This week in PLOS Biology

In PLOS Biology this week you can read about modelling Ebola containment measures, a conceptual framework for IPBES, and new insights into how the injectisome works.


Fighting Ebola in Liberia


Image credit: NIAID, Flickr

In 2014, a major epidemic of human Ebola virus emerged in West Africa. There are still key questions about the path to containment – the relative importance of transmission under medical care versus community-acquired infection, how much hospital capacity must increase and which interventions will be most effective? In a new paper published this week, John Drake, Andrew Park and colleagues use a novel modelling approach to attempt to assess the impact of health care interventions on the current Ebola epidemic in Liberia. Their model is multi-branching and incorporates the impacts of changes in behaviour on potential transmission scenarios. Projections based on up-to-date data suggest that 85% hospitalisation rates have the potential to end the outbreak by June 2015. Also read this blog post about how we expedited publication of this article, and (update Jan 21st) – we just published a great Primer by Gerardo Chowell and Hiroshi Nishiura that sets this study in context.


Nature’s Benefits to People – A Conceptual Framework for IPBES

The Intergovernmental Platform on Biodiversity & Ecosystem Services (IPBES) came about in April 2012, as a unified group for reviewing, assessing and synthesizing knowledge gathered on biodiversity and ecosystem services. In a new Community Page this week, Sandra Diáz, Anne Larigauderie & colleagues set out the conceptual framework for IPBES – a simplified model of the interactions between nature and people.


A Dynamic Role for the Injectisome’s C-Ring

Credit: doi:10.1371/journal.pbio.1002039

Credit: doi:10.1371/journal.pbio.1002039

The type III secretion system, also known as the injectisome, is a key virulence factor in many gram-negative bacteria, responsible for the injection of bacterial proteins directly into host cells. It shares many attributes with its evolutionary cousin, the bacteria flagellum. However, the function of the injectisome’s cytosolic C-ring, whose flagellar counterpart determines switching of rotational direction, has remained enigmatic. New research by Andreas Diepold, Judith Armitage & colleagues used fluorescently tagged protein subunits to allow them to analyse its behaviour, revealing that the cytosolic C-ring structure has a dynamic relationship to the rest of the complex — suggestive of a role in regulating the secretion of effectors by the injectisome.


Category: Biology, Disease, Ecology, Environment, Microbiology, Policy, Research | Leave a comment

Publishing to Keep up with Ebola

Image credit: NIAID, Flickr

Ebola viruses (green) emerge from a cell. Image credit: NIAID, Flickr

As you read this, thread-like viruses less than one micron in length are spreading through human populations in West Africa, taking lives, wrecking communities and generally creating havoc in the countries affected. Infection with the Ebola virus results in an appalling death in about half of all cases within a few weeks, and transmission rates are high, cruelly exploiting contact with the dead or dying. The death toll stands at more 8,235, from the initial outbreak in Dec 2013 up to data available on Jan 4th 2015.

Clearly this was no time for hanging around, and when we received a manuscript that described a new model of Ebola virus transmission, with potentially immediate implications for the management of the current Ebola outbreak, we were concerned about the conflict between responsible high-quality publishing and the pressing need to inform the ongoing ground-fight against the virus.

We straightaway asked the authors to deposit their manuscript in a pre-print server so that it would be immediately available to the public while we put it through the peer-review process. The reviewers returned their comments very rapidly, but several expressed concerns about the possibility of delivering a timely publication.

The timeliness problem arose because the manuscript uses real-life data from medical units in Liberia, and generates projections about how the Ebola outbreak will respond to various changes in clinical management and public behaviour (see the images below). Both the data inputs and the projected outputs are extremely time-sensitive, and the normal publication process ran the risk of delivering a paper that had already been rendered obsolete by the march of events on the ground.

After some editorial heart-searching as to whether it was fair to the authors to pursue a further round of revision and review at PLOS Biology, we decided that we would continue to consider the paper but only if we could expedite publication of the most up-to-date version possible.

The obvious way to do this was as a blog post, a trail already blazed by one of our sister journals, PLOS Neglected Tropical Diseases – also with an Ebola-related paper. However, luck was on our side, as that very week saw the introduction of a new production pipeline at PLOS that promised a greater speed to publication of fully typeset, copy-edited and proof-read papers.

