This week in PLOS Biology

In PLOS Biology this week, you can read about brain folding in mammals, misfolded proteins in human genetic disease, and mechano-transduction.

 

Evolution of the Mammalian Cortex – Folded or Unfolded?

10.1371/journal.pbio.1002000

10.1371/journal.pbio.1002000

The neocortex of the brain is highly expanded in humans, and is involved in high-level functions such as language and conscious thought. However the adaptive mechanism that evolved along certain mammalian lineages to produce a large and folded neocortex has not been clear. In a study published this week, Wieland Huttner, Iva Kelava, Eric Lewitus and colleagues found that mammals fall into two principal groups associated with distinct ecological niches: those with less folding (such as mice and tarsiers) and more folding (such as dolphins and humans). It seems that a highly folded neocortex requires a specific class of progenitor cell-type to adopt a special mode of cell division, and that folding is in fact the ancestral state for mammals. Read more in the accompanying synopsis.

 

When Stress Management Becomes the Problem

The function of all proteins in our bodies is dependent on their correct folding. Therefore emergency systems exist to manage protein folding if something goes wrong. But what happens if levels of misfolded proteins are always high, as in the case of some genetic diseases, such as cystic fibrosis, where mutations disrupt folding? A new research article by Daniela Martino Roth, William Balch, and colleagues, suggests that chronic activation of the stress response can be detrimental, exacerbating the disease phenotype. They call this effect a ‘maladaptive stress response’. Their provocative message is that we should ask ourselves if stress responses can sometimes be part of the problem, as well as being helpful in acute situations. Read more in the accompanying synopsis.

journal.pbio.1000617.g001

Image credit: journal.pbio. 1000617

 

Mechano-Transduction: From Molecules to Tissues

All cells and tissues of the body are subject to external forces, such as fluid shear stress, osmotic forces and stretch. Changes in these forces, or how cells respond to them, can result in abnormal embryonic development and diseases in adults. In this new essay, Beth Pruitt, James Nelson and colleagues discuss mechano-transduction – the cellular process that converts a mechanical input, for example stretching, into intracellular signal transduction – as it applies to protein conformation, cellular organization, and multi-cellular tissue function.

 

 

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Monitoring progress in translational bioinformatics

It is with great enthusiasm that the PLOS Computational Biology Education Editors present this invited blog post from Russ Altman, in what we hope will be a yearly feature for PLOS Biologue. It is a recapture of his annual review on translational bioinformatics, a topic very close to our interests and the focus of the first PLOS online book, part of the PLOS Computational Biology Education section. We hope you enjoy this blog post, and find this a useful and convenient way for us to share this information and perspective with you.

Joanne Fox and B.F. Francis Ouellette, Education Editors, PLOS Computational Biology

 

Image courtesy of Russ Altman

Image courtesy of Russ Altman

Each year the American Medical Informatics Association (AMIA) holds a meeting on Translational Bioinformatics as part of its “Joint Summits on Translational Science”, along with a meeting on Clinical Research Informatics. For the last several years, I have been invited to present a “Year in Review” for Translational Bioinformatics in which I summarize notable papers within translational bioinformatics during the previous 12-14 months. The meeting happens in March, so the summary usually covers the preceding calendar year plus some extra weeks.

 

This activity is both rewarding and quite stressful, as there is always a large body of work to review, and I would like to do a good job highlighting the work that is novel and exciting, while not just automatically choosing papers published in high impact journals. I have developed some rules to make this manageable. Primarily, I have a fairly strict definition of translational bioinformatics: the candidate papers should present a novel methodological approach to combining clinical entities (patients, diseases, drugs, signs, symptoms) and molecular/cellular entities (genes, proteins, RNA, DNA, small molecules, pathways, networks). After all, translational science is the study of how we move discoveries from bench to bedside, so translational bioinformatics should be informatics work that does the same. If there are no clinical entities, then the paper is not eligible. If there are no biological entities, then the paper is not eligible. I prefer novel informatics methodological content, but will allow papers that use off-the-shelf methods to do something really remarkable.

 

I try to track papers all year, but honestly have to do a lot of reviewing in the few weeks before the talk. The main sources of papers are two: (1) the recommendations of colleagues from whom I request nominations around January (self-nominations are OK, but nominating others is particularly valued); and (2) a set of somewhat ad hoc PubMED searches seeking papers that combine clinical/biological/informatics concepts. It is also fine for anyone to send me nominations throughout the year by email (russ.altman[at]stanford.edu) or even twitter (@rbaltman) and I have a system for tracking them. I then review several hundred articles, first at the title/abstract level (mostly to triage the ineligible ones), and then more deeply to find the contributions that most excite me. I do as many passes through the list as needed to reduce it to a length that allows me to present it in one hour. This is usually about 35 papers with an additional 10-15 “shout outs”, which I mention only by title.

