-2014-102691
Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly.
http://jmg.bmj.com/content/ear.....1.abstract
http://www.gene-tools.com/cont.....phenotypes
Another encouraging case of an answered question.
Meikin is a conserved regulator of meiosis-I-specific kinetochore function
doi:10.1038/nature14097
The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis.
Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase.
Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier.
Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive.
MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin.
These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner.
[…] the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.
http://www.nature.com/nature/j.....14097.html
Geometry and force behind kinetochore orientation: lessons from meiosis
doi:10.1038/nrm3349
During mitosis, replicated chromosomes (sister chromatids) become attached at the kinetochore by spindle microtubules emanating from opposite poles and segregate equationally.
In the first division of meiosis, however, sister chromatids become attached from the same pole and co-segregate, whereas homologous chromosomes connected by chiasmata segregate to opposite poles. [why?]
Disorder in this specialized chromosome attachment in meiosis is the leading cause of miscarriage in humans.
Recent studies have elucidated the molecular mechanisms determining chromosome orientation, and consequently segregation, in meiosis.
Comparative studies of meiosis and mitosis have led to the general principle that kinetochore geometry and tension exerted by microtubules synergistically generate chromosome orientation. [how?]
http://www.nature.com/nrm/jour.....m3349.html
The centrosome orientation checkpoint is germline stem cell specific and operates prior to the spindle assembly checkpoint…
Asymmetric cell division is utilized by a broad range of cell types to generate two daughter cells with distinct cell fates.
In stem cell populations asymmetric cell division is believed to be crucial for maintaining tissue homeostasis, failure of which can lead to tissue degeneration or hyperplasia/tumorigenesis.
Asymmetric cell divisions also underlie cell fate diversification during development.
Accordingly, the mechanisms by which asymmetric cell division is achieved have been extensively studied, although the check points that are in place to protect against potential perturbation of the process are poorly understood.
http://www.ncbi.nlm.nih.gov/pubmed/25480919
Getting there. Work in progress. 🙂
Work in progress…
PLEKHM1: A Multiprotein Adaptor for the Endolysosomal System
DOI: http://dx.doi.org/10.1016/j.molcel.2014.12.022
Two papers by McEwan et al. ( McEwan et al., 2015a, 2015b ) identify interactions of PLEKHM1 with autophagosome-associated Atg8 proteins and Salmonella typhimurium effector, SifA, linking autophagy and the Salmonella-containing vacuole (SCV) to the endolysosomal Rab7/HOPS-regulated tethering machinery.
PLEKHM1 Regulates Autophagosome-Lysosome Fusion through HOPS Complex and LC3/GABARAP Proteins
DOI: http://dx.doi.org/10.1016/j.molcel.2014.11.006
The lysosome is the final destination for degradation of endocytic cargo, plasma membrane constituents, and intracellular components sequestered by macroautophagy.
Fusion of endosomes and autophagosomes with the lysosome depends on the GTPase Rab7 and the homotypic fusion and protein sorting (HOPS) complex, but adaptor proteins that link endocytic and autophagy pathways with lysosomes are poorly characterized.
Depletion of PLEKHM1 blocks lysosomal degradation of endocytic (EGFR) cargo and enhances presentation of MHC class I molecules.
Moreover, genetic loss of PLEKHM1 impedes autophagy flux upon mTOR inhibition and PLEKHM1 regulates clearance of protein aggregates in an autophagy- and LIR-dependent manner.
PLEKHM1 is thus a multivalent endocytic adaptor involved in the lysosome fusion events controlling selective and nonselective autophagy pathways.
http://www.cell.com/molecular-.....14)00871-5
Functional Splicing Network Reveals Extensive Regulatory Potential of the Core Spliceosomal Machinery
DOI: http://dx.doi.org/10.1016/j.molcel.2014.10.030
Pre-mRNA splicing relies on the poorly understood dynamic interplay between >150 protein components of the spliceosome.
The steps at which splicing can be regulated remain largely unknown.
We systematically analyzed the effect of knocking down the components of the splicing machinery on alternative splicing events relevant for cell proliferation and apoptosis and used this information to reconstruct a network of functional interactions.
The network accurately captures known physical and functional associations and identifies new ones, revealing remarkable regulatory potential of core spliceosomal components, related to the order and duration of their recruitment during spliceosome assembly.
In contrast with standard models of regulation at early steps of splice site recognition, factors involved in catalytic activation of the spliceosome display regulatory properties.
The network also sheds light on the antagonism between hnRNP C and U2AF, and on targets of antitumor drugs, and can be widely used to identify mechanisms of splicing regulation.
http://www.cell.com/molecular-.....ll%20Press
ATM-mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint.
doi: 10.1093/carcin/bgu087.
The spindle assembly checkpoint (SAC), which blocks anaphase onset until all chromosomes have bi-oriented, is one of the key self-monitoring systems of the eukaryotic cell cycle for genome stability.
The mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is hyperphosphorylated in mitosis.
However, the kinases responsible for Mad1 phosphorylation and its functional significance are not fully understood.
http://www.ncbi.nlm.nih.gov/pubmed/24728176
Protein Folding Issues
http://biowiki.ucdavis.edu/Bio....._Stability
http://chemwiki.ucdavis.edu/Bi.....in_Folding
http://en.wikipedia.org/wiki/Protein_folding
http://en.wikipedia.org/wiki/Protein_structure
Regulation of autophagy by protein post-translational modification
doi:10.1038/labinvest.2014.131
Autophagy is a lysosome-mediated intracellular protein degradation process that involves about 38 autophagy-related genes as well as key signaling pathways that sense cellular metabolic and redox status, and has an important role in quality control of macromolecules and organelles.