Drake et al's projections through June 2015 of the consequences of the status quo (top) versus 85% hospitalisation (bottom). Credit: 10.1371/journal.pbio.1002056

Drake et al’s projections through June 2015 of the consequences of the status quo (top) versus 85% hospitalisation (bottom). Credit: 10.1371/journal.pbio.1002056

The academic editor was happy that if he could check the final updated projections and we could publish with a couple of weeks then a meaningful – and potentially useful – publication was at least in principle possible. The expedited paper has just been published, almost exactly three weeks later (holidays aren’t the best conditions under which to roll out a brand-new production system). One step closer to the day when the printing press can out-run the virus.

Update Jan 21st – we just published a great Primer by Gerardo Chowell and Hiroshi Nishiura that sets this study in context.


ResearchBlogging.orgDrake JM, Kaul RB, Alexander LW, O’Regan SM, Kramer AM, Pulliam JT, Ferrari MJ, Park AW. (2015). Ebola Cases and Health System Demand in Liberia. PLoS Biology, 13 (1) : 10.1371/journal.pbio.1002056


Chowell G, Nishiura H. (2015). Characterizing the Transmission Dynamics and Control of Ebola Virus Disease. PLoS Biology, 13 (1) : 10.1371/journal.pbio.1002057


Category: Biology, Computational biology, Disease, Infectious disease, Open access, PLOS Biology, Publishing | 3 Comments

This week in PLOS Biology

In PLOS Biology this week you can read about the perception and self-regulation of paina computational model of operant learning and improving the computer-friendliness of phenotypic data.


Two Parallel Pathways to Pain

 Image credit: 10.1371/journal.pbio.1002036

Image credit: 10.1371/journal.pbio.1002036

Understanding how pain is processed in the brain is a controversial area of neuroscience, because there doesn’t seem to be a single ‘‘pain cortex’’ that directly codes the subjective perception of pain. Although we’ve known for some time that we can self-regulate pain we experience, it is unclear which circuits underpin this. Choong-Wan Woo, Tor Wager & colleagues used fMRI to show that two distinct parallel neural systems independently contribute to our overall experience of pain — separately modulated by noxious input and by cognitive self-regulation. Read more in the accompanying Primer.


How Animals Select Actions with Rewarding Outcomes

A key component of survival is learning to associate rewarding outcomes with specific actions, such as searching for food. Actions are represented in the cortex, and rewarding outcomes activate neurons that release dopamine. These signals are then sent to the striatum— the input station for a collection of brain structures called the basal ganglia, which play an important role in action selection. A new paper by Kevin Gurney, Mark Humphries & Peter Redgrave uses a computational model that shows how the brain’s internal signal for outcome changes the strength of neuronal connections, leading to the selection of rewarded actions and the suppression of unrewarded ones. Read more in the accompanying Synopsis.


Computing Phenotype

Image credit: doi:10.1371/journal.pbio.1002033.g001

Image credit:


Phenotypic data (i.e. observable traits such as anatomy and behaviour) represent much of what we know about life and drive much of life science research. A new Perspective by Andrew Deans & colleagues argues that the current form in which phenotypic data are recorded inhibits their productive use. Their article asks us to imagine a future in which we could compute across phenotype data as easily as genomic data, calls for efforts to realize this vision, and discusses the potential benefits.




Category: Bioinformatics, Biology, Computational biology, Neuroscience, PLOS Biology, Systems biology | Leave a comment

Media response: forecasting diseases using Wikipedia

“It’s a perfect mix of exciting science, modern everyday technology, and public health.” Dr Marcel Salathé

Many of us use Wikipedia solely as an online encyclopedia but we need to think bigger – there’s a huge amount to be learnt from the way people interact with sites like this. A recent PLOS Computational Biology article explores this idea in a way that has caught the public’s imagination.

According to recently published research, analysing page views of Wikipedia articles could make it possible to monitor and forecast diseases around the globe.

Analysing page views of Wikipedia articles could make it possible to monitor and forecast diseases around the globe.  Image Credit: Stephen Ritchie / Flickr

Analysing page views of Wikipedia articles could make it possible to monitor and forecast diseases around the globe.
Image Credit: Stephen Ritchie / Flickr

Dr Sara Del Valle and her team from Los Alamos National Laboratory successfully monitored influenza outbreaks in the United States, Poland, Japan and Thailand, dengue fever in Brazil and Thailand, and tuberculosis in China and Thailand.