 

After I have the final list of papers, I assemble them into 5-8 ad hoc groupings that provide some structure for the talk. I then create a slide deck with a rigid format: every paper is summarized by a single slide with title, first author, journal and PubMED ID, and then my bulleted summary of:

  • Goal: what are they trying to do?
  • Method: how did they approach the problem methodologically?
  • Result: what did they find?
  • Conclusion: what should we take away from the paper?

I stress that the “conclusion” is my own conclusion, not necessarily the conclusion of the authors, and functions as my pulpit to justify why I chose the paper. The next 1-2 slides are always key graphics from the paper that illustrate or summarize what impressed me about it.

 

So what papers did I highlight from Jan 2013 to March 2014? Well, the complete slide deck is available at my blog “Building Confidence”, as are all the slide decks from 2008 to 2014 (see QR code in the final slide of this blog). Just to provide some comparison and baseline for this year, the topics last year (January 2012 to March 2013) were:

  • Omics medicine
  • Cool methods
  • Cancer
  • Drugs
  • Delivery (of healthcare)

And the topics this year were:Slide 9

  • Controversies

This was a new category this year, and I used iSlide 11t to highlight two non-publications. I lead off with the FDA letter to the direct-to-consumer genetic testing company, 23andme, which is mandatory reading for anyone interested in translational genomics.  Next, I highlighted the blog of colleague Lior Pachter, as he engaged in an entertaining (and informative) polemic about network science applied to cell biology.

 

 

 

  • Clinical genomicsSlide 26

Here I highlight informatics papers pushing the agenda of clinical genomics. This included the much-awaited results of the warfarin dosing pharmacogenomics vs. clinical algorithm trials, which were split, and an analysis of the ubiquity of pharmacogenomic variants in the general population. Another good paper, shown here, by Kircher et al., introduces the Combined Annotation-Dependent Depletion (CADD) score for evaluating the probable impact of a SNP on health.Slide 30

 

  • Drugs

There are always many good papers about using informatics to learn things about drugs, including side effects and new uses. This category had several excellent papers. One paper reported the manual curation of 88,000 scientific articles, mined for drug-disease and drug-phenotype interactions. That was impressive because of the scale, if nothing else.  Another favorite Slide 42was a paper showing how publicly-available gene expression data suggested that an antidepressant may be a useful adjuvant drug in lung cancer—and it’s now in clinical trials!

 

  • Genetic basis of disease

These are all informatics papers showing methods for inferring new things about the Slide 47underlying mechanisms and genetics of diseases. My favorite in this category was a paper showing the many complex diseases that co-occur with Mendelian diseases, and suggesting deep genetic overlaps—as if there is a “code” in which complex diseases result from less-severe mutations in the same genes that are associated with Mendelian diseases. The implications of this work for how we interpret genome-wide association studies and think about complex disease are significant.

 

  • Emerging data sourcesSlide 63

The interesting aspect of this topic is that we get a preview of the future—emerging work in the roles of long non-coding RNA, immune diversity, metabolomics, and the microbiome in disease. One exciting paper looked at the DNA sequences of B-cell antibodies and created lineage for 17 volunteers, comparing young to old in the pre- and post-vaccine state. The future is now.

 

  • Mice.  Can’t live with ‘em, can’t live without ‘em.

Slide 75One of my hard rules (usually) is that the talk will only focus on human studies and disease.  This year I made an exception because of several relevant papers in mice. One praised the ability of mouse knockouts to discover/model new drugs. My favorite, however, showed that gene expression measurements on mice after burn, trauma and endotoxemia—all inflammatory conditions—not only do not correlate with similar measurements made in humans, but do not correlate with each other!

 

  • Scientific processSlide 80

This was a fun category that included a paper about why some publications achieve high impact, based on citation analysis. Of course, my favorite is the PLOS Computational Biology decision to publish a textbook of translational bioinformatics as a series of individual chapters. A spectacularly good idea, and a credit to PLOS.

 

  • Odds and ends

Slide 84Many years require a final bucket to include important papers that don’t fit into neat categories.  This year included such a category, which featured papers on social networks for tracking infections in a hospital, and for global tracking of disease based on airplanes as efficient infection-dissemination vehicles. A very important set of papers this year were those reporting the genome sequence of the HeLa cell. We all owe a debt to Henrietta Lacks for providing such a valuable biomedical research resource (under very non-optimal conditions), and these sequences help us interpret the results of HeLa experiments more precisely and with knowledge of the genome alterations underlying the cell line.

