Modelling cell interaction, deciding on optimal paths and tracking tumour evolution: The PLOS Comp Biol August Issue

Here is our selection of PLOS Computational Biology highlights for August.

Using a model of collective learning to understand how individual learning affects consensus group decisions. Image credit: Albert Kao

During the embryonic development of multicellular organisms, millions of cells cooperatively build structured tissues, organs and whole organisms, a process called morphogenesis. It is still not entirely understood how the behaviour of so many cells is coordinated to produce complex structures. In response to this question, Roeland Merks et al. propose a new computational model that shows a simple form of mechanical cell-cell communication suffices for reproducing the formation of blood vessel-like structures in cell cultures. These findings advance our understanding of biomechanical signalling during morphogenesis, and introduce a new set of computational tools for modelling mechanical interactions between cells. Combining the present mechanical model with aspects of previously proposed mechanical and chemical models may lead to a more complete understanding of in vitro angiogenesis.

Human behaviour has long been recognised to display a hierarchical structure, in that we organise tasks into subtasks, which fit into extended goal-directed activities. Arranging actions hierarchically has well established benefits, allowing behaviours to be represented efficiently by the brain, and allowing solutions to new tasks to be discovered easily. But how do we learn to subdivide our goals in this way?  Matthew M. Botninick et al. have developed a mathematical account for how we differentiate between hierarchies and choose the optimal path. The authors then presented results from four behavioural experiments, suggesting that human learners spontaneously discover optimal action hierarchies.

Errors in sample annotation or labelling often occur in large-scale genetic or genomic studies and are difficult to avoid completely during data generation and management. For integrative genomic studies, it is critical to identify and correct these errors. On that basis, Jun Zhu et al. developed a computational approach, Multi-Omics Data Matcher (MODMatcher), to identify and correct sample labelling errors in multiple types of molecular data, which can be used in further integrative analysis.

Often, accurately characterizing a tumour requires analysing multiple samples from the same patient. To address this need, Li Ding et al. present SciClone, a computational method that identifies the number and genetic composition of subclones by analysing the variant somatic mutations. They used it to detect subclones in leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumour sample. By doing so, they tracked tumour evolution and identified the spatial origins of cells resisting therapy.

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This week in PLOS Biology

In PLOS Biology this week you can read about citizen science oceanography, de-differentiation and drug resistance in cancer, fine-tuning of DNA repair and action potential initiation in cortical neurons.

Crowdsourcing the Collection of Oceanographic Data


Image credit: Rachelle Lauro

In a new Community Page, Frederico Lauro and colleagues argue that the vast size of the oceans and the costs of research inhibit the gathering of oceanographic data. They propose using ‘Citizen Scientists’ to improve spatial and temporal density of observations - i.e. by fitting simple, low-cost instrumentation to sailing vessels. Examples of the types of data that could be collected include biological samples, surface weather conditions and debris sightings.


Striking the Balance in DNA Repair

Du thumb2Double-strand breaks in DNA strands can have catastrophic consequences if left unrepaired. The repair process requires careful resection of one strand, maintaining a delicate balance of nuclease activities so as to achieve accurate repair without erosion of the end of the DNA strand. New research by Jia-Min Zhang, Li-Lin Du and colleagues identified a key protein – Pxd1 in the fission yeast Schizosaccharomyces pombe which helps coordinate the multi-enzyme activities taking place during DNA repair. This protein minimizes the potentially deleterious consequences of the process by inhibiting one nuclease while activating another.


Blocking Multi-Drug Resistance in Tumours

There are often two key features of the most dangerous cancerous tumours – they tend to be both de-differentiated (i.e. have regressed to an earlier developmental stage) and multi-drug resistant. In their research article published this week in PLOS Biology, Catherine Del Vecchio, Piyush Gupta and colleagues asked how these two things might be linked. They found that PERK-Nrf2 signalling was involved with therapy resistance in poorly differentiated breast cancer cells. Nrf2 is activated when the cancer cells de-differentiate. Their results suggest a novel therapeutic role for drugs that block this signalling pathway, which when coupled with chemotherapy might improve the responsiveness of resistant tumours to treatment.