As with other major cellular pathways, autophagy proteins are subjected to regulatory post-translational modification.
Phosphorylation is so far the most intensively studied post-translational modification in the autophagy process, followed by ubiquitination and acetylation.
An interesting and new area is also now emerging, which appears to complement these more traditional mechanisms, and includes O-GlcNAcylation and redox regulation at thiol residues.
Identification of the full spectrum of post-translational modifications of autophagy proteins, and determination of their impact on autophagy will be crucial for a better understanding of autophagy regulation, its deficits in diseases, and how to exploit this process for disease therapies.
http://www.nature.com/labinves.....4131a.html
Post-translational Regulation of the Type III Inositol 1,4,5-Trisphosphate Receptor by miRNA-506.
doi: 10.1074/jbc.M114.587030.
The type III isoform of the inositol 1,4,5-trisphosphate receptor (InsP3R3) is apically localized and triggers Ca(2+) waves and secretion in a number of polarized epithelia.
However, nothing is known about epigenetic regulation of this InsP3R isoform.
http://www.ncbi.nlm.nih.gov/pu...../#comments
Principles of Translational Control: An Overview
doi: 10.1101/cshperspect.a011528
http://cshperspectives.cshlp.o.....hort?rss=1
Regulation of mRNA Translation by Signaling Pathways
doi: 10.1101/cshperspect.a012252
http://cshperspectives.cshlp.o.....hort?rss=1
The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges
doi: 10.1101/cshperspect.a011544
http://cshperspectives.cshlp.o.....hort?rss=1
FASEB
Nanoparticles
http://www.faseb.org/pdfviewer.....rticle.pdf
Epigenetics
http://www.faseb.org/pdfviewer.....rizons.pdf
Prostaglandin:
http://en.wikipedia.org/wiki/Prostaglandin
#134 addendum
What about the ‘role’ that remains ‘elusive’? Did they mean that the role ‘remained’ elusive before their experiment finally cleared it?
Is that ‘role’ described in the paper?
The title of this paper refers to an ‘orchestration’ but is that ‘orchestration’ described in details within this paper, or through references to other sources?
That’s something to look at later. But it’s not clear in the abstract.
Just revealing that someone was at a location where certain event took place does not say what role that someone had in the given event.
If we say that the role of that person in that event remains elusive, then we reveal that that person was at the location where the event occurred, still the person’s role in the event remains unclear.
If we add that on the cases where the same person wasn’t present at the given location the referred event did not occur, then we can say that it looks as though that person’s presence makes a difference, but the ‘role’ of that person in that event still remains unclear.
The abstract seems to indicate that their experiments confirmed that the presence or absence of the Chromatin remodeling made a difference, but it’s not clear how it made the difference.
Perhaps the paper provides more details, but the abstract does not indicate explicitly that the ‘role’ is described, or the ‘orchestration’ is described.
Later, if we look into the actual paper text, we might find the detailed description of the ‘role’ and the ‘orchestration’. In that case the abstract could have been written saying that the ‘role’ remained elusive until this paper, but no longer. But maybe that’s what they meant? we’ll have to look into the paper to see if that’s the case. That will have to wait until the next phase of the project. It’s not important now. This was just for illustration.
Some interlocutors in this site have complained about my use of ‘bold’ characters to highlight part of the text. FYI – the highlighted text is a personal reminder to look for additional information (within the referred paper or somewhere else) in order to explain or describe with more details the highlighted text.
How do Hsp70 and Hsp90 appear on the post-translational scene? how are they regulated to be available when needed for their combined chaperoning tasks? are they constantly produced, hence always available when needed? or produced on demand upon request by some signaling pathways and regulatory mechanisms?
Protein Folding in the Cell, from Atom to Organism
doi: 10.1096/fj.14-1202ufm
Proper cell function requires proper protein folding.
Misfolding of specific proteins, caused either by mutation or environmental stress, underlies many human diseases, including cancer and diabetes and Parkinson’s, Huntington’s, and Alzheimer’s disease.
http://www.fasebj.org/content/28/12/5034.full
Revealing the inner workings of a molecular motor
In research published in the Journal of Cell Biology, scientists from the RIKEN Brain Science Institute in Japan have made important steps toward understanding how dynein—a “molecular motor”—walks along tube-like structures in the cell to move cellular cargo from the outer structures toward the cell body of neurons.
The action of this molecule is important for a number of cell functions including axonal transport and chromosome segregation, and its dysfunction is known to lead to a congenital developmental brain disorder known as lissencephaly.
Read more at: http://phys.org/news/2015-01-r.....r.html#jCp
http://phys.org/news/2015-01-r......html#nRlv
The epigenetic switchboard
Epigenetic signals help determine which genes are activated at which time in a given cell.
A novel analytical method enables systematic characterization of the relevant epigenetic tags, and reveals that the system adapts to the loss of single epigenetic writer and eraser enzymes.
Read more at: http://phys.org/news/2015-01-e.....d.html#jCp
How do those signals work? where do they come from? when? what triggers them? what determines their timing?
Perhaps this is explained in the same paper or in other papers or textbooks?
http://phys.org/news/2015-01-e......html#nRlv
noncoding RNA can be vital for successful pregnancy
The proteins that underlie nearly all biological mechanisms are produced from RNA molecules transcribed from genetic sequences in DNA.
However, a large proportion of transcribed RNA is not transcoded into proteins and appears to have no significant function.