 

Each talk ends with a “crystal ball” section where I speculate what we may see in the coming year, and do a scorecard for my predictions the previous year. As a wise person once said, predictions are very hard, especially about the future. This year’s predictions are:

  • We will see more emphasis on non-European descent populations for discovery of disease associations;
  • There will be a crowd-based discovery in translational bioinformatics;
  • Methods will emerge for recommending treatment for cancer based on genome/transcriptome;
  • There will be more “trained systems” (like IBM Watson) applications in the field;
  • There will be drug repurposing methods that suggest more than one drug used synergistically;
  • There will be more cost-effectiveness evidence for genomic medicine;
  • Powerful methods focused on linking genes, targets and drug response will emerge.

That’s the summary of this year’s talk.  I have been invited to repeat the talk next year, and hope to see you there.

Slide 93

By Russ Altman, PLOS Computational Biology Editorial Advisor.

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This week in PLOS Biology

In PLOS Biology this week, you can read about the evolution of thermostable proteins, the Addgene initiative, microenvironment influence on tumour metastasis and communication between neurons and glia.

 

Adapting to Life at High Temperature

Image credit: Flickr user Filip Goč

Image credit: Flickr user Filip Goč

A new research article from Kathryn Hart, Susan Marqusee and colleagues aims to understand the evolutionary history of the thermostability of homologous bacterial enzymes – one which lives at moderate, and one which lives at extreme high temperatures. They ask how these structurally similar proteins can have such different thermostabilities. While thermostability appears to have been strongly shaped by selection, the biophysical mechanisms used to tune protein stability appear to have varied throughout evolutionary history. Read more in the accompanying synopsis.

 

Addgene: Sharing Plasmids, Opening Science

In a new Community Page this week, Joanne Kamens describes the Addgene initiative, which seeks to improve access to useful research materials and information. The non-profit organisation solicits published plasmids and receives and archives samples (40,000 and counting) for tracking through their lab inventory management software. They play a key role in helping scientists overcome logistical barriers to sharing, improving experimental reproducibility, and optimizing use of limited resources.

 

Tumour Microenvironments and Metastasis

10.1371/journal.pbio.1001995

10.1371/journal.pbio.1001995

A large proportion of cancer deaths result from the cancer spreading to other parts of the body – metastasis. This research article by Bojana Gligorijevic, Aviv Bergman & John Condeelis looks at the link between microenvironment and tumour cell phenotypes. They found that single cells from mouse mammary carcinoma can move using a fast- or slow-locomotion mode depending on different levels of cues present in the tumour microenvironment. The ability to define and predict conditions under which tumour cells disseminate offers potential therapeutic benefits in regulating tumour progression.

 

A Protein-Shedding Dialogue between Neurons and Glia

Although glial cells substantially outnumber neurons in the mammalian brain, much remains to be discovered regarding their functions. One type of glial cell – oligodendrocytes – differentiate from their precursors to produce the myelin sheaths that insulate neuronal axons. These precursor cells also uniquely receive direct synaptic input from neurons. A new research paper by Dominic Sakry, Thomas Mittmann and colleagues shows a bidirectional communication between neurons and oligodendrocyte precursors: neuronal activity regulates the cleavage of a glial membrane protein and the release of an extracellular domain that in turn modulates synaptic transmission between neurons. Read more in the accompanying synopsis.

 

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Understanding images: Under the skin of PLOS Genetics’ October issue image

This is the first installment in a new series of blog posts from PLOS Genetics about our monthly issue images. Ian Smyth and Tia DiTommaso talk about October’s image from their article, DiTommaso et al.

Authors: Ian Smyth and Tia DiTommaso  (Monash University, Australia)

Competing interests: Ian Smyth and Tia DiTommaso  are authors of the two papers discussed in this blog.

pgen.v10.i10

Image credit: Tia DiTommaso

The skin is the body’s largest organ and it is exquisitely adapted to support life in the harsh, gaseous, terrestrial environment in which we live.  One of its principal roles is to maintain “barrier function” – in essence preventing “bad” things from entering your body (bacteria, chemicals etc.) and ensuring the good things (like water) are retained.  It also has important functions in repair (wound healing), thermoregulation and in providing a front line in immune surveillance. A particular feature of skin is its regional specialization to form structures like hair follicles and secretory sebaceous glands, both of which are featured on this month’s cover.  In this issue of PLOS Genetics, we describe the application of a “reverse genetics” screening approach to identify new genes which play important roles in maintaining the normal function of the skin.

Since the skin comprises most of the surface of the body it is supremely accessible, making it an attractive organ in which to assess gene function in experimental models.  Doing so in the mouse is particularly relevant for understanding human disease, because of the genetic and physiological similarity between the two organisms.  We took a high throughput approach to assessing gene function in the skin; systematically inactivating genes in mice and then asking what effect this had on skin development and structure.  In total examining the potential contributions of more than 500 genes to skin biology, identifying many novel factors that were important for different skin functions [1].