Sodium Channels Bring Variety to Inhibitory Interneurons

SExcitatory neurons in the cortex of the brain are regulated by inhibitory neurons, but it appears that not all inhibitory neurons are the same.  Tun Li, Yousheng Shu and colleagues investigated two different populations of neurons (parvalbumin- and somatostatin-expressing) in the cerebral cortex. They found that they had varying electrical properties, caused by the presence of different types of sodium channels in their membranes.

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This week in PLOS Biology

In PLOS Biology this week, you can read about the evolution of symbiosis, the role of Epstein-Barr virus in disease and the neural correlates of social status in macaques.


Epstein-Barr Virus: a Smoking Gun? 

Sugden thumb

Image credit pbio.1001939

In a new Essay, Bill Sugden examines the evidence that links this ubiquitous human pathogen to cancer and multiple sclerosisEpstein-Barr virus is notorious for causing multiple kinds of cancer. It has also been increasingly linked to multiple sclerosis. What evidence now supports or can be sought potentially to strengthen this linkage?




 Neural Circuitry of Social Hierarchy

Noonan pic

Image credit pbio.1001940

In their new research paper, MaryAnn Noonan, Matthew Rushworth and colleagues tease apart the neural correlates of social status. This neuroimaging study reveals that individual variation in brain circuits in structures below the cerebral cortex of rhesus macaques is associated with experience at different ends of the social hierarchy. Read the accompanying Primer.


Symbiosis Plasmids Bring Their Own Mutagen to the Party 

Image credit pbio.1001942

Image credit pbio.1000280

The symbiotic bacteria that form nitrogen-fixing nodules in leguminous plants started off as free-living soil bacteria, but how do they make the transition to cohabiting so intimately with plants? Philippe Remigi, Catherine Masson-Boivin and colleagues use an experimental evolution approach to show that stress-responsive error-prone DNA polymerase genes ease the evolution of the soil bacterium Ralstonia solanacearum into a legume endosymbiont by accelerating adaptation of the bacterial genome to its new plant host. Read more in the accompanying Synopsis.

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How Much of Your Genome Is Functional?

On the 24th of July, 2014 PLOS Genetics published an article entitled: “8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover across Functional Element Classes in the Human Lineage”. Two weeks later the article had been viewed 12,307 times, it already had one citation, and had been shared on social media 436 times. This means that, on average, 36 people had been viewing the article online every hour.

Unlike many other papers that might attract this level of interest through traditional press coverage, this article was primarily picked up by social media. This flurry of activity was in part driven by coverage in ifls, which has been shared on Facebook 12,200 times. However, it wasn’t just a social media piece, it has also been featured in Nature, Sci-news, the Guardian, the French Tribune, and the International Business Times.

It is pleasing to see that the article has received lots of views of course. I think article metrics like views and shares on social media (such as twitter and facebook) are important metrics because they are nearly instantaneous measures of impact (compared to citations) and they imply there is a public interest in the research. I believe science communication is important, particularly for publicly funded research such as this. The open access publishing at PLOS helps promote science communication.” – Chris Rands (author)

What made this article such a hit? The paper explores how much of the human genome can be considered ‘functional’. While scientists were able to successfully sequence the human genome over a decade ago, it has been unclear how much of the genome is doing something useful. In 2012 some members of the ENCODE consortium suggested that as much as 80% of the genome might be considered functional. Chris Rands and colleagues argue that this might be as little as 8.2%; ten times less than the ENCODE estimate.


The researchers used a computational approach to compare the whole DNA sequences of various mammals, including human, horse, bush baby, panda, and mouse. Image Credit: George Lu CC BY Flickr

Natural selection is expected to preserve important DNA, removing insertion and deletion (indel) mutations from these genomic regions. In order to find the sequences with evidence of functionality, Chris Rands and colleagues identified areas of the human genome that have been unusually evolutionarily stable with respect to these indel mutations. The researchers used a computational approach to compare the complete DNA sequences of various mammals, including human, horse, bush baby, panda, and mouse.

