Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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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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Understanding how SR proteins regulate AS is crucial to understanding the role AS plays in tissue development and homeostasis. Alternative isoform selection is a product of coordinated promoter selection, AS regulation, and poly(A) site selection—all regulated by SR proteins and other transcriptional and RNA-processing machineries. Understanding SR protein regulation beyond AS will allow greater understanding of the integration of gene expression regulation between multiple regulatory networks.
SR proteins control a complex network of RNA-processing events Todd Bradley, Malcolm E. Cook and Marco Blanchette doi: 10.1261/rna.043893.113 RNA 2015. 21: 75-92 http://rnajournal.cshlp.org/content/21/1/75.full

Complex complexity Work in progress... stay tunedDionisio_{December 28, 2015
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With the improved quality of plant genomic sequences, discovery of new lncRNAs will be more thorough and convenient. Many novel lncRNAs will be identified in plants with the increasingly-sophisticated high-throughput sequencing technology, especially strand-specific RNA-seq technology Systematic discovery and identification of mutant plants will help resolve the biological functions of lncRNAs.
Long Non-coding RNAs and Their Biological Roles in Plants Xue Liu, Lili Hao, Dayong Li, Lihuang Zhu, Songnian Hu doi:10.1016/j.gpb.2015.02.003 Genomics, Proteomics & Bioinformatics Volume 13, Issue 3, 2015, Pages 137–147 http://www.sciencedirect.com/science/article/pii/S167202291500042X

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The rapid development of high-throughput RNA-seq and related bioinformatics methods provides revolutionary ways for discovering novel lncRNAs. In recent years, many more lncRNA transcripts have been identified. Their number and types are far beyond previous expectations. lncRNA studies have become one of the new hotspots in current molecular biology. However, compared to the studies on humans and animals, the research in plants is still premature
Long Non-coding RNAs and Their Biological Roles in Plants Xue Liu, Lili Hao, Dayong Li, Lihuang Zhu, Songnian Hu doi:10.1016/j.gpb.2015.02.003 Genomics, Proteomics & Bioinformatics Volume 13, Issue 3, 2015, Pages 137–147 http://www.sciencedirect.com/science/article/pii/S167202291500042X

Complex complexity Work in progress... stay tunedDionisio_{December 27, 2015
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Alternative splicing can have profound consequences for protein activity, but the functions of most alternative splicing regulators are not known. [...] regulation of Crumbs alternative splicing by the Obelus helicase modulates epithelial polarity during development.
The Ski2-family helicase Obelus regulates Crumbs alternative splicing and cell polarity Athea Vichas, Matthew T. Laurie and Jennifer A. Zallen JCB vol. 211 no. 5 1011-1024 The Rockefeller University Press, doi: 10.1083/jcb.201504083 http://jcb.rupress.org/content/211/5/1011.abstract

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[...] additional studies are necessary to test whether each protein directly binds to the pre-mRNAs that are regulated to help establish primary versus secondary effects—particularly in light of the cross-regulation observed among RBPs and effects on AFE events. [...] we do not believe that coregulated splicing events are due to secondary effects from changes in the other RNA binding proteins assayed; however, we cannot rule out secondary effects from other splicing regulators [...]
Regulation of alternative splicing in Drosophila by 56 RNA binding proteins Angela N. Brooks, Michael O. Duff, Gemma May, Li Yang, Mohan Bolisetty, Jane Landolin, Ken Wan, Jeremy Sandler, Benjamin W. Booth, Susan E. Celniker, Brenton R. Graveley and Steven E. Brenner doi: 10.1101/gr.192518.115 Genome Res. 2015. 25: 1771-1780 http://genome.cshlp.org/content/25/11/1771.full

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[...] associations between interacting proteins and mRNA products from the same genes could be ribosome proximal or ribosome mediated. It could be that the protein complexes studied here undergo cotranslational assembly. This is also an intriguing possibility. Importantly, our assays measure time and space averages across ensembles of homogeneous, but not identical or synchronized cells. Hence, while it is clear that the proteins copurify and bind the same RNA targets, it may be that these associations occur on different individual RNA molecules that are neither spatially nor temporally localized with the proteins they encode. Additional assays, particularly high-content imaging approaches, will be needed to resolve these possibilities and to elucidate the intriguing biology at the basis of feedback in post-transcriptional regulatory networks.
Extensive cross-regulation of post-transcriptional regulatory networks in Drosophila Marcus H. Stoiber, Sara Olson, Gemma E. May, Michael O. Duff, Jan Manen, Robert Obar, K.G. Guruharsha, Peter J. Bickel, Spyros Artavanis-Tsakonas, James B. Brown, Brenton R. Graveley and Susan E. Celniker doi: 10.1101/gr.182675.114 Genome Res. 2015. 25: 1692-1702 http://genome.cshlp.org/content/25/11/1692.full