Shinichi Nakagawa from the RIKEN RNA Biology Laboratory and colleagues have now found that one particular long noncoding RNA (lncRNA) is essential for fertility in some circumstances.
Read more at: http://phys.org/news/2015-01-m.....l.html#jCp
Appearances can be deceiving.
http://phys.org/news/2015-01-m......html#nRlv
Tumour-blocking role found for cell regulation molecule
Manchester scientists have explored the role of a protein in regulating tumour development and found that it suppresses liver cancer growth in the lab.
Read more at: http://phys.org/news/2015-01-t.....e.html#jCp
JNK Suppresses Tumor Formation via a Gene-Expression Program Mediated by ATF2
DOI: http://dx.doi.org/10.1016/j.celrep.2014.10.043
http://www.cell.com/cell-repor.....all%3Dtrue
mysterious molecular mechanism powering cells
A team led by structural biologists at The Scripps Research Institute (TSRI) has taken a big step toward understanding the intricate molecular mechanism of a metabolic enzyme produced in most forms of life on Earth.
Read more at: http://phys.org/news/2015-01-s.....m.html#jCp
Old consensus broken? 🙂
How come? what went wrong in their previous thinking?
What went wrong with their previous wide assumptions?
Morphology-based taxonomies do not accurately reflect genealogical relationships of rock sponges
http://phys.org/news/2015-01-m......html#nRlv
Deceptive Desmas: Molecular Phylogenetics Suggests a New Classification and Uncovers Convergent Evolution of Lithistid Demosponges
•DOI: 10.1371/journal.pone.0116038
http://www.plosone.org/article.....ne.0116038
Researchers have looked at a species of fish to help unravel one of the biggest mysteries in evolutionary biology.
“The importance of this work lies in the fundamental question: how and why do variants of the same animal exist in nature,” he said.
“Colour variants of the same species are a striking example of biological variation, yet the adaptive significance and what evolutionary processes maintain them, remains unknown.”
“Given the complexities of colour variants in species, more work is needed to understand how differences in colouration might influence the susceptibility of dark and gold individuals to different predators and under different environmental conditions,”
Read more at: http://phys.org/news/2015-01-devil.html#jCp
How do the associated mechanisms function? what effect do they have?
Check the given paper or other papers for more details
Where is the beef?
Ok, that’s cool, thanks.
But how did it all start? 🙂
http://phys.org/news/2015-01-a......html#nRlv
Where is the beef?
Bleb-driven chemotaxis of Dictyostelium cells
doi: 10.1083/jcb.201306147
http://jcb.rupress.org/content/204/6/1027
Dictyostelium uses ether?linked inositol phospholipids for intracellular signaling
DOI 10.15252/embj.201488677
http://emboj.embopress.org/con.....8.abstract
How blebs and pseudopods cooperate during chemotaxis
doi: 10.1073/pnas.1322291111
http://www.pnas.org/content/111/32/11703.abstract
A unified vision of the building blocks of life?
doi:10.1038/ncb0908-1015
From the discovery of DNA to the sequencing of the human genome, the template-dependent formation of biological molecules from gene to RNA and protein has been the central tenet of biology.
Yet the origins of many diseases, including allergy, Alzheimer’s disease, asthma, autism, diabetes, inflammatory bowel disease, Lou Gehrig’s disease, multiple sclerosis, Parkinson’s disease and rheumatoid arthritis, continue to evade our understanding.
http://www.nature.com/ncb/jour.....-1015.html
The mitotic checkpoint protein kinase BUB1 is an engine in the TGF-? signaling apparatus
DOI: 10.1126/scisignal.aaa4636
The mitotic checkpoint guarantees faithful chromosomal segregation during cell division.
…the mitotic checkpoint kinase BUB1 promotes the activity of TGF-? receptors, which adds new molecular links between these fundamental biological processes.
http://stke.sciencemag.org/con.....de0b10bfc9
Know Your Limits: The Role of Boundaries in the Development of Spatial Representation
DOI: http://dx.doi.org/10.1016/j.neuron.2014.03.017
http://www.cell.com/neuron/abs.....14)00247-5
Dionisio, this slightly more recent paper for the development of spatial representation is also excellent:
Coherence among Head Direction Cells before Eye Opening in Rat Pups.
Bjerknes TL, Langston RF, Kruge IU, Moser EI, Moser MB.
doi: 10.1016/j.cub.2014.11.009. Epub 2014 Nov 26.
http://www.ncbi.nlm.nih.gov/pubmed/25466682
The bolded information at the end of its abstract is vital to the further development of the Grid Cell Attractor Network and earlier model that Edvard Moser knows about. The new paper seems to have been worded so that someone like myself would immediately recognize its significance, and know how to make it work in a computer model.
Mechanism of suppression of chromosomal instability by DNA polymerase POLQ.
doi: 10.1371/journal.pgen.1004654
Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified.
Here we define the specific mechanism by which POLQ restricts harmful DNA instability.
This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations.
Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.
http://www.ncbi.nlm.nih.gov/pubmed/25275444
#153 Gary S. Gatlin
Thank you for sharing the reference to that interesting paper.
Genome resilience and prevalence of segmental duplications following fast neutron irradiation of soybean
doi: 10.1534/genetics.114.170340
http://www.ncbi.nlm.nih.gov/pubmed/25213171
Explain the details describing that resilience.
Does the paper contain ALL the details?
ALL? This means that no potential questions have been left unanswered?