Using this method they estimate that between 7.1-9.2% of the human genome can be considered ‘functional’. If this is the case, then the majority of the human genome can experience mutations without affecting fitness. Coding exons, bound motifs and DNase1 footprints make up around 9% of the human genome. These are areas that we would expect to be considered functional, based on what we know about their roles within the genome. While these areas will not encompass all of the functional sections and there may be sequences outside of these sections that are functional, it could be taken as an indication that the estimate that Chris Rands and colleagues suggest is in the right ballpark.


Mouse as a model organism may miss many subtle aspects of human noncoding biology. Image Credit: Duncan Hull CC BY Flickr

As well as an indication of DNA functionality Chris Rands tells PLOS Genetics that We find that only 2.2% the human genome is ‘functional’ and shared with mouse too; the remaining 6% has gained ‘functionality’ in the human lineage since humans diverged from their common ancestor with mice 80 million years ago.”

 Their findings could therefore provide a more quantitative basis for assessing the relevance of model organisms to specific questions of human biology.

“Although the main media message about the paper has been about the proportion of the human genome that is ‘functional’, the main novel research contribution is about the turnover of ‘functional’ sequence as it is lost and gained over time. Given we estimate that approximately 3 times as much sequence is ‘functional’ in the human genome as is ‘functional’ and shared with mouse, this implies that mouse as a model organism may miss many subtle aspects of human noncoding biology, although the real practical implications of this tentative conclusion remain to be fully explored.”


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This week in PLOS Biology

In PLOS Biology this week, you can read about the generation of neural stem cells, compensatory evolution, the evolution of language and focusing of attention by the frontal and parietal areas of the cortex.


Briscoe thumbStem cells are providing insight into embryo development and offering new approaches to clinical and therapeutic research. During embryo development, spinal cord and the adjacent paraxial mesoderm (which later forms muscle and bone) arise from precursors called neuromesodermal progenitors (NMPs). In new research published this week, Mina Gouti, James Briscoe and colleagues were able to make NMPs in vitro, and showed that in mice and human cells, the decision between spinal cord and mesoderm involves a gene, Brachyury, that promotes mesoderm production by inhibiting spinal cord generation. This could have important applications, as the production of neural stem cells is a desirable goal for therapeutic uses. Read more in the accompanying synopsis.


While core cellular processes are generally conserved during evolution, the constituent genes differ somewhat between related species with similar lifestyles. Why should this be so? In a large scale evolutionary experiment using baker’s yeast, Béla Szamecz, Csaba Pál and colleagues set out to show that organisms can recover fitness by the accumulation of compensatory mutations elsewhere in the genome. They took 180 strains of yeast, each lacking a specific gene which compromised fitness, and allowed them to evolve through 400 generations to see if the yeast could ultimately compensate for the lost gene. Interestingly, 68% of the genotypes reached near wild-type fitness through adaptive mutations. Genomic analysis revealed that compensatory mutations were generally specific to the functional defect incurred, but that the evolutionary outcomes were not phenotypically equivalent.


Credit: Pieter Bruegel the Elder

Credit: Pieter Bruegel the Elder

In a new essay published this week, Johan Bolhuis, Ian Tattersall, Noam Chomsky and Robert Berwick discuss the controversial topic of how language evolved. The authors begin by explaining that the definition of language itself is not even clearly defined, although they argue for the theory that syntax is the key feature of language. Using this idea, its evolution is very hard to study – syntax having no equivalent in non-humans. Bolhuis and colleagues argue that the appearance of symbolic thought arose around 100,000 years ago, when Homo sapiens first produced symbolic artefacts.


In their new research paper, Sara Szczepanski, Robert Knight and colleagues addressed the important question of how the frontal and parietal areas of the cerebral cortex work together to focus attention. They applied electrodes directly onto the cortex of patients who were about to undergo surgical treatment for epilepsy and asked them to perform a reaction time task. They conclude that coupling between delta/theta phase and high gamma amplitude components of electrical brain activity serves to coordinate information within – and perhaps between – frontal and parietal areas during coordination of visuospatial attention.