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[...] it is striking that feedback appears to function broadly at the level of an entire regulatory process. [...] widespread post-transcriptional regulation of post-transcriptional regulators may be an emergent property of local cross-regulation [...] [...] protein interaction–associated post-transcriptional regulation is common and, hence, constitutes a general layer of feedback in the hierarchy of gene regulation.
Extensive cross-regulation of post-transcriptional regulatory networks in Drosophila Marcus H. Stoiber, Sara Olson, Gemma E. May, Michael O. Duff, Jan Manen, Robert Obar, K.G. Guruharsha, Peter J. Bickel, Spyros Artavanis-Tsakonas, James B. Brown, Brenton R. Graveley and Susan E. Celniker doi: 10.1101/gr.182675.114 Genome Res. 2015. 25: 1692-1702 http://genome.cshlp.org/content/25/11/1692.full

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Transcriptome-wide analyses, as well as studies that focus on CWC22 function under stress conditions, could therefore extend our knowledge on the regulatory mechanisms that control the activity of CWC22 and the specific role of its C-terminal domain. How a disproportionate competition for the splicing machinery is mechanistically detected and what molecular characteristics define competitive splicing substrates will be interesting directions for future research. Future studies will be required to understand how the interaction between eIF4A3 and the spliceosome is regulated.
CWC22-dependent pre-mRNA splicing and eIF4A3 binding enables global deposition of exon junction complexes Anna-Lena Steckelberg, Janine Altmueller, Christoph Dieterich and Niels H. Gehring Nucl. Acids Res. 43 (9): 4687-4700. doi: 10.1093/nar/gkv320 http://nar.oxfordjournals.org/content/43/9/4687.full

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The EJC plays a central role in the post-splicing life of mRNAs. Two models have been proposed to explain how transcription can influence splicing: the ‘recruitment model’ and the ‘kinetic model’ [...] the EJC participates in multiple alternative splicing events. The analysis of specific splicing events will certainly allow molecular links between the EJC and splicing regulation to be established.
Transcriptome-wide modulation of splicing by the exon junction complex Zhen Wang, Valentine Murigneux and Hervé Le Hir Genome Biology 15:551 doi:10.1186/s13059-014-0551-7 http://www.genomebiology.com/2014/15/12/551

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#1450 follow-up Here's an explanation of the alleged "chicken-egg" problem:
The vast majority of mammalian pre-mRNAs contains multiple introns. Once assembled onto an exonic junction, the EJC and its associated factors could serve as a splicing regulator in the recognition of neighbouring splice sites, and in turn modulate the splicing pattern.
Transcriptome-wide modulation of splicing by the exon junction complex Zhen Wang, Valentine Murigneux and Hervé Le Hir Genome Biology 15:551 doi:10.1186/s13059-014-0551-7 http://www.genomebiology.com/2014/15/12/551

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#1449 follow-up The chicken-egg conundrum seems to come to mind, doesn't it?Dionisio_{December 25, 2015
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So far, pre-mRNA splicing is the only known process able to assemble the EJC core. Thus, how does a fully assembled EJC regulate alternative splicing, given that it is deposited and assembled after the splicing decision has been made ?
Transcriptome-wide modulation of splicing by the exon junction complex Zhen Wang, Valentine Murigneux and Hervé Le Hir Genome Biology 15:551 doi:10.1186/s13059-014-0551-7 http://www.genomebiology.com/2014/15/12/551