One such gene, Keratin76 (Krt76), seemed to play a particularly important role in skin biology.  The keratins encode a large family of proteins which form networks in the cells of epithelial organs (like the skin) and which contribute greatly to their structural integrity.  It was found that Keratin76 was required both for the normal process of wound healing and to maintain the waterproofing “barrier” function of the skin.  Interestingly, neither of these features seemed to be associated with a role for Keratin76 in maintaining structural stability, because cell lysis or tissue blistering was not evident in mice lacking the gene.  Instead, defects were described in the function of structures called “tight junctions”; microscopic connections which form a seal between neighboring skin cells. To understand this finding better, they examined whether the proteins which normally assemble to form the tight junction were present in cells lacking Keratin76.   Strikingly, one of the principal protein components of the tight junction, Claudin 1, was mislocalised. The normal localization of Claudin1 is shown in the featured image, where it is found on the surface of skin cells in the normal hair follicle.  Images of this type were key to highlighting a possible link between Keratin76 and Claudin1 and they provided the starting point for molecular studies confirming that the two proteins were physically as well as functionally associated.  Our paper therefore proposes that Keratin76 contributes to normal tight junction function by ensuring that Claudin1 localises appropriately to the structure [2].

These studies are important for a number of reasons.  Firstly, they highlight the potential for large scale “reverse genetic screens” in mice to identify new genes important for the biology of different organs. Secondly, they provide one of the first descriptions of an association between keratins and tight junctions themselves.  Finally, they challenge the historical view that keratins are simply structural scaffolds, in so doing adding to an emerging body of research which indicates a much more active role in the biology of the cell. Although considerable work remains to elucidate the mode of action of Keratin76 (and indeed the many other genes identified in the screen), this work establishes important precedents for our understanding of the biology of your largest organ.

1.             DiTommaso T, et al. (2014) Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse. PLoS Genetics 10(10):e1004705. doi:10.1371/journal.pgen.1004705

2.             DiTommaso T, et al. (2014) Keratin 76 is required for tight junction function and maintenance of the skin barrier. PLoS Genetics 10(10):e1004706. doi:10.1371/journal.pgen.1004706

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Protein structure prediction, pleiotropic patterns, and more: the PLOS Comp Biol October Issue

Here are our highlights from October’s PLOS Computational Biology.

Proteins execute many functions in the cell, and these biological functions are strongly linked to their three-dimensional structure. By constructing a probabilistic model for sequence variability, Erik Aurell and colleagues present an advance in how to predict protein structure in three-dimensional space. In the paper “Improving Contact Prediction along Three Dimensions”, the authors highlight that it is possible to improve along the second dimension by going beyond the pair-wise Potts models from statistical physics, which have so far been the focus of the field.

Rendering of complete dendritic morphologies for 2770 generated granule cells from the center 20 µm of the model dentate gyrus. Image credit: Calvin James Schneider

Rendering of complete dendritic morphologies for 2770 generated granule cells from the center 20 µm of the model dentate gyrus. Image credit: Calvin James Schneider

Pleiotropy refers to a phenomenon in which a single genetic locus affects two or more phenotypic traits. The study of pleiotropy is useful in gene function discovery and in the study of the evolution of a gene. In “Canonical Correlation Analysis for Gene-Based Pleiotropy Discovery”, Jose Seoane and colleagues present a new methodology, based on Canonical Correlation Analysis, for multiple association testing with high dimensional datasets. In applying the methodology to a genotype dataset and a set of cardiovascular related phenotypes, the authors discovered a new association between gene NRG1 and phenotypes related with left ventricular hypertrophy. The methodology can also be used to find pleiotropic patterns or multiple associations in other omics datasets.

Genome-scale metabolic models provide a powerful means of harnessing information from genomes to deepen biological insights. However, manually constructing accurate metabolic networks is a difficult task, and computational algorithms that rely on network topology-based approaches can result in solutions that are inconsistent with existing genomic data. Nathan Price and colleagues have developed an algorithm that directly incorporates genomic evidence into the decision-making process for gap-filling reactions. This algorithm both maximizes the consistency of gap-filled reactions with available genomic data and identifies candidate genes for gap-filled reactions.

Many protein-protein interactions (PPIs) are compelling targets for drug discovery. Disrupting the interaction between two large proteins requires forming a high affinity binding site that can bind both peptides and non-peptide drug-like compounds. Through a comparison of ligand-free and ligand-bound structures, Sandor Vajda and colleagues examine the mechanism of binding site formation in the interface region of proteins that are PPI disruption targets. The measures used for structure comparison are based on binding hot spots, regions that are major contributors to the binding free energy. The results provide insight on the origin of sites that can bind small molecules in protein-protein interfaces.

Category: Bioinformatics, Biology, Cell biology, Community, Computational biology, Genetics, Molecular biology, PLOS Computational Biology | Tagged , | Leave a comment

This week in PLOS Biology

In PLOS Biology this week, you can read research articles about the regulation of glial cell activation, zinc regulation in E. coli and a new regulator of Wg/Wnt signalling. Also read articles from our magazine section on parasite tolerance, informal science education and genomic privacy.