Dionisio I appreciate the paper that you provided, which linked to the open access Moser intelligence laboratory paper that was published just in time for Christmas. With my day job and all else I didn’t have time to keep up with their progress. Now I just need to figure out the details, which is sure not easy for a paper like this one. And I honestly doubt for something like this I’ll find much help from UD, Biologic or Discovery Institute.
Regulation of RNA granule dynamics…
DOI: http://dx.doi.org/10.7554/eLife.04591
RNA granules have been likened to liquid droplets whose dynamics depend on the controlled dissolution and condensation of internal components.
The molecules and reactions that drive these dynamics in vivo are not well understood.
http://elifesciences.org/content/3/e04591
Lentivirus?mediated silencing of spindle and kinetochore?associated protein 1
doi: 10.3892/mmr.2015.3175
Spindle and kinetochore?associated protein 1 (SKA1) is an important component of the human kinetochore, which plays a key role in mitosis.
http://www.ncbi.nlm.nih.gov/pubmed/25573192
From Single-Cell Noise to Transcriptional Music
Although an orchestra warming up before a performance may produce a meaningless mixture of sounds, the individual musicians are probably playing bits and pieces from the same score.
If only listeners could isolate the fragmentary themes and motifs, and move them backwards and forwards in the imagination, order would emerge from chaos, the sense of musical arrangements would become clear.
Something like this organizational power has been needed in single-cell genomics.
Although individual cells all play from the same score—the genome—they don’t necessarily act as though they are following a conductor’s baton.
Even cells of the same type may appear to be transcriptionally distinct simply because they are at different stages of the cell cycle, or are different ages.
Confounding factors such as these can obscure deep commonalities or—to return to the orchestra analogy—unheard harmonies.
http://www.genengnews.com/gen-...../81250824/
Bifurcation analysis of single-cell gene expression data reveals epigenetic landscape
doi: 10.1073/pnas.1408993111
http://intl.pnas.org/content/111/52/E5643.full
The centrosome orientation checkpoint is germline stem cell specific and operates prior to the spindle assembly checkpoint
http://www.ncbi.nlm.nih.gov/pubmed/25480919
Asymmetric cell division is utilized by a broad range of cell types to generate two daughter cells with distinct cell fates.
In stem cell populations asymmetric cell division is believed to be crucial for maintaining tissue homeostasis, failure of which can lead to tissue degeneration or hyperplasia/tumorigenesis.
Asymmetric cell divisions also underlie cell fate diversification during development.
Accordingly, the mechanisms by which asymmetric cell division is achieved have been extensively studied, although the check points that are in place to protect against potential perturbation of the process are poorly understood.
This study may provide a framework for identifying and understanding similar mechanisms that might be in place in other asymmetrically dividing cell types.
What mechanisms determine that a protein is ubiquitously expressed? Branch out on this expression subtopic.
What determines the localization of TRAIP? Branch out on this protein localization subtopic.
Search the answers within the payer first, then in other papers.
Evolution leading to a potential revolution?
http://www.uncommondescent.com.....ent-543230
🙂
How many details have to work right in the biological systems in order for the systems to function properly ?
For the above highlighted text, explain ‘how’ in details, by indicating the paper(s) where they answer such questions.
Drive, sense, leads, govern, produce, … how?
How exactly is that dynamics? Timers, actors or executors, scenarios, signaling pathways. regulatory networks, etc.?
Fascinating issues that raise questions about interesting interconnected structures/circuits and their interrelated functioning.
[?] – any valid combination of these questions: why? how? when? where? what for?
[?] – any valid combination of these questions: why? how? when? where? what for? Also, explain the availability (always or on demand?; everywhere or specifically localized?) of the factors involved in the mechanisms.
The importance of understanding, as precisely as possible, the interrelated functioning of interconnected biological subsystems, may be noticeable in this biomedical research example, dealing with single nucleotide polymorphisms (SNPs) of genes involved in spindle assembly checkpoint (SAC).
http://meetinglibrary.asco.org/content/104590
#178 addendum
http://rstb.royalsocietypublis...../1584/3595
http://www.ncbi.nlm.nih.gov/pubmed/22084386
#178 addendum
http://rstb.royalsocietypublis...../1584/3595
Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.
http://www.ncbi.nlm.nih.gov/pubmed/25411801
http://www.mdpi.com/1422-0067/15/11/21381
The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation
doi: 10.3389/fphys.2014.00368
http://journal.frontiersin.org.....00368/full
http://www.nature.com/nrm/jour.....m3494.html
Interesting presentation topics:
Biology, Driven by Data
#189 addendum
Keystone Symposia on Molecular and Cellular Biology
Endoderm Lineages in Development and Disease
http://www.keystonesymposia.or.....n=Cell15B2
Proteins of the mitotic checkpoint and spindle…
doi:10.1136/jclinpath-2014-202728
http://jcp.bmj.com/content/ear.....2728.short
With so many things that can go wrong and mess everything up, how does the whole system still work?
Does the word robustness come to mind?
198 follow-up
What factors determine the location(s) of the DNA Methylation? Assuming it is a stochastic process, what systemic configuration allows such stochastic process to produce the results it does? How does such structural configuration get setup to begin with?
OMICS Tutorial
Feb 1, 2015 (Vol. 35, No. 3)
Systems Biology Tools for Integrated Omics Analysis
Understanding Disease Mechanisms through Multi-Omics Data Integration Pathway Analysis
Advancements in next-generation sequencing (NGS) technologies have enabled researchers to generate genome-wide data of unprecedented quality and quantity.
Genomics, expression, microRNA, chromatin IP, methylation, histone modification, and more recently chromosome confirmation capture are rapidly moving into the clinical setting.