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#1447 follow-up Many of us don't like unknowns, hence want to know all this ASAP:
How this greater stability of the junctional complex is translated into absence of cell polarization remains unknown. Furthermore, it is currently unclear whether the strength of E- and N-cadherin-based junctions is different. Whether the transmembrane domain of E-cadherin carries additional functions, as recently reported for VE-cadherin, still remains to be addressed. Whether p120 regulates Rac1 activity directly via a Rac GEF […] or whether it acts on Rac1 indirectly by controlling integrin activation in the vicinity of the cell-cell contact […] remains to be investigated. Whether the forces generated by the newly formed protrusions are transmitted directly to the cell-cell junction or whether these forces are necessary to generate a “trailing back” environment at the junction […] remains unknown.
That's why we look forward, with increasing anticipation, to reading future research papers about new discoveries that shed more light on the elaborate cellular and molecular choreographies orchestrated within the biological systems. Complex complexity Work in progress… stay tunedDionisio_{December 25, 2015
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E-cadherin exerts a mild but significant effect on junctional stability in NC, which could explain the greater accumulation of adhesion proteins in the E-cadherin junction observed here. How this greater stability of the junctional complex is translated into absence of cell polarization remains unknown. Furthermore, it is currently unclear whether the strength of E- and N-cadherin-based junctions is different. Whether the transmembrane domain of E-cadherin carries additional functions, as recently reported for VE-cadherin, still remains to be addressed. Whether p120 regulates Rac1 activity directly via a Rac GEF [...] or whether it acts on Rac1 indirectly by controlling integrin activation in the vicinity of the cell-cell contact [...] remains to be investigated. Whether the forces generated by the newly formed protrusions are transmitted directly to the cell-cell junction or whether these forces are necessary to generate a “trailing back” environment at the junction [...] remains unknown. In conclusion, our study suggests a molecular mechanism linking two processes, EMT and CIL, leading to cell dissociation and cell dispersion. The generality of these processes raises the possibility that a wider range of cell types (i.e., metastatic cancer cells, other embryonic cells) undergoing similar qualitative changes of their cadherin repertoire might acquire CIL as part of their progression through EMT, contributing to disease progression or developmental morphogenesis.
Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces Elena Scarpa, András Szabó, Anne Bibonne, Eric Theveneau, Maddy Parsons, Roberto Mayor doi:10.1016/j.devcel.2015.06.012 Developmental Cell Volume 34, Issue 4, Pages 421–434 http://www.sciencedirect.com/science/article/pii/S1534580715004013

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Are ICM progenitors generated as a result of the fourth or fifth cleavage, or more precisely from cells with differing exposures to TE-differentiation, molecularly equivalent? The reason for enhanced Fgfr2 nuclear localisation is unclear, [...] [...] early mammalian development is highly regulative, indicating, by definition, the existence of multiple complementary and overlapping pathways that must work together to guide, rather than restrict, the appropriate cell-fate decisions required. [...] phosphorylation of Yap1 is normally associated with its cytoplasmic sequestration in response to active hippo-signalling, and neither the reason nor its functional significance are clear. TE, EPI and PrE fates all begin their segregation at the fourth cleavage division and are guided by relative differences in the exposure of the founding cells to TE-differentiative cues and the timely activation (or liberation from suppression) of the hippo-signalling pathway.
The first two cell-fate decisions of preimplantation mouse embryo development are not functionally independent Aleksandar I. Mihajlovi? , Vasanth Thamodaran & Alexander W. Bruce Scientific Reports 5, Article number: 15034 (2015) doi:10.1038/srep15034 http://www.nature.com/articles/srep15034

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one important function of the mitotic inhibitor Pom1 is to buffer cell size during glucose starvation. Future work should reveal whether this is due to the modification of a homoeostatic sizer system.
PKA antagonizes CLASP-dependent microtubule stabilization to re-localize Pom1 and buffer cell size upon glucose limitation Manasi Kelkar & Sophie G. Martin Nature Communications 6, Article number: 8445 doi:10.1038/ncomms9445 http://www.nature.com/ncomms/2015/151007/ncomms9445/full/ncomms9445.html

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LARP7 could, in addition to protecting 7SK from exonucleases, assure the required specificity for 7SK to function in the crowded nucleoplasm of human cells.
Structural insight into the mechanism of stabilization of the 7SK small nuclear RNA by LARP7 Emiko Uchikawa1,2,3,4,†, Kundhavai S. Natchiar1,2,3,4,†, Xiao Han5,6,7,8,†, Florence Proux5,6,7, Pierre Roblin9,10, Elodie Zhang5,6,7, Alexandre Durand1,2,3,4, Bruno P. Klaholz1,2,3,4 and Anne-Catherine Dock-Bregeon5,6,7,* Nucl. Acids Res. (31 March 2015) 43 (6): 3373-3388. doi: 10.1093/nar/gkv173 http://nar.oxfordjournals.org/content/43/6/3373.full

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The presentation of protein antigens on the cell surface by major histocompatibility complex (MHC) molecules coordinates vertebrate adaptive immune responses, thereby mediating susceptibility to a variety of autoimmune and infectious diseases. MHC polymorphisms contribute to defining an individual’s unique microbial fingerprint that influences health. [...] there are a myriad of additional potential mechanisms by which MHC-mediated antigen presentation could influence commensal populations. Whether MHC class II expression by gut epithelial cells influences microbial communities is completely unknown, but warrants attention given the direct physical interaction between these cells and commensal microbes. Future studies using conditional knockout mice will be crucial for empirically defining the process by which MHC antigen presentation sculpts microbiota architecture. Understanding how MHC shapes microbiota diversity to influence colonization resistance could yield important insights into the treatment of emerging enteric infectious diseases of man.
MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection Jason L. Kubinak, W. Zac Stephens, Ray Soto, Charisse Petersen, Tyson Chiaro, Lasha Gogokhia, Rickesha Bell, Nadim J. Ajami, Joseph F. Petrosino, Linda Morrison, Wayne K. Potts, Peter E. Jensen, Ryan M. O’Connell & June L. Round Nature Communications 6, Article number: 8642 doi:10.1038/ncomms9642 http://www.nature.com/ncomms/2015/151023/ncomms9642/full/ncomms9642.html