The team was able to forecast all but one of these outbreaks (tuberculosis in China) at least 28 days in advance. The results suggest that people start searching for disease-related information on Wikipedia before they seek medical attention. However, the way the Wikipedia data is currently released limits their ability to geo-locate the disease-related information.

The paper outlined several shortcomings in regards to transparency, openness, and reproducibility that need to be overcome before an operational, global disease monitoring and forecasting system can be built. Del Valle said, “We are currently working with the Wikimedia Foundation, the operators of Wikipedia, to develop a public, geo-located form of the access logs which preserves reader and editor privacy.”


In the media:

Since the paper’s publication in November 2014 the article has gained much media attention. The paper was notably reported around the world, in outlets such as The Washington Post, Le Monde, BBC, Los Angeles Times, Agerpres, Sü, The Atlantic,  and Popular Mechanics. The team further participated in a Reddit “Ask Me Anything” (AMA) which received over 2944 “upvotes”, 483 comments, and landed on the front page.

The crux of public interest is channelled through social media. Looking at the stats alone the article has been tweeted over 130 times, mentioned on Facebook over 180 times, had a BuzzFeed article and the paper has since received its first Wikipedia citation.

Simply put, within one month the article has gained over 19,000 views. We therefore asked authors and editor for their thoughts about the high volume of public interest surrounding this paper.


The authors told us:

“We were very surprised by the level of public interest in our work,” said Nicholas Generous, lead author of the article. “While we thought the topic was interesting enough that a few outlets would pick it up, we didn’t expect anything like what actually happened. Having the opportunity to directly interact with the public on a topic they were genuinely interested in was extremely rewarding.”

Sara Del Valle and her team Image Credit: Sara Del Valle

Sara Del Valle and her team
Image Credit: Sara Del Valle


Sara Del Valle: “We were overwhelmed by the media response to our paper. We are thrilled that the public can connect with what we are doing and hope to continue bringing new ideas that can transform public health. Engaging the public in scientific endeavors is what really makes our work exciting.”


The editor told us:

The editor, Dr Marcel Salathé from the Center for Infectious Disease Dynamics at Penn State University, says the paper is part of a new, rapidly growing field called Digital Epidemiology.

“With the unprecedented growth of global access to the internet, we are only at the beginning of what will be a major shift in epidemiology.

“I’m excited that PLOS Computational Biology takes a leading role in publishing research in this area. Open Access will play a key part to rapidly establish standards and best practices, as well as to foster a public debate around the ethical challenges facing the field. As such, I’m both thrilled and not very surprised at the same time to see that the paper has attracted so much media attention. It’s a perfect mix of exciting science, modern everyday technology, and public health.”

Category: Biology, Computational biology, Data, Disease, Infectious disease, Open access, PLOS Computational Biology | Tagged , , | 2 Comments

This week in PLOS Biology

In PLOS Biology this week you can read about wolves in Yellowstone National Park, regulation of hair growth, how proteins evolve new RNA-binding functions and the regulation of heat-shock response by histone demethylation.


Yellowstone Wolves and their Effects on Natural Systems

Image credit: Daniel Stahler/National Park Service (NPS) journal.pbio.1002025.g001

Image credit: Daniel Stahler/National Park Service (NPS) journal.pbio.1002025.g001

Wolves were re-introduced to Yellowstone National Park in 1995 and 1996 after a 70-year absence. Since then, wolves have had effects on Yellowstone that ripple across the entire structure of the food web that defines biodiversity in the Northern Rockies ecosystem. In a new essay, Andy Dobson discusses the different ecological interpretations of the effects wolves have had on the ecosystem. He argues that ecology in general needs more ecosystem-level studies of species interactions, which ultimately drive levels of biodiversity. A new generation of scientists who can grapple with the vast complexities of these questions is needed.


Hair Growth is Regulated by Macrophages



The cyclic life of hair follicles consists of recurring phases of growth, decay, and rest. Using a mouse model, Donatello Castellana, Ralk Paus & Mirna Perez-Moreno report that macrophages in the skin signal to skin stem cells via Wnt ligands in the resting phase of the follicle life cycle. This tale of niche cells modulating stem cell behaviour could be relevant for the development of technologies with potential applications in regeneration, aging, and cancer.