Projects like 1000 Genomes, Encode, Blueprint, and many smaller projects are providing a rich source of background information and understanding of the genome and the epigenome in relation to normal and disease states.
With data generation growing at an exponential rate, the need for efficient analyses, data reduction, and comprehensible visualizations is critical for biomedical interpretation of NGS data.
http://genengnews.com/gen-arti.....ysis/5410/
What’s Next for Next-Gen Sequencing?
A More Embedded, Pervasive Genomics Sets the Stage for Increasingly Ambitious Applications
MaryAnn Labant
http://genengnews.com/gen-arti.....cing/5405/
(*) this term ‘evolution’ seems correctly used in this context. Here it seems to refer to a particular cellular/molecular mechanism they can see happening. It’s not a gross extrapolation of an adaptability mechanism.
205 addendum
#204 addendum
How did these creatures appear to begin with?
Is that explained anywhere?
http://www.washingtonpost.com/.....tional_pop
Bacteria evolution is seem everyday. Ever heard of antibiotics resistance? But they remain bacteria, as far as I’m aware of.
Isn’t there evolution within every species? But how did their complex development mechanisms evolve into the development mechanisms of another species?
For the following paper, a question could be: how did these creatures appear to begin with? Is that explained anywhere? Did I miss that memo? 🙂
http://www.pnas.org/content/ea.....2.abstract
Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre.
The Walter and Eliza Hall Institute for Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia.
Immunology Today (Impact Factor: 9.49). 10/2000; 21(9):436-41. DOI: 10.1016/S0167-5699(00)01687-X
Source: PubMed
Until recently, the relationship between apoptosis, selection in the germinal centre (GC) and production of high-affinity antibody-forming cells (AFCs) and memory B cells has been unclear.
Here, Tarlinton and Smith present a model that accounts for the switch in GC production from high-affinity AFCs to memory B cells, and explain how Bcl-2, an inhibitor of apoptosis, can influence memory cells but not bone marrow AFCs.
http://www.researchgate.net/pu.....nal_centre
Specificity, polyspecificity, and heterospecificity of antibody-antigen recognition
DOI: 10.1002/jmr.2394
The concept of antibody specificity is analyzed and shown to reside in the ability of an antibody to discriminate between two antigens.
Initially, antibody specificity was attributed to sequence differences in complementarity determining regions (CDRs), but as increasing numbers of crystallographic antibody-antigen complexes were elucidated, specificity was analyzed in terms of six antigen-binding regions (ABRs) that only roughly correspond to CDRs.
It was found that each ABR differs significantly in its amino acid composition and tends to bind different types of amino acids at the surface of proteins.
In spite of these differences, the combined preference of the six ABRs does not allow epitopes to be distinguished from the rest of the protein surface.
These findings explain the poor success of past and newly proposed methods for predicting protein epitopes.
Antibody polyspecificity refers to the ability of one antibody to bind a large variety of epitopes in different antigens, and this property explains how the immune system develops an antibody repertoire that is able to recognize every antigen the system is likely to encounter.
Antibody heterospecificity arises when an antibody reacts better with another antigen than with the one used to raise the antibody.
As a result, an antibody may sometimes appear to have been elicited by an antigen with which it is unable to react.
The implications of antibody polyspecificity and heterospecificity in vaccine development are pointed out.
Copyright © 2014 John Wiley & Sons, Ltd.
http://www.researchgate.net/pu.....ecognition
An Outdated Notion of Antibody Specificity is One of the Major Detrimental Assumptions of the Structure-Based Reverse Vaccinology Paradigm, Which Prevented It from Helping to Develop an Effective HIV-1 Vaccine.
DOI: 10.3389/fimmu.2014.00593
The importance of paradigms for guiding scientific research is explained with reference to the seminal work of Karl Popper and Thomas Kuhn.
A prevalent paradigm, followed for more than a decade in HIV-1 vaccine research, which gave rise to the strategy known as structure-based reverse vaccinology is described in detail.
Several reasons why this paradigm did not allow the development of an effective HIV-1 vaccine are analyzed.
A major reason is the belief shared by many vaccinologists that antibodies possess a narrow specificity for a single epitope and are not polyspecific for a diverse group of potential epitopes.
When this belief is abandoned, it becomes obvious that the one particular epitope structure observed during the crystallographic analysis of a neutralizing antibody-antigen complex does not necessarily reveal, which immunogenic structure should be used to elicit the same type of neutralizing antibody.
In the physical sciences, scientific explanations are usually presented as logical deductions derived from a relevant law of nature together with certain initial conditions.
In immunology, causal explanations in terms of a single cause acting according to a law of nature are not possible because numerous factors always play a role in bringing about an effect.
The implications of this state of affairs for the rational design of HIV vaccines are outlined.
An alternative approach to obtain useful scientific understanding consists in intervening empirically in the immune system and it is suggested that manipulating the system experimentally is needed to learn to control it and achieve protective immunity by vaccination.
http://www.researchgate.net/pu.....-1_Vaccine
Posts #9-13 in the thread “antibodies affinity maturation”
are references to research papers, starting here:
http://www.uncommondescent.com.....ent-546453
#214 addendum
http://www.ncbi.nlm.nih.gov/pubmed/25477882
How advances in immunology provide insight into improving vaccine efficacy
doi: 10.1016/j.vaccine.2014.03.078
Vaccines represent one of the most compelling examples of how biomedical research has improved society by saving lives and dramatically reducing the burden of infectious disease.