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On our way to @FEBSEMBO2014

PLOS is heading to the FEBS EMBO 2014 meeting starting next Saturday, 30th August through Thursday 4th September.

If you’re going to be there please stop by to say hello, we’ll be at Booth 72

I’ll be there representing PLOS Biology, and there’ll be other representatives from PLOS ONE, and PLOS as a whole. We’ll have a couple of Meet the Editor sessions on the booth, but feel free to tweet us if you want to arrange a time to talk about OA, PLOS, or any of the PLOS journals.

The line-up of speakers looks fantastic, and I can’t wait for some of these talks. Everything kicks off on Saturday with Keynotes from Catherine Dulac and Svante Pääbo, and there are Plenary Lectures aplenty interspersed with concurrent sessions. FEBS EMBO 2014 is the largest meeting for the life sciences in Europe this year. It will feature >100 lectures, workshops and symposia on established and emerging areas of research.

It’s also a really exciting year for this meeting, marking several anniversaries, the 50th anniversary of The Federation of European Biochemical Sciences (FEBS) and EMBO and the centennial of The French Society for Biochemistry and Molecular Biology (SFBBM).

With thanks in advance to the organizers for what promises to be a stellar meeting. We hope to see you there!

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This week in PLOS Biology

In PLOS Biology this week you can read about a survival strategy employed by Salmonella bugs, transcript capping in the cytoplasm and differences in the architecture of the visual cortex between rodents and higher mammals.


image.pcbi.v06.i08.g001 (1)

Image credit: image.pcbi.v06.i08.g001

The mammalian visual cortex contains 50 to 100 thousand neurons per cubic millimetre, most of which are excitatory (85%) and the minority, inhibitory (15%). Unlike neurons in the retina, neurons in the visual cortex are preferentially activated by lines or edges of a particular orientation. In the visual cortex of higher mammals like cats and monkeys, neurons that share an orientation preference are clustered in functional columns. However, in rodents like mice, orientation preferences are randomly distributed. In a new study, Rita Bopp, Morgane Roth and colleagues asked whether the differences between columnar and non-columnar cortex are correlated with differences in the connectivity patterns between excitatory and inhibitory neurons in mice. Their results show that the ratio of excitatory-inhibitory neurons in the mouse visual cortex is similar to that of cat or monkey visual cortex, but in the mouse local pyramidal neurons target proportionately many more inhibitory neurons compared to other studies in higher mammals. This suggests that inhibition may stand in for columns as the organising principle.


Bacterial populations grow rapidly and asexually, generating millions of genetically identical progeny. However despite genetic and environmental uniformity, we now know that differences can occur, through stochastic molecular processes. But what are the advantages of this in a group of clonal organisms? Markus Arnoldini, Martin Ackermann and colleagues studied the human pathogen Salmonella typhimurium, which is known to vary in levels of virulence factors called ttss-1. Those bugs which express high levels of the factor grow slower, but the authors showed that they were also better able to survive antibiotic treatments. So it seems that this is a ‘bet-hedging’ strategy that pays off when disaster strikes. This has implications for antibiotic use, as selection for tolerance of the drug might also inadvertently select for high virulence. Read more in the accompanying synopsis.



Image credit: pbio.1001933

Messenger RNA ‘capping’ was previously thought to happen only in the nucleus, with subsequent degradation in the cytoplasm. However there has been recent evidence of capping taking place in the cytoplasm. In this week’s issue of PLOS Biology work by Chandrama Mukherjee, Baskar Bakthavachalu and Daniel Schoenberg build on this discovery. They have identified a domain of the cytoplasmic Capping Enzyme, which is required for its function in cytoplasmic capping. This allows it to bind to the adapter protein Nck1 – Nck1 is better known as a player in kinase-mediated signalling pathways, but here they show that it also helps provide a scaffold for assembly of the cytoplasmic capping complex.