 

A Tailored Response to Damaged Nerves

Image credit: pbio.1001985

Image credit: pbio.1001985

Glial cells are extremely sensitive to disruptions in the central nervous system. When axons are damaged, glial cells are activated and engulf the axonal debris. In a new research paper, Johnna Doherty, Marc Freeman and colleagues identify (in Drosophila) two novel regulators for Draper – the cell membrane receptor in glia that controls engulfment. First, PI3K signalling sets the baseline levels of Draper, and second, the transcription factor stat92E forms a novel auto-regulatory loop, allowing the level of activation to match the degree of damage incurred.

 

How to Live with the Enemy: Understanding Tolerance to Parasites

CaptainOates

Image credit: Flickr user CaptainOates

A new Primer by Lars Råberg brings together the findings of three research articles recently published in PLOS Biology on the subject of tolerance to parasites. All three of these studies address our understanding of the causes and consequences of variation in tolerance. In a study of HIV in humans, Regoes et al. show that an MHC class I gene affects not only resistance (as previously known) but also tolerance. In a study of voles, Jackson et al. identify a transcription factor mediating age differences in tolerance to macroparasites. Finally, Hayward et al. demonstrate that tolerance to intestinal parasites in sheep is under positive directional selection, but that most of the variation is environmentally induced rather than heritable. These studies increase our knowledge of the genetic and physiological sources of variation in tolerance, and how this variation affects Darwinian fitness.

 

Redefining Genomic Privacy: Trust and Empowerment

4422952630_79f17554b8_o

Image credit: Duncan Hull

Fulfilling the promise of the genetic revolution requires the analysis of large datasets containing information from thousands to millions of participants. Current models of protecting human subjects create a zero-sum game of privacy versus data utility. Yaniv Erlich, Robert Kain and colleagues, propose the use of techniques that facilitate trust between researchers and participants. This article is part of a PLOS Biology collectionPublic Engagement in Science. Browse the collection here.

 

An Exquisite Nose for Zinc

O'Halloran (14-02860) Striking Image

Image credit: pbio.1001987

Zinc is an essential nutrient for most organisms, with the Zn2+ ion performing numerous structural and catalytic roles in a range of proteins. However, like many nutrients, organisms need to be able to maintain steady levels of zinc in the face of near-zero environmental or excessively high concentrations. In their new paper, Benjamin Gilston, Thomas O’Halloran and colleagues look at how the bacterium E. coli does this, by examining the structure and function of Zur, a transcriptional repressor that is sensitive to Zn2+ concentration. They show how Zur binds to DNA – two molecules of Zur, each binding two Zn2+ ions (three in some species), grip adjacent sites from opposite sides of the DNA strand.

 

Informal Science Education: Lifelong, Life-Wide, Life-Deep

Grand Canyon Trail of Time - Supergroup stromatolite - 0368

Image credit: Erin Whitakker

The words ‘‘science education’’ once evoked images of a professor in a white coat lecturing at a blackboard filled with equations or students in a lab conducting ‘‘experiments’’ with beakers and Bunsen burners. Such limited views of science education no longer hold today, when science, technology, engineering, and math (STEM) learning takes place in a wide variety of social dynamics and settings. In their new Community Page, Kalie Sacco, John Falk and James Bell discuss how informal science education cultivates diverse opportunities for lifelong learning outside of formal classroom settings, from museums to online media, often with the help of practicing scientists.

 

Armless – A New Shield for Armadillo

The Wg/Wnt signaling pathway, found in most animals, is essential for regulating tissue growth and the formation of different cell types during development. Defects in the Wg/Wnt signaling relay can have serious consequences, from aberrant organ patterning to malignant tumor formation. Gerlinde Reim, Konrad Basler and colleagues have identified a regulator of this pathway in Drosophila – the Armless protein, which acts as a positive regulator of Wg/Wnt signalling by interacting with the AAA-ATPase Ter94 and thereby protecting Armadillo/β-Catenin from being tagged for degradation.

 

 

Category: Biology, Cell biology, Cell signalling, Data, Developmental biology, Disease, Ecology, Education, Genomics, Infectious disease, Microbiology, Neuroscience, PLOS Biology | 1 Comment

This week in PLOS Biology

In PLOS Biology this week, you can read about access to research data, regulation of cell asymmetry and septum formation in Caulobacter, and unfolding and refolding RNA.

 

Access to Data – The Publishers’ Role

pbio.1001779

Image credit: pbio.1001779

A new community perspective piece by Jennifer Lin and Carly Strasser calls on publishers to promote and contribute to increasing access to data. This call to action emerged from a summit attended by data experts from diverse stakeholder groups; the Perspective outlines eight recommendations and a set of suggested action items for publishers to enhance access to data.