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Methylation of cytosine deoxynucleotides generates 5-methylcytosine (m5dC), a well-established epigenetic mark. However, in higher eukaryotes much less is known about modifications affecting other deoxynucleotides. [...] m6dA is widely distributed across the eukaryotic genome and is present in different cell types but is commonly depleted from gene exons. Thus, direct DNA modifications might be more widespread than previously thought.
Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications Magdalena J Koziol, Charles R Bradshaw, George E Allen, Ana S H Costa, Christian Frezza & John B Gurdon Nature Structural & Molecular Biology (2015) doi:10.1038/nsmb.3145 http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3145.html

[emphasis mine] Complex complexity Work in progress... stay tunedDionisio_{December 24, 2015
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Given the complexity and the wide variety of entities like epigenetic modifications and genetic variants, which perturb normal biological processes, we need new strategies to integrate data driven and knowledge driven approaches to unravel the mechanisms behind these complex diseases. [...] dedicated effort towards investigating the role of the new candidate genes and related bioprocesses is required. It is obvious that we need to extend the syntax of the modelling language in order to formally represent this type of variation and develop algorithms that assess the functional impact based on biological network models.
Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis Afroza Khanam Irin,1,2 Alpha Tom Kodamullil,1,2 Michaela Gündel,1,2 and Martin Hofmann-Apitius Journal of Immunology Research Volume 2015 (2015), Article ID 737168, 10 pages http://dx.doi.org/10.1155/2015/737168 http://www.hindawi.com/journals/jir/2015/737168/

[emphasis mine] Complex complexity Work in progress... stay tunedDionisio_{December 24, 2015
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Epigenetics is a major mechanism that accommodates gene-expression changes in response to gene-environment interactions.
Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis Afroza Khanam Irin,1,2 Alpha Tom Kodamullil,1,2 Michaela Gündel,1,2 and Martin Hofmann-Apitius Journal of Immunology Research Volume 2015 (2015), Article ID 737168, 10 pages http://dx.doi.org/10.1155/2015/737168 http://www.hindawi.com/journals/jir/2015/737168/

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[...] it is tempting to speculate that histone variants and histone acetylation could act synergistically to create the facilitator “open” chromatin structures responsible for what, over the years, has been taken as one of the most important hallmarks of transcriptionally active genes: nuclease hypersensitivity
The Structural Determinants behind the Epigenetic Role of Histone Variants Manjinder S. Cheema and Juan Ausió Genes 2015, 6(3), 685-713; doi:10.3390/genes6030685 http://www.mdpi.com/2073-4425/6/3/685/htm

[emphasis mine] ...could act synergistically to create the facilitator “open” chromatin structures responsible for... That's a mouthful (tongue-twister), isn't it? :) Complex complexity Work in progress... stay tunedDionisio_{December 24, 2015
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In the case of histone H3 variants, despite the controversial role of CenH3 in the nucleosome organization, the mechanism of its epigenetic inheritance is quite well understood. This mechanism is not as clear in H3.3, but a post-translationally-mediated process that involves the specific methylation of H3.3 at lysine 4 has been invoked. It would be fascinating to pursue an understanding of the mechanisms involved in the accumulation of this variant, as well as of H1.0, with aging. It is actually amazing that it has taken over 30 years to rediscover this very interesting problem!
The Structural Determinants behind the Epigenetic Role of Histone Variants Manjinder S. Cheema and Juan Ausió Genes 2015, 6(3), 685-713; doi:10.3390/genes6030685 http://www.mdpi.com/2073-4425/6/3/685/htm

[emphasis mine] Complex complexity Work in progress... stay tunedDionisio_{December 24, 2015
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The structural details surrounding this functional duality are not yet clearly understood, although it is likely that histone PTMs play a role in it.
The Structural Determinants behind the Epigenetic Role of Histone Variants Manjinder S. Cheema and Juan Ausió Genes 2015, 6(3), 685-713; doi:10.3390/genes6030685 http://www.mdpi.com/2073-4425/6/3/685/htm