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What’s the Buzz on Bee Pathogens?

US National Honey Bee Day is August 16th. Read below for a selection of papers from PLOS Pathogens on honey bee decline in the world of pathogenesis. 

This post has been modified since its original posting on August 15, 2014. 

Honey bees at a hive entrance. Image credit: Warden, Wikimedia Commons

Honey bees at a hive entrance.
Image credit: Warden, Wikimedia Commons

Given the current issues affecting global health— the Ebola outbreak in West Africa, the battle to eradicate polio in Pakistan, and the rise of type 2 diabetes in the United States— honey bee health seems like it would be last on our list of worries. However, August 16, 2014 marks the 5th US National Honey Bee Day, an organized day to raise honey bee awareness. Honey bee health and the awareness day commemorating it seem mainly geared towards the agricultural, farming, and small-scale bee-keeping communities; however, there is more interest in honey bee health from the scientific community than you may think.

The decline of honey bees is a major agricultural concern and the Agricultural Research Service (ARS), the USDA’s internal research agency, is leading several efforts to gain more information on the possible causes. The rate at which honey bee colonies are declining is alarming. According to the 2013-2014 annual survey conducted by the Bee Informed Partnership and the U.S. Department of Agriculture (USDA), total losses of managed honey bee colonies from all causes were 23.2 percent nationwide for the 2013-2014 winter. Although these losses are less than previous winters, the 2013-2014 annual survey reports that “losses still remain above the level that beekeepers consider economically sustainable.” The honey bee industry is vital to large agriculture which feeds most of the world; however National Honey Bee Day is aimed at increasing involvement from concerned citizens, most of whom are backyard gardeners and nature-loving beekeepers.

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This Week in PLOS Biology

In PLOS Biology this week you can read about a regulatory pathway in meiosis, genetic variability of avian influenza and ancient cell membranes.


Meiosis is a type of cell division which is essential for halving the number of chromosomes to make gametes needed for sexual reproduction in animals, plants and fungi. A further feature of meiosis, and one of the main driving forces behind the success of sex, is that it affords the organism a chance to shuffle its genome, using well distributed recombination events (“crossovers“) to make a new meld of its parents’ genotypes. Although crossovers benefit from being randomly placed, their number and approximate position needs to be tightly regulated. In a new research article by Marina Jahns, Mathilde Grelon and colleagues, they investigate how this is done. They identified a novel regulatory pathway controlling crossover localisation in Arabidopsis plants, which may also be conserved in mammals. This pathway involves post-translational modification via neddylation (covalent attachment of the ubiquitin-related protein Nedd8).



Image credit: journal.pbio.1001931

Despite the public health significance of Avian influenza viruses (pivotal to the origination of human pandemic strains) much is not understood about their ecology and evolution in wild birds. The host pool in birds supports a very large range of strains, but once in humans the genetic diversity is much reduced. Benjamin Roche, Pejman Rohani and colleagues present comparative analyses of human and avian viruses and use computational models to try to explain these differences. They conclude that the combination of the short lifespan of wild birds, and greater durability of viruses in aquatic environments, is key to maintaining the high levels of flu virus diversity observed in wild birds.




10.1371journal.pbio.1001926 (1)

Image credit: journal.pbio.1001926

The archaea and the bacteria – the two deepest branches of the tree of life. They share many features in common, but their cell membranes are profoundly different. It seems therefore that the membranes must have evolved after the two diverged from their last universal common ancestor (“LUCA”). But if that ancestor did not have a membrane, how could it harvest energy, and why did the archaeal and bacterial progeny produce such different membrane structures? Victor Sojo, Andrew Pomiankowski, and Nick Lane developed a mathematical model of primordial membrane bioenergetics, showing that a leaky membrane of simple lipids could be a precursor of both types of modern membrane. Read more in the accompanying synopsis.

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Gordon Research Conference on Mammalian Reproduction: Marisa Bartolomei

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, with posts written by the organizers or PLOS Genetics editors who are involved.