 

***Two-for-One Offer on Caulobacter Papers!!!

 

1. Stopping Cell Division in Case of Damage

Cells have evolved sophisticated mechanisms for repairing their DNA and maintaining genome integrity. A critical aspect of this process is the arrest of cell cycle progression until the genome has been repaired. In new research, Joshua Modell, Michael Laub and colleagues explore the mechanisms behind inhibition of cell division in the bacterium Caulobacter crescentus. They report a new mechanism, in addition to the previously known ‘SOS response,’ which involves the inhibition of division septum formation by DidA. Read more in the accompanying Synopsis.

 

2. Reversal of Fortune: Flipping a Kinase

Sharipo 1

Image credit: pbio.1001979

A fundamental strategy of asymmetric cell division is to place different signalling molecules in each nascent daughter cell, which then go on to drive the two cells toward different fates. In Caulobacter crescentus, a bacterial model used to study this process, a critical molecular driver is a “response regulator” protein called DivK, which interacts with pseudo-histidine kinase called DivL. Normally, information flows from histidine kinases, which transfer a phosphate signal to their response regulator; however in this issue of PLOS Biology, Seth Childers, Qingping Xu, Lucy Shapiro, and colleagues show that DivL has taken an unusual evolutionary twist that allows it to serve as a highly specific sensor for the phosphorylation state of DivK, thereby reversing the normal flow of information. Read more in the accompanying Synopsis.

 

 

 

Unfolding and Refolding RNA

Russell

Image credit: pbio.1001981

RNAs function in many essential cellular processes, often requiring them to form a specific three-dimensional structure. However they also have a propensity to become trapped in non-functional, misfolded structures. DEAD-box proteins are known to help by disrupting such misfolded structures. In a new research article, Cynthia Pan, Rick Russell and colleagues reveal how DEAD-box proteins capture transiently exposed RNA helices, preventing any tertiary contacts from reforming and potentially destabilizing the global RNA architecture. Helix unwinding by the DEAD-box protein then allows the product RNA strands to form new contacts. Read more in the accompanying Synopsis.

 

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This week in PLOS Biology

In PLOS Biology this week, you can read about managing disease outbreaks, alpha band oscillations, human embalming techniques, unexpected effects of synaptic size and staying asleep.

 

Controlling Disease Outbreaks Adaptively

Disease outbreak management is a highly relevant topic given the current Ebola outbreak in West Africa. In a new research article, Katriona Shea, Matthew Ferrari and colleagues present an ‘adaptive management’ approach. This model allows initial uncertainties to be acknowledged, but builds in knowledge gained during an outbreak to update ongoing interventions. They apply the model to two past outbreaks – foot-and-mouth in the UK and a 2010 measles outbreak in Malawi. They argue that in both cases, using adaptive management could have reduced costs or cases of disease, respectively.

 

Filtering the Outside World

Jensen 14-01746 (2)

Image credit: pbio.1001965

In order to filter only relevant sensory information from our environment, we rely on powerful mechanisms in the brain. Johanna Zumer, Ole Jensen and colleagues used electroencephalography and fMRI to test the role of alpha band oscillations in the occipital lobe in acting as a filter for irrelevant information. Their results suggest that alpha band oscillations are indeed involved as a gating mechanism in routing attended information downstream to other regions of the brain.

 

 

 

 

From “Silent Teachers” to Models

Eisma Credit Emmanouil Kapazoglou (2)

Image credit: Emmanouil Kapazoglou

Embalmed cadavers are an invaluable tool for medical teaching; indeed, they’re how many medical students get their first experience of real human anatomy. Preservation is necessary to bridge the gap between death and use, but the traditional formaldehyde method is limited in its usefulness. In a new essay by Roos Eisma and Tracey Wilkinson, the authors describe the method developed by W. Thiel. Where this method is available, it results in more flexible, realistic cadaver models with many uses – from surgical training to testing new equipment and techniques.

 

Synapses – Size Matters!

The process of neurotransmission involves the conversion of electrical signals into the release of a chemical neurotransmitter from a neuron’s synaptic terminal. In a new research article, Tom Baden, Anton Nikolaev, Leon Lagnado and colleagues worked on the synaptic terminals of bipolar cells in the zebrafish retina. Using a variety of techniques, they discovered that the physical property of synapse volume affected neurotransmitter release. Large synapses were slow and small synapses were fast. You can read more about this research area in the accompanying Primer.