[emphasis mine] Complex complexity Work in progress... stay tunedDionisio_{December 24, 2015
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Of all histones variants, histone H2A family represent the most abundant class [75]. Their structural and functional characteristics are mainly exerted through their N-and C-terminal tails [31], with the length of the C-terminal end playing a critical role in nucleosome stability—as evidenced by the low stability of H2A variants such as H2A.Z.2.2 and H2A.Bbd that are truncated at this region. Variations in their C-terminal domains also play important structural roles that globally result in an impairment of histone H1 binding; however, how these roles are epigenetically transmitted and inherited is less clear.
The Structural Determinants behind the Epigenetic Role of Histone Variants Manjinder S. Cheema and Juan Ausió Genes 2015, 6(3), 685-713; doi:10.3390/genes6030685 http://www.mdpi.com/2073-4425/6/3/685/htm

[emphasis mine] Complex complexity Work in progress... stay tunedDionisio_{December 24, 2015
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NcRNAs, such as miRNAs, lncRNAs, siRNAs, snoRNAs, snRNAs, circRNAs, and piRNAs, have recently been shown to play a role in the development and progression of various cancers including CRC, and they have been identified as novel diagnostic and prognostic biomarkers. The growing number of studies on ncRNAs in CRC has increased our understanding of their molecular mechanisms and biological processes, which has opened new fields of research in CRC. [...] tRNAs have yet to be linked specifically to CRC, this may represent a potential future avenue of research. [...] further studies are needed to explore their roles and mechanisms in CRC.
Regulatory Roles of Non-Coding RNAs in Colorectal Cancer Jun Wang †?, Yong-Xi Song †?, Bin Ma?, Jia-Jun Wang?, Jing-Xu Sun?, Xiao-Wan Chen?, Jun-Hua Zhao?, Yu-Chong Yang? and Zhen-Ning Wang * ? Int. J. Mol. Sci. 2015, 16(8), 19886-19919; doi:10.3390/ijms160819886 http://www.mdpi.com/1422-0067/16/8/19886

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Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. [...] further research efforts are necessary to explore the functions of these ncRNAs. [...] the biological processes and molecular mechanisms of CRC remain unclear. The dysregulation of ncRNAs has recently gained attention because of its close association with human diseases including cancer.
Regulatory Roles of Non-Coding RNAs in Colorectal Cancer Jun Wang †?, Yong-Xi Song †?, Bin Ma?, Jia-Jun Wang?, Jing-Xu Sun?, Xiao-Wan Chen?, Jun-Hua Zhao?, Yu-Chong Yang? and Zhen-Ning Wang * ? Int. J. Mol. Sci. 2015, 16(8), 19886-19919; doi:10.3390/ijms160819886 http://www.mdpi.com/1422-0067/16/8/19886

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Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual’s susceptibility to cancer.
Junk DNA and the long non-coding RNA twist in cancer genetics H Ling, K Vincent, M Pichler, R Fodde, I Berindan-Neagoe, F J Slack and G A Calin Oncogene 34, 5003-5011 doi:10.1038/onc.2014.456 http://www.nature.com/onc/journal/v34/n39/full/onc2014456a.html

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The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown.
Junk DNA and the long non-coding RNA twist in cancer genetics H Ling, K Vincent, M Pichler, R Fodde, I Berindan-Neagoe, F J Slack and G A Calin Oncogene 34, 5003-5011 doi:10.1038/onc.2014.456 http://www.nature.com/onc/journal/v34/n39/full/onc2014456a.html

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[...] 32 of the cis-rSNPs that regulate the expression of lncRNAs have been identified in GWAS as risk variants for human diseases or traits. [...] the identified cis-rSNPs for lncRNA are enriched to active enhancer regions in monocytes, which suggests a mechanism for their cis-regulatory functions. The reported 32 risk SNPs from GWAS that are strongly associated with the expression of non-coding RNAs provides interesting leads for further characterization and functional clues into immune diseases. Some of the GWAS SNPs are located in enhancer regions, which could be the cause of the allele specific expression of the lncRNA. Thus our study suggests more complex functional mechanisms underlying findings from GWAS than regulatory variants or expression levels of nearby protein coding genes, and provides novel insights into the relationship between genetic variation and human diseases.
Carlsson Almlöf J, Lundmark P, Lundmark A, Ge B, Pastinen T, Cardiogenics Consortium, et al. (2014) Single Nucleotide Polymorphisms with Cis-Regulatory Effects on Long Non-Coding Transcripts in Human Primary Monocytes. PLoS ONE 9(7): e102612. doi:10.1371/journal.pone.0102612

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