From tRNA Loading to mRNA Splicing Via Promiscuity

Image credit: doi:10.1371/journal.pbio.1002028.g003

Image credit: doi:10.1371/journal.pbio.1002028.g003

New research by Lilian Lamech, Anna Mallam & Alan Lambowitz addresses the broad question of how proteins evolve new RNA-binding functions. Specifically, the way in which a fungal mitochondrial tyrosyl-tRNA synthetase (mtTyrRS) has evolved to promote the splicing of group I introns. Using small-angle X-ray scattering (SAXS) and biochemical assays, the study supports the theory of pre-adaptive or constructive neutral evolution, and identify a previously unappreciated role for non-specific interactions in the evolution of RNA-binding proteins and other multi-subunit protein and ribonucleoprotein complexes.


Recruiting Histone Demethylase to Target Genes

The methylation state of the histone subunits of nucleosomes regulates gene transcription, but the delicate balance of counteracting methyl-transferases and demethylases is crucial for establishment and maintenance of appropriate methylation. This paper by Mo-bin Cheng, Yan Zhang, Ye Zhang, Yu-fei Shen & colleagues reports how specific phosphorylation of the histone demethylase KDM3A by the kinase MSK1 allows it to be  recruited to promoters by Stat1 in response to heat shock, permitting the coordinated expression of many genes in human cells.


Category: Biology, Cell biology, Cell signalling, Developmental biology, Ecology, Epigenetics, Evolution, Molecular biology, PLOS Biology, Regeneration, Research | 1 Comment

Deep Ancestry: A source of inspiration by Michael Harris

The second of our Deep Reads blog series follows the PLOS Genetics Deep Reads article, “Strands in the History of Molecular Genetics”, published yesterday. Deep Ancestry: A source of inspiration” was written by Michael Harris, a PhD student at the University of Cambridge. His current research is focused on the use of optogenetics in cell signalling. When not in the lab he can be found cooking, trekking and keeping up on his science books.

I’ve wanted to be a scientist since I was 8 years old. Being somewhat dyslexic, I used to struggle a lot with reading, but it was always the science books that engaged me: Are We Hardwired: the Role of Genes in Human Behavior (William R. Clark); Endless Forms Most Beautiful: The New Science of Evo Devo (Sean B. Carroll); Stiff: The Curious Lives of Human Cadavers (Mary Roach); the list goes on. I couldn’t get enough of them! There is, however, one book that stands out above the rest in my mind as driving me toward becoming a geneticist, Deep Ancestry: Inside the Genographic Project by Spencer Wells. I was 17 when I read it, and the experience influenced my decision to undertake a degree in Genetics with Japanese Language & Linguistics at the University of Manchester.

In this book, Wells describes how DNA can be used to track patterns of human migration. He explains how, through the use of parsimony, small changes in sequence between distinct groups of peoples can be compared to generate a kind of family tree, and model past migrations and human history.  This book also introduces basic population genetics and molecular biology concepts in an engaging and relevant context (even if some of the claims are now a little outdated).  I can attest to how much reading this book helped me during the first year of my undergraduate degree!


Xunantunich, Belize – taking in the view after completing the field course.
Image credit: Michael Harris

Despite outlining how small mutations in the genome can be used to elucidate when distinct human populations diverged from one another, Wells emphasises that the goal of the Genographic Project is not to highlight the differences between people, but to illustrate that we are all linked together by our ancestry. He des this by telling the stories of five key people that he met during the course of his research, and explaining how the sequencing of their DNA helped provide important evidence for a particular course of human migrations joining us all together.

Researchers from the Genographic team travelled the world collecting DNA samples from indigenous populations at far flung places across the globe. As a nerdy British teenager growing up in Japan and a devoted member of my school’s Biology Club, I could scarcely imagine more exciting research! Travelling the world, interacting with all sorts of amazing cultures, and ultimately helping solve one of mankind’s greatest philosophical musings: where do we come from? I was sold! I wanted so badly to be those researchers, out scouring the globe, piecing together the puzzle of our past. And to an extent I’ve lived this dream.