Despite the importance of vaccinology, we are still in the early stages of understanding how the best vaccines work and how we can achieve better protective efficacy through improved vaccine design.
Most successful vaccines have been developed empirically, but recent advances in immunology are beginning to shed new light on the mechanisms of vaccine-mediated protection and development of long-term immunity.
Although natural infection will often elicit lifelong immunity, almost all current vaccines require booster vaccination in order to achieve durable protective humoral immune responses, regardless of whether the vaccine is based on infection with replicating live-attenuated vaccine strains of the specific pathogen or whether they are derived from immunization with inactivated, non-replicating vaccines or subunit vaccines.
The form of the vaccine antigen (e.g., soluble or particulate/aggregate) appears to play an important role in determining immunogenicity and the interactions between dendritic cells, B cells and T cells in the germinal center are likely to dictate the magnitude and duration of protective immunity.
By learning how to optimize these interactions, we may be able to elicit more effective and long-lived immunity with fewer vaccinations.
http://www.ncbi.nlm.nih.gov/pubmed/24709587
Mathematical modeling provides kinetic details of the human immune response to vaccination
doi: 10.3389/fcimb.2014.00177
With major advances in experimental techniques to track antigen-specific immune responses many basic questions on the kinetics of virus-specific immunity in humans remain unanswered.
To gain insights into kinetics of T and B cell responses in human volunteers we combined mathematical models and experimental data from recent studies employing vaccines against yellow fever and smallpox.
Yellow fever virus-specific CD8 T cell population expanded slowly with the average doubling time of 2 days peaking 2.5 weeks post immunization.
Interestingly, we found that the peak of the yellow fever-specific CD8 T cell response was determined by the rate of T cell proliferation and not by the precursor frequency of antigen-specific cells as has been suggested in several studies in mice.
We also found that while the frequency of virus-specific T cells increased slowly, the slow increase could still accurately explain clearance of yellow fever virus in the blood.
Our additional mathematical model described well the kinetics of virus-specific antibody-secreting cell and antibody response to vaccinia virus in vaccinated individuals suggesting that most of antibodies in 3 months post immunization were derived from the population of circulating antibody-secreting cells.
Taken together, our analysis provided novel insights into mechanisms by which live vaccines induce immunity to viral infections and highlighted challenges of applying methods of mathematical modeling to the current, state-of-the-art yet limited immunological data.
http://journal.frontiersin.org.....7/abstract
Oops! Are they serious?
Some interlocutors and their comrades strongly dislike the highlighting of certain words and phrases in the abstracts. Maybe they’ll get used to it, eventually. 🙂
Some interlocutors and their comrades strongly dislike the highlighting of certain words and phrases in the abstracts. Maybe they’ll get used to it, eventually. 🙂
An Integrated View of Cellular Systems
FREE Webinar
Thursday February 26, 2015
2:30 – 4:00 p.m. Eastern Time
By integrating information from the genome, transcriptome, proteome, and metabolome, dynamic interactions can be examined to decipher complex biological networks.
This systems approach involves the integration of high-throughput technology and multiple interdisciplinary areas or fields, including molecular biology, cell biology, genomics, proteomics, metabolomics, and bioinformatics.
The Scientist brings together a panel of experts to discuss emerging technologies for studying complex biological interactions.
Attendees will have an opportunity to interact with the experts, ask questions, and seek advice on topics that are unique to their research.
Topics to be covered:
• Approaches and considerations for analyzing complex biological networks
• Tools and strategies for integrating data to provide biological insights
• How a systems approach can be used to understand disease phenotypes
http://www.the-scientist.com//.....r-Systems/
Interesting paper about the design of analytical tools for cell polarity.
#234 highlight
Many folks in this site may benefit from thinking about this seriously.
OT: clarification for some confused interlocutors in this or in other threads:
I’m not an ID proponent, though I agree with their fundamental principle. I’m not a YEC, or an OEC, or any other ‘classification’ being used these days to label people. None of them apply to me.
My identity is in Christ alone. When He created all or how He did it are unknown to me. I just believe He did it. Generally, that’s not what the ID proponents claim.
The details about when and how He did it are not that important to me, though I would not mind knowing it. That’s not what the YEC/OEC folks state.
I’m a sinner gracefully redeemed by the Savior of the world and thus eternally reconciled with our Maker. Christ is the King of kings, the Lord of lords, the Light, the Way, the Truth and the Life. Without Him there is no seeing, no going, no knowing, no living.
🙂
Polar ejection forces promote spindle assembly checkpoint satisfaction by generating intra-kinetochore stretch
https://www.ibmc.up.pt/events/seminars/phd-training-series-polar-ejection-forces-promote-spindle-assembly-checkpoint
Some interlocutors and their comrades strongly dislike the highlighting of certain words and phrases in the referenced papers. Maybe they’ll get used to it, eventually. 🙂
Some interlocutors and their comrades strongly dislike the highlighting of certain words and phrases in the referenced papers. Maybe they’ll get used to it, eventually. 🙂
Cep126 is required for pericentriolar satellite localisation to the centrosome and for primary cilium formation
doi: 10.1111/boc.201300087
The centrosome is the primary microtubule-organising centre of animal cells and it has crucial roles in several fundamental cellular functions, including cell division, cell polarity, and intracellular transport.
The mechanisms responsible for this are not completely understood.
http://www.ncbi.nlm.nih.gov/pm.....MC4293463/
Positive and Negative Regulation of Vertebrate Separase by Cdk1-Cyclin B1 Might Explain why Securin Is Dispensable
doi: 10.1074/jbc.M114.615310
http://www.jbc.org/content/ear.....5310.short
Could this be a case of reliability and robustness through redundancy?