 

The Neurobiology of Staying Asleep

Kim

Image credit: pbio.1001974

The fruit fly Drosophila melanogaster has become a key model organism for sleep research. Previously, a seminal fluid protein, Sex Peptide (SP), has been shown to act via the Sex Peptide Receptor (SPR) to reduce the daytime “siesta” sleep of females after mating. Yangkyun Oh, Sung-Eun Yoon, Young-Joon Kim and colleagues investigated the role of SPR in sleep regulation in Drosophila further, finding that another ligand of SPR, called MIP, is required for stable sleep in both sexes. MIP does this by acting via SPR to silence specific neurons that otherwise keep flies awake.

 

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Chromatin and Epigenetics: From Omics to Single Cells

As part of its mission to encourage engagement within the genetics community, PLOS Genetics is sponsoring a number of conferences and meetings this year. In order to raise awareness about these conferences and the researchers who attend them we are featuring a number of these conferences on Biologue.

At the Chromatin and Epigenetics Conference, which took place in Strasbourg, France, on the 14th and 15th of October, PLOS awarded a student travel award to Paul Fields. Paul talks about his experiences at the conference, the topics discussed and the beauty of Strasbourg.

Few conferences are able to blend the beauty and history of old Europe with cutting-edge science from around the world, but that is exactly what Abcam achieved with their “Chromatin and Epigenetics: From Omics to Single Cells” meeting in Strasbourg, France.  Robert Schneider and Maria Elena Torres-Padilla put together a fantastic lineup of speakers from all over Europe and the United States, creating a very exciting meeting with highly relevant topics.  While the conference was aptly titled “From Omics to Single Cells”, it could just as easily have been called Omics AND Single Cells.  It was clear from early on that a common theme throughout the conference would be the integration of these two concepts to produce insights into the nature of chromatin and epigenetic regulation and how this contributes to cell state regulation.

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The picturesque cathedral in the center of Strasbourg. Image credit: Paul Fields

I got into Strasbourg the night before the conference and was only able to see a little of the beauty of the town before the start.  I managed to sneak in some of the wonders of Strasbourg over the few days I was here, including the picturesque cathedral in the center of town.  Day one of the conference was loosely centered on the omics perspective, including a variety of new methods to identify and characterize DNA methylation and its various intermediates.  Already in the second talk of the conference Sebastian Smallwood blended the omics and the single cell, presenting a fascinating method to address single cell heterogeneity in DNA methylation using single cell bisulfite sequencing.  Another recurring theme of the first day, which would carry over into the second day, was understanding chromatin and chromosomal structures within the cell.  Both Wouter de Laat and Susan Gasser presented new insights into our understanding of the feedback between chromosomal positioning and silencing/heterochromatin using two very different systems and approaches.  The end of day one was headlined by keynote speaker John Gurdon, who presented new work into understanding why some cells resist the process of cellular reprogramming.  Along with this he demonstrated just how far and how rapidly our understanding of cellular regulation from a chromatin perspective has come.   The day finished up with a fantastic French dinner; lots of food and a surplus of wine, as well as great conversations about the topics of the day.

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The conference venue: the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France. Image credit: Paul Fields

Day two began, as people straggled in after a long night of dancing, with the focus shifting towards single cells.  Bas van Steensel led off the day.  He was probably one of the most cited speakers of the conference, for his pioneering work into understand nuclear lamin interactions.  He has now pushed our understanding of nuclear lamin interactions to the single cell level.  Following in the vein of creative approaches, many of the speakers across the day presented new adaptations of old methodologies to address questions at a single cell level.  As Alex van Oudenaarden said, just because you don’t think it will work, doesn’t mean it’s not worth trying. His group was able to adapt TriZOL-based methods to generate single cell RNA-sequencing.  From that approach they could then try to identify rare cell types, integrating both novel sequencing methods as well as new approaches to computationally handle outliers.  One of the more humorous moments of the day was Peter Fraser’s analogy for why we need to study single cells, comparing a panel of Wayne Rooney’s various expressions to a population of cells. If averaged across, only the most defining features stand out, his ears, ignoring the intricacies of the individual moments.  Tony Kouzarides was the second keynote speaker. His long ties to both Robert Schneider and Maria Elena Torres-Padilla provided humorous introductions and his body of work has dramatically broadened our understanding of chromatin mechanisms.  Furthering the topic of taking both omics and single cell readouts to a functional level, Brad Bernstein proved an appropriate final speaker, as his work on both histone modifications and single cell analysis of transcription across cancers provides a model for how this work can be used therapeutically to treat patients.

One of the great things about getting so many fascinating speakers into one conference is it becomes easy to see how researchers continue to feed off of each other, and in turn benefit from a wide range of expertise.  Across the speakers (and also in the posters) at this conference, approaches ranged from genetic to biochemical to biophysical and everywhere in between, yet all having a similar goal to better understand the mechanisms of chromatin and epigenetics.  As the problems become more difficult it will take a host of new integrated approaches to continue to solve these questions and apply them outside of the lab.  In closing, I would like to thank Abcam and PLOS for the opportunity to experience this conference in person, and visit the beautiful city of Strasbourg.