In 2010, I was selected to work on a field course in conservation genetics in Belize. Not quite human population genetics, but I wasn’t going to turn down this opportunity! And while I was up to my chest in a rainforest pond at two in the morning gathering data, I just had to think to myself with a smile, “Well, this is what you wanted…” To me this is the embodiment of science; it’s about discovery and adventure, and that constant desire for knowledge and understanding, something that I think Deep Ancestry captures beautifully. Wells enthusiastically recounts stories of accomplishments in the Genographic Project and conveys the true spirit of scientific research. This is something that I continue to strive for, whether I’m in the field studying 100-year-old mahogany trees or at the microscope watching fluorescent proteins being tracked through the cytoplasm of a cell. I can’t help but feel a constant sense of awe and wonder at the natural world in everything that I do.

Wells also gives a good account of the multidisciplinary nature of research. It is by collaborating with linguists, climatologists, historians, archeologists and many others that he and his team are able to build a more accurate picture of the patterns of human migration. This is something else that I’ve also tried to incorporate into my scientific career. Though I’ve not lost my passion for genetics, I have now begun a PhD at Cambridge University in Immunology & Infectious Disease; that is, after being a plant scientist, a developmental biologist, a parasitologist, and a pharmacologist. I love genetics and I also love science as a whole, with all of its overlap and interconnectedness.


The Eagle, Cambridge – getting more ‘inspiration’ at the pub made famous by Watson and Crick.
Image credit: Michael Harris

Deep Ancestry by Spencer Wells, though the most influential for me, is just one book among many that has helped shape me into the scientist that I am today. There is no doubt in my mind that reading about great scientists from the past (or present) can help inspire the current generation of researchers. As the Confucian saying goes: “No matter how busy you may think you are, you must find time for reading, or surrender yourself to self-chosen ignorance.”


Category: Blog, Books, Community, Ecology, Evolution, Genetics, Genomics, PLOS Genetics | Tagged , , , , , | Leave a comment

This week in PLOS Biology

In PLOS Biology this week you can read about life without microbes, host-parasite coevolution, the temporal precision of distinguishing odours and how viruses package their genomes.


Life in a World without Microbes

Credit: Hieronymus Bosch

Credit: Hieronymus Bosch

According to Louis Pasteur, “Life would not long remain possible in the absence of microbes.” Or would it? In a new Perspective, Jack Gilbert and Josh Neufeld explore the challenges of a microbe-free existence. In doing so they hope to promote discussion about the value of microbial services supporting life on this planet. They explore the human gut microbiome, the scenario of a world without Bacteria and Archaea, and conclude with the implications of a world without all microbes, including microbial eukaryotes and viruses.


Parasitism Drives the Evolution of Complexity

It is obvious to any observer that evolution often proceeds towards increasing complexity. But when and why is greater complexity favoured? One hypothesis is that antagonistic coevolution between hosts and parasites drives this process by promoting evolutionary ‘arms races.’ As it would be incredibly difficult to examine this kind of evolution using conventional experiments, instead Luis Zaman, Charles Ofria & colleagues used the digital evolution of self-replicating computer programs in a scenario where hosts and parasites compete for processing power; their results show that coevolution promotes complexity and evolvability. Note that PLOS Biology featured a paper using a related digital evolution approach back in May


Smellyvision – Mice Perceive Odours with a Resolution of 13 Milliseconds

Different odours evoke different spatial patterns of activity in the odour-processing regions of the brain. For example, the timing of neuronal activity in a brain region called the olfactory bulb, relative to when an animal sniffs, conveys important information about odours. In a study published this week in PLOS Biology, Michelle Rebello, Justus Verhagen and collaborators provide evidence that the mammalian olfactory system is capable of very high rates of transmission of transient information. Using an innovative optogenetics approach, they found that mice can precisely discriminate virtual “odour movies” associated with patterns of neuronal activity that differed by as little as 13 ms. Read more in the synopsis.