The last of these conferences is the Gordon Research Conference on Mammalian Reproduction, which takes place at Colby Sawyer College from the 10th to the 15th of August. Marisa BartolomeiPLOS Genetics editor who will be chairing the discussion on Epigenetic Programming and Reproduction, describes the topics that will be discussed at the conference, and their relevance to everyday life.

A new Gordon Research Conference (GRC) on Mammalian Reproduction is being launched this week. This conference will continue the legacy of two previous GRCs dealing with aspects of mammalian reproduction – one on Mammalian Gametogenesis & Embryogenesis and one on Reproductive Tract Biology.  Both of those GRCs ran successfully for more than 30 years but were stopped around three years ago.  This new GRC on Mammalian Reproduction seeks to combine the best of the legacies of those two meetings to create a new conference focused on cutting-edge research of greatest relevance to the field of reproductive biology as it applies to mammals.


Image credit: Public domain


The theme of this inaugural gathering in what we hope will become another long-standing and successful GRC on reproduction is “Translating Basic Science into Clinical Applications.”  To this end, sessions are focused on topics in which novel basic discoveries have lead and/or are leading to novel and effective clinical applications.  The opening session will focus on “Fate Determination and Development of Reproductive Tissues,” which will feature recent discoveries into developmental origins of germ cells and somatic cells in reproductive tissues.  Such insight can be used to help understand how defects in these developmental mechanisms may lead to infertility or to diseases of reproductive tissues.  In addition, these developmental mechanisms can be replicated to direct differentiation of stem cells to restore these functions.

The second session will focus on “Epigenetic Programming and Reproduction.” The reproductive system – especially the germ line – is a site of extensive epigenetic programming/reprogramming during each generation.  These mechanisms are responsible for proper development of each generation, and defects in these mechanisms can lead to transgenerational epigenetic inheritance resulting in heritable transmission of disease via a non-genetic paradigm.  A related topic will be explored in the third session – “Stem Cells and Reproduction.”  Once again, a basic understanding of the manner in which normal endogenous stem cells function in the reproductive system will provide insight into how exogenous stem cells can be used to treat reproductive defects including infertility or disease.  In yet another related session – “Environmental Effects on Reproductive Functions” – the manner in which various environmental agents can disrupt normal reproductive functions will be explored.  This has become a particularly active area of research in recent years and this conference will bring together experts from the reproductive biology and environmental health fields to further address key questions in this area.

In the fifth session, the conference will transition its focus to questions of women’s health and infertility and contraception.  Thus, the fifth session will focus on “Pregnancy and Parturition” and will address key immunological and pathological mechanisms operating during this time.  The sixth session will then be focused on “Infertility and Contraception” and will include presentations describing new information regarding molecular mechanisms that impact fertility, as well as those describing novel approaches to contraception.


Image credit: gabi menashe Flickr CC BY

The seventh session will focus on the male reproductive system and male fertility with an emphasis on mechanisms operating in the “Male Reproductive Tract.”  Then in the eighth session, the focus will turn to larger scale “Genomics/Systems Biology Approaches to Reproduction.”  This will include studies utilizing genomics, transcriptomics, and other high-throughput approaches to more comprehensively examine reproductive functions. Epigenetics section editor Wolf Reik will present a talk in this session describing the role of DNA modifications in signaling in epigenetic reprogramming.

The final session is entitled the “Founders’ Forum – Milestones in Reproductive Biology.”  This is a special session that recognizes senior investigators in the field who have made particularly significant and extensive contributions to the field.  This forum affords these individuals an opportunity to present their most recent work and to place that in a large historical context related to the particular sub-discipline under the reproduction umbrella in which they are most interested.

In addition to invited longer talks, the conference will feature a number of short talks by young investigators, from graduate students to assistant professors. There are also more than 100 posters that will be presented from Monday to Thursday afternoon. We are thrilled that over 150 people have registered to attend this inaugural Gordon Research Conference.

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