 

Category: Biology, Community, Conference, Education, Epigenetics, Genetics, PLOS Genetics, Research | Leave a comment

Melanoma Cells: A Fatal Attraction to LPA

Credit: Flickr user Phil Whitehouse.

A beautiful day, but what’s happening under the surface? Credit: Flickr user Phil Whitehouse.

A hot day, blue sky and an even bluer sea. A perfect day to spend on the beach. But while our skin is sizzling, very few of us are aware of what some of our cells might be up to. Melanoma cells could be busy dividing and trying to escape the skin in search of a blood vessel through which to colonize other parts of our body. But how do they decide it’s time to migrate from the skin? Is there some sort of “go” signal that makes them leave their safe haven and cause havoc elsewhere?

 

Andrew Muinonen-Martin and researchers from the Beatson Institute at the University of Glasgow led by Robert Insall have been busy trying to find a way to stop this aggressive cancer spreading. In a new article just published in PLOS Biology, they tell us about a very promising breakthrough in their search for this “go” signal that could be disrupted to prevent metastasis of these tumors.

 

Why should we worry if we suddenly realize that we have a strange mole growing in our skin at an alarming pace? Melanocytes (a specialised skin cell) produce a pigment called melanin whenever we are exposed to sunlight – this is what gives us the highly desired tanned look. However these melanocytes aren’t born in the skin, but in a far-away developmental tissue called the neural crest; their long migration to the skin where they can protect us against UV light means that they’re naturally good ‘runners’.

 

Credit: doi:10.1371/journal.pbio.1001966

Credit: doi:10.1371/journal.pbio.1001966

As we well know, these guardians of our skin can occasionally turn nasty – when a dangerous mutation occurs that transform them in cancer cells, they start proliferating horizontally within the skin. This would be unpleasant if it remained confined to the skin, but then something happens that make these cells to migrate downwards instead until they manage to escape into the body. This is the dreaded phase of melanoma: within weeks these highly mobile cancer cells can spread all around the body, with disastrous and often lethal consequences.

 

Insall, Muinonen-Martin and colleagues focus their research on chemotaxis – chemical cues that attract and direct cells’ movements – and they set up to try to identify a potential signal that might be triggering the melanoma cells’ deadly migration. They tested the effect of several known chemoattractants by closely watching the migration of melanoma cells in direct-viewing chambers that they previously developed. They found that lysophosphatidic acid (LPA), a fatty chemical common in human tissues – and in the serum used in cell culture medium – was able to attract these cells particularly efficiently. But in order to attract cells, a chemoattractant needs to be present in the form of a gradient so that cells can move from a region with less of the chemical to areas where it is more abundant. How is a potential LPA gradient formed in these tumors?

 

Watch this video of melanoma cells swarming from an area of low LPA – on the left -  to an area of high LPA – on the right (credit: doi:10.1371/journal.pbio.1001966):

https://www.youtube.com/watch?v=OlAIIbrJLXA&feature=youtu.be.

 

The team analyzed the culture medium from groups of melanoma cells with different densities and saw that the cells were effectively breaking down the LPA molecules nearest to them. The result is a self-generated LPA gradient; low where cells have grown a lot – for example a tumour – and high away from the tumour where there are no melanoma cells. The researchers then looked closely at the more realistic ‘in vivo’ scenario in real tumours from mutant mice that are susceptible to melanoma. They took biopsies from different areas around the tumour, and use mass spectrometry to measure LPA levels. Again, this revealed an outward gradient. Cells located close to the center of the tumour were exposed to low levels of LPA, whereas cells at the edges of the tumour had access to much higher levels. Inevitably, this gradient seems to attract melanoma cells out of the tumour, following the scent of LPA and blazing a trail outwards, perhaps to a handy blood vessel.

 

LPA - the fatal attractant.

LPA – the fatal attractant.

The conclusion is, therefore, that the melanoma generates the signal for its own metastasis. But the researchers’ identification of the bearer of this signal leaves a door open for hope. If we can manage to stop LPA gradients being generated in the tumor –perhaps by inhibiting the enzyme that breaks LPA down – metastasis of these cells might become preventable. In the meanwhile, while a ray of hope shines in the sky, make sure you and your skin stay well protected with sunscreen.

 
ResearchBlogging.org
Muinonen-Martin, A., Susanto, O., Zhang, Q., Smethurst, E., Faller, W., Veltman, D., Kalna, G., Lindsay, C., Bennett, D., Sansom, O., Herd, R., Jones, R., Machesky, L., Wakelam, M., Knecht, D., & Insall, R. (2014). Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal PLoS Biology, 12 (10) DOI: 10.1371/journal.pbio.1001966

Category: Biology, Cancer, Cell signalling, Developmental biology, Disease, PLOS Biology | Leave a comment