Viral DNA-Packing Machine in the Corner

Credit: 10.1371/journal.pbio.1002024

Credit: 10.1371/journal.pbio.1002024

Chuan Hong, Wah Chiu & colleagues have used cryo-electronmicroscopy and modelling to tease apart how PRD1, a dsDNA membrane-containing virus, packages its genome. They characterise a unique vertex of this icosahedral virus, identifying the structure and function of a complex of proteins that forms a DNA-packaging motor and a transmembrane conduit which together serve to fill the viral particle with its genome. Check out the following stunning movies:


Movie S1:

Movie S2:

Movie S3:


Category: Biology, Computational biology, Evolution, Microbiology, Molecular biology, Neuroscience, Policy, Research, Resources | Leave a comment

This week in PLOS Biology

In PLOS Biology this week, you can read about neural activity in bird song, the utility of mathematical models in evolutionary biology, how diet can shape the genome and the robustness of protein interaction networks.


Oiseaux Exotiques: How Birds Encode Birdsong

Credit: Sam Sober

Credit: Sam Sober

One of the fundamental problems in neuroscience is understanding the relationship between neural activity and the behaviour it produces. For motor systems, firing rates of neurons are traditionally quantified, whereas in sensory systems the temporal patterns in neuron spikes have emerged as critical. New work by Claire Tang, Samuel Sober, and colleagues in this issue of PLOS Biology indicates that, just as in sensory systems, the motor output that controls bird song is dictated not only by firing rate but also by the precise firing pattern and the information inherent in those patterns greatly exceeds the information available in simple spike counts. Read more in the accompanying synopsis.


Mathematical Models in Evolutionary BiologyWhat Are They For?

In a new Essay, Maria Servedio, Justin Yeh and co-authors discuss the utility of proof-of-concept modeling in evolutionary biology. They argue that the complexity of the processes and the long timescales involved in evolutionary biology means that mathematical approaches have long been required. However some people are still sceptical about the value of mathematical models in the field. They attempt to clarify, using examples, the unique utility of proof-of-concept models.


Codons May Depend on Diet

Credit: 10.1371/journal.pbio.1002015

Credit: 10.1371/journal.pbio.1002015

Ribosomes translate mRNA into protein using tRNAs, but the genetic code contains multiple synonyms – with the same amino acid specified by differing codon triplets. However all codons are not created equal – as some tRNAs read them with differing speed and accuracy. John Zaborske, Allan Drummond and colleagues have found that the way in which proteins are encoded has changed systematically across several closely related fruit fly species. Variation in the availability of a specific nutrient – queuine (from bacteria), influences tRNA anticodon modification from guanosine to queuosine in multiple drosophilid species (they test 12 species). The effects of this on translational accuracy have left their mark on the way that protein sequences are encoded in the flies’ genomes. Read more in the accompanying synopsis.


Signaling Networks Tolerate Domain Rearrangements

Credit: 10.1371/journal.pbio.1002012

Credit: 10.1371/journal.pbio.1002012

Cells use complex protein interaction networks to sense and process external signals. The proteins involved often comprise a string of several functional units called domains. Mutations that rearrange these domains therefore have the potential to create novels proteins that can process different signals – useful on an evolutionary timescale, but how well is this tolerated at the shorter timescale of the individual lifespan? Using a yeast model system, Paloma Sato, Sergio Peisajovich and colleagues found that signalling complexes are essentially more malleable than we previously thought. This is useful not only for evolution, but for manipulation of signaling pathways by synthetic biologists.


Category: Biology, Cell biology, Cell signalling, Evolution, Genomics, Microbiology, Molecular biology, Neuroscience, PLOS Biology | Leave a comment

Predicting diseases with Wikipedia, how the brain modifies memories, and hypersynchrony: the PLOS Comp Biol November Issue

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

Predicting Diseases with Wikipedia

Effective and timely disease surveillance is a critical component of prevention and mitigation strategies that can save lives. Nicholas Generous and colleagues have proposed a new approach for detecting and monitoring epidemics based on freely available Wikipedia article access logs. The authors’ proof-of-concept experiments suggest that Wikipedia is a broadly effective data source for predicting the present, as well as forecasting outbreaks up to 28 days in advance. The approach could help to overcome some of the key gaps in existing traditional and internet-based techniques.

How the Brain Modifies Memories

Rendering of Parkin's opening conformers resulting from molecular dynamics simulations. Image Credit: Thomas R. Caulfield

Rendering of Parkin’s opening conformers resulting from molecular dynamics simulations.
Image Credit: Thomas R. Caulfield

When do we modify old memories, and when do we create new ones? Samuel J. Gershman and colleagues suggest that the question can be answered statistically. When sensory data change gradually over time, the brain infers that the environment has slowly been evolving, and the current representation of the environment (an existing memory trace) is updated. In contrast, abrupt changes indicate transitions between different structures, leading to the formation of new memories. The authors use a new model of statistical inference to show that humans use temporal discontinuities in the structure of the environment to determine when to form new memory traces.