Isn’t that a commonly seen approach in engineering and computing?
How did each variant come to be to begin with?
Lentivirus?mediated silencing of spindle and kinetochore?associated protein 1 inhibits the proliferation and invasion of neuronal glioblastoma cells.
doi: 10.3892/mmr.2015.3175
Spindle and kinetochore?associated protein 1 (SKA1) is an important component of the human kinetochore, which plays a key role in mitosis.
The resent study was designed to investigate the role of SKA1 in human glioblastoma.
The results of the present study demonstrated that SKA1 was expressed in human glioblastoma cells.
In addition, the knockdown of SKA1 expression in the A172 and U251 human glioblastoma cell lines was accomplished using a lentivirus infection method.
An MTT assay demonstrated that downregulation of SKA1 may inhibit cell proliferation, without affecting the cell cycle.
Furthermore, knockdown of SKA1 expression resulted in reduced cell invasion.
The results of the present study indicated that SKA1 may be a potential target protein for antiproliferative and anti?invasive therapeutic strategies of human glioblastoma.
http://www.ncbi.nlm.nih.gov/pubmed/25573192
Are there other factors besides meikin?
How exactly does meikin get into this and how does it work?
Are there any timing issues?
Why does in work in one meiosis but not in the other? why not in mitosis?
How is it produced? how much of it? why?
#256 addendum
http://www.nature.com/nature/j.....14097.html
An Integrated View of Cellular Systems
By integrating information from the genome, transcriptome, proteome, and metabolome, dynamic interactions can be examined to decipher complex biological networks.
This systems approach involves the integration of high-throughput technology and multiple interdisciplinary areas or fields, including molecular biology, cell biology, genomics, proteomics, metabolomics, and bioinformatics.
http://www.the-scientist.com//.....r-Systems/
Measuring Extracellular Vesicle Stability: A New Frontier in Analytical Technology
The study of extracellular vesicles is an area that has recently become the subject of intense interest.
These vesicles are apparently ubiquitous in prokaryotic and eukaryotic organisms and it is believed they have a wide role to play in many physiological and pathological processes.
They are typically described either as exosomes, which are produced from the cell endosome, or microvesicles, produced by cell membrane budding.
Despite increased academic and commercial interest, much of the understanding of their cellular origin, structure, functions and size is still the subject of debate, as are the preferred methods of isolation and characterization.
http://www.biosciencetechnolog.....cation=top
#263 addendum
Can’t wait to see their dream become real. It should be fascinating to understand how that complex machinery functions.
#265 addendum
Bacterial armor holds clues for self-assembling nanostructures
http://www.rdmag.com/news/2015.....cation=top
The real marvel on display is the capacity of Darwinists to stare at the unveiling of the most sophisticated software/engineering/technology ever witnessed, beyond what has ever been imagined, and resolutely insist that it all occurred completely undirected by any intelligence whatsoever.
Religious zealotry is blinding Darwinists to the mounting evidence before their eyes.
William J Murray:
You are perfectly right. Observing intelligent people who force their cognitive “creativity” to defend what is utterly indefensible is an experience at the same time funny and sad.
Unable to explain the origin of one single functional protein, they happily accept the dogma that complex and irreducible systems implying that coordinated and controlled interactions of hundreds of proteins and structures certainly originated by the same mythical mechanism which exists only in their imagination and faith
#279 addendum
Trip6 protein localizes to focal adhesion sites and along actin stress fibers. [why?] [how?]
Recruitment of this protein to the plasma membrane occurs in a lysophosphatidic acid (LPA)-dependent manner and it regulates LPA-induced cell migration.
http://www.ncbi.nlm.nih.gov/gene/7205
http://www.jimmunol.org/content/194/4/1395.short
So many things can mess up the delicate biological systems. How can they function at all?
B cell TLR1/2, TLR4, TLR7 and TLR9 interact in induction of class switch DNA recombination: modulation by BCR and CD40, and relevance to T-independent antibody responses.
doi: 10.3109/08916934.2014.993027.
http://www.ncbi.nlm.nih.gov/pubmed/25536171
Did they say ‘choreography’? 🙂
Pretty simple, isn’t it?
Sometimes I highlight text that I might have further questions on, but this time I would have to highlight almost the entire article.
Did they write ‘orchestrated’ and ‘choreographed’ ?
🙂
It takes two to tango, but apparently there are more dancers in the center of the ballroom. 🙂
Do they have to ‘design’ something in order to imitate the functioning of biological components that allegedly were not designed?
🙂
Several ‘how?’ and’ why?’ questions come to mind, don’t they? 🙂
Did they say ‘orchestrate’? 🙂
Contrary to expectations,? what expectations?
Surprisingly, ? why? did they expect something else?
complex, layered regulatory code?
Hmmm… where did that come from? FUCA, LUCA? how?
The time allotted for the current learning phase is about to end. Next moving on to another phase in the project. Will try to stop by and keep an eye on what’s going on here -specially the interesting discussions.
Embryo engineering alarm:
A prudent path forward for genomic engineering and germline gene modification
http://www.sciencemag.org/cont.....01.summary
Remaining Mysteries of the Cytoplasm
Timothy J. Mitchison
Department of Systems Biology, Systems Biology, Harvard Medical School, Boston, MA 02115
Nothing epitomizes the mystery of life more than the spatial organization and dynamics of the cytoplasm. How can a bunch of molecules, no matter how sophisticated, generate spatially complex behavior on a scale that is much larger than the molecules themselves?
http://www.molbiolcell.org/content/21/22/3811
say what?
design?
invented the rules?