Hypersynchronous Neural Activity

In the study of neurological disorders, a number of approaches have been used to study the mechanisms of seizure activity. John R. Terry and colleagues have developed a new computational modelling framework to explain the interplay between local dynamics and global networks in the emergence of hypersynchronous neural activity. By applying this framework to collected data sets from people with idiopathic generalized epilepsy, the authors demonstrate that brain networks of people with epilepsy have a much greater tendency to hypersynchronize than do brain networks of people without epilepsy. This finding demonstrates a critical role for network structure in the tendency to have seizures.

Category: Community, Computational biology, Image, Infectious disease, Neuroscience, PLOS Computational Biology | Tagged , | Leave a comment

The Corrupting Power of Cancer

When we think of antioxidants, we think of good, protective things, like blueberries, red wine, and dark chocolate (God, I love antioxidants). But cancer, that nefarious creature, finds a way to corrupt even the most benign cellular functions, bending them to its will in its selfish pursuit of proliferation.

Image credit: kev-shine (Flickr)

Cancer researchers have found that certain types of cancer cells acquire what’s called multidrug resistance by producing lots of antioxidant enzymes and cellular pumps that export drugs out of the cell. This leads to cancers that are much harder to treat, as these cells can inactivate or expel drugs before they are able to perform their cancer-killing actions. How these cancers acquire multidrug resistance seemed to be linked to a type of cancer cell state known as a de-differentiation, but how de-differentiation leads to drug resistance was not understood until a recent publication in PLOS Biology from Catherine Del Vecchio, Piyush Gupta and co-authors at the Whitehead Institute.

So what is de-differentiation? To understand de-differentiation, one must first understand the process of differentiation. Stem cells have the capacity to become any specialized cell in the body, from a liver cell to a muscle cell to a skin cell. As a stem cell becomes a specialized cell, let’s say a skin cell, it loses the characteristics that make it a stem cell and gains the characteristics that make it a skin cell; this process is called differentiation. De-differentiation is the reverse of this process, where a skin cell loses its specialized characteristics and regains a more stem cell-like state. When de-differentiation occurs in cancer cells it results in the development of invasive and metastatic properties and is associated with poor prognosis.

Cancer promotes de-differentiation because less differentiated cells are better at proliferating than specialized cells, generally speaking. Additionally, as a tumor develops, the environment that the cancer cells experience becomes vastly different, forcing the cancer cells to adapt. Tumors are often nutrient-poor and lack adequate access to the blood stream, resulting in hypoxia and a buildup of cellular waste products. This toxic environment leads the cancer cells to turn on their antioxidant pathways to protect their ability to grow. And it turns out that it is this induction of the antioxidant pathways before chemotherapy that confers drug resistance on these de-differentiated cancer cells.

For the cell signaling nerds in the audience, the authors found that the master regulator of the oxidative stress response, the Nrf2 transcription factor, was activated in de-differentiated cancer cells by phosphorylation by the endoplasmic reticulum membrane kinase PERK in the absence of drug treatment and oxidative stress. Having Nrf2 constantly activated by PERK protected de-differentiated cells from chemotherapy by reducing reactive oxygen species and increasing drug efflux.

Now, back to the main point. While normal cells only activate their antioxidant pathways in response to oxidative stress (makes sense, huh?), cancer cells inhabit a stressful environment and thus already have their antioxidants on full bore. This makes the cancer cells able to withstand the additional stress caused by chemotherapy. Fortunately, now that we have a better grasp on the mechanism of drug resistance, therapies can be designed to target it. In fact, Del Vecchio and colleagues show that treatment with an inhibitor of the signaling pathway that turns on these antioxidants (i.e. a PERK inhibitor) re-sensitized cancer cells to chemotherapies. So we can reclaim antioxidants from the corrupting influence of cancer and return them to where they belong: our wine glass.


Category: Biology, Blog, Cancer, Cell biology, Cell signalling, PLOS Biology, Research, Stem cells | Tagged , , , , , | 1 Comment