Read the whole paper and see the detailed mathematical description of the physical model describing this complex machinery. Very simple… Really cool! 🙂
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
Outstanding development questions?
This was said 4 years ago in official lectures at a very prestigious educational institution by a scientific authority in the given subject. This is serious stuff.
However, maybe by now some (or all) of those raised questions have been answered? Research is advancing fast these days, hence recent discoveries could have resolved the issues presented in these two video lectures?
Please, note that the below indicated time marks may not be exact, therefore start a little earlier and keep listening until the professor changes the subject and moves on to the next topic. You may just listen to the marked comments. Each takes just a couple of minutes or less. Enjoy it!
Development 1:
Development 2:
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
We want those questions answered ASAP, don’t we? Perhaps some of them are already answered by NW, since the paper is kind of old (2009?).
Sorry, no time left for OOL discussions. 🙂
Really? How?
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
Significant progress! We like that, don’t we?
The sooner science will fill the outstanding gaps in biological understanding, the greater possibilities to get better medicines and health maintenance treatments for all.
Also, every new discovery sheds more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems. And doubtless many of us -specially those with information technology background- enjoy that kind of stuff, right?
Best regards to all.
Engineering design quality assurance procedures for testing different possible scenarios before the product is implemented or released to final customers have been known for many years. Also, some organizations test products available in the market, in order to check how they function and publish reports for potential consumers. Those tests may try to cover as many situations as possible.
Now, is that what they call “evolutionary approach” in this recent paper?
http://rnajournal.cshlp.org/content/21/2/202.full
Also, regarding the actual objects being tested, are they showing anything besides elaborate built-in adaptation mechanisms in action?
Did I get this wrong? Please correct me. Thanks.
This is exciting news.
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
This is exciting news.
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
Glad to see more interest in that important aspect of development.
There yet? 🙂
Work in progress…
Dionisio @ 325,
I watched the complete lecture. First off, the complexity is truly astounding. Naming the processes facilitates categorization, but it also makes them sound ordinary, even inevitable, which is of course not the case.
Yes, the professor did imply that the 3D structural instructions were sequential rather than located in a comprehensive “master plan” (which of course doesn’t obviate a master plan), and she indicated that she didn’t have *enough time* to explore this further. But she just couldn’t bring herself to say that researchers are utterly clueless on how the cells are made to respond in order to assemble themselves in an organ by a method other than simply forming sheets by preferential adhesion.
The film showing a cell moving was amazing!
How can students just sit there? How can they learn without asking questions?
-Q
It seems like there are more new questions after they answered some outstanding ones?
Apparently it ain’t easy to figure all that out. Is it?
Let’s stay tuned… more to come.
Querius @341
You have made very important observations and raised interesting questions.
Thank you.
Almost there…
Let’s look forward, with much anticipation, to reading future research reports shedding more light on this important subject.
Fascinating!
What occurs to me is that it would not be unreasonable to use analogy to predict the amount of information and complexity required to control the described organogenesis. One could map out the control systems and the mechanisms employed to activate, monitor, and deactivate these processes. Anticipating this information is already being done of course, but the volume of interdependent information might be able to fine-tune investigation. This is an excellent example of the utility of the ID paradigm in my opinion, and it once again falsifies the incrementalism required for the theory of evolution.
There’s also the design behind organ. Specifically regarding cochlear operation, in addition to sensitivity to a frequency band and logarithmic amplitude, it’s my understanding that it also acts as a comb filter, which provides additional spatial feedback. Genius!
-Q
Querius @349
Interesting comment. Thank you.
Let’s look forward, with much anticipation, to reading future research reports shedding more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems.
Fascinating choreographies orchestrated within the biological systems.
(*) how?
(*) how?
#359 DDR?
[OT]
One funny thing about this contextual acronym: before 1990 there was a country in Europe that was identified by that same acronym (in their own language).
Back then DDR = RDA = NRD = GDR.
Nicely compacted ncRNA review. Kudos to the authors!
BTW, Unexpected Contributors? Why unexpected? What did they expect? Nothing? Something else?
Do expressions like “being open-minded” and “thinking out of the box” come to mind? 🙂
Hmm… 🙂
Work in progress…
Interesting statement:
Based on our results, we would like to argue that the prevailing view should be challenged…
Getting closer… almost there… 🙂
A few questions remain.
Almost there… getting closer. 🙂
Work in progress… [that was a little over two years ago, maybe concluded by now?]
Those are really intelligent cells, aren’t they? 🙂
Work in progress…
A few questions remain…
Hey, encouraging news!!!
We’re almost there!!! 🙂
Check this out:
Serious work. Interesting study material.
The jury is still out… stay tuned… 🙂
Look forward, with much anticipation, to reading future research papers on this and related subjects, shedding more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems.
🙂
A few questions remain… stay tuned…
design principle ?
(*) 2012
This was 3 years ago… maybe these questions are answered now?
(*) look forward to reading newer papers confirming this hypothesis
(**) look forward to reading newer papers changing this term “may control” to just “control(s)”. Basically removing the word “may” so that the statement becomes a sure affirmation.
Work in progress… not there yet. A few* questions remain to be answered.
(*) 🙂
Interesting.
http://link.springer.com/artic.....ltext.html
Work in progress… a few questions remain unanswered.
Stay tuned.
Over 10 years old paper.
#409 follow-up?
About 7 years after @409?