Software collection: Open Access meets Open Source in PLOS Computational Biology

By PLOS Computational Biology
Posted: November 30, 2012
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PLOS Computational Biology is proud to present its collection of Software articles. The Software section was launched in 2011, with the express purpose of fostering the creation of open source software that can be adapted and reused by the communities of computational biology and bioinformatics. With the launch of the collection, the previously published articles are grouped together for the first time, which will allow for their easy access by both scientists and the general public alike. The collection includes seven existing Software articles as well as an editorial by PLOS Computational Biology Software Editors Andreas Prlić and Hilmar Lapp, published yesterday. New Software articles will be added to the collection as they are published.

Image credit: PLOS

The topics of these Software articles are as varied as the topics covered by PLOS Computational Biology: from an algorithm that can produce chemical reactions in silico for use in pharmaceutical development, to software that tracks the movement of rodent whiskers. This diversity is as essential to the Software collection as its dedication to Open Access content.

What makes Software possibly more distinctive than other collections is its focus on utility, as well as content. The articles not only present novel biological insight, but also promote open reuse, redistribution, and modification of the scientific software – software which, according to the criteria for publication, must use a license approved by the Open Source Initiative (OSI). The combination of Open Access and Open Source can only help push the development of computational biology’s many diverse fields.

Another goal of the Software collection is to bring recognition to the developers of software. As Andreas Prlić and Hilmar Lapp state in the collection’s Editorial, “software and those who develop it are generally underrated by the academic system. This is our effort to bring more recognition to them”. It is therefore our hope that the launch of the collection will further encourage the submission of more quality work, the publication of which will reward these relatively unsung contributors to the world of computational biology.

You can visit the collection at www.ploscollections.org/software.

By Chris Hall

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Fractaltastic Evolution

By Catriona MacCallum
Posted: November 9, 2012
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One of the iconic metaphors of evolution is that of the ‘tree of life’ – it is the image we all have for how species relate to each other in evolutionary time. In a perspective article last year, David Penny (one of our editorial board) points out that this is originally a biblical phrase and not, as is sometimes assumed, one that was coined by Darwin. He also argues that Darwin’s use of this phrase has often been misinterpreted. Darwin used the phrase only once and then to denote competition between species (and groups of species) rather than relationships per se. To illustrate his point, he quoted the only explicit mention of it from a typically beautiful passage in the Origin of Species:

“buds give rise by growth to fresh buds, and these, if vigorous, branch out and overtop on all sides many a feebler branch, so by generation I believe it has been with the great Tree of Life, which fills with its dead and broken branches the crust of the earth, and covers the surface with its ever branching and beautiful ramifications”

Although Penny concludes that Darwin rejected the phrase ‘tree of life’ in favour of a more mechanistic and less simplistic view of evolution, the image of a tree as a representation of the basic evolutionary relationships between species (i.e. a phylogenetic tree) remains pervasive, compelling and incredibly useful. But, as the sheer number of known different species grows, it has become more and more difficult to visualise what these ‘megatrees’ really look like. Instead we are presented with small snapshot views of bits of the tree – basically what can fit on a flat 2 dimensional page. We were therefore delighted last month to publish a community page article by James Rosindell, from Imperial College London and Luke Harmon from the University of Idaho describing a new concept and software platform – OneZoom – that escapes the ‘paper paradigm’ and radically changes the way we can view and explore the whole tree. It uses fractal geometry, which essentially means you have an infinite amount of space to explore, and was inspired by the technology behind online maps, which allows you to zoom to a particular house on a specific street and then zoom out again to view the whole street, the town, the entire continent or even the whole world. To understand how it works, the authors have provided a tutorial on their site and on You Tube:

It has been three weeks since its publication and the article has been downloaded more than 14,000 times and, within only five days of the launch, the website hosting the platform was viewed more than 100,000 times. And the numbers here are a genuine reflection of the excitement that people from all sections of society had for the initiative (see the storify of the some of the tweets below).

OneZoom is just at the start of its life and features only the branch of the tree containing  mammals (more than 5000 species) but gradually the authors will add other branches as data becomes available from other research projects such as the Open Tree of Life Project. Already the authors have added the conservation status of each species (information from the IUCN Red List) and you can connect straight to Wikipedia to find out more about your species. They even aim to make an app for OneZoom.

It is, as the authors acknowledge, not perfect but that’s not the point. Like the tree, it will evolve – and because all the software is open source, others will also be able to use and adapt it for their own purposes. Most important, however, it opens up a wholly new way to view and explore evolutionary history and is not only useful for research scientists but also educators, museums and any interested member of the public. It is humbling, for example, to see how Homo sapiens fits in – just one small and relatively recent leaf. As Joel Cracraft noted in a quote for the press release of the article:

“This will revolutionize how we teach and understand the Tree of Life.  It is an invaluable tool for communicating the grand scope of life’s history to children as well as adults.”

And because we all thought it was just so cool, we used the article to launch a new series in the Community Page section of PLOS Biology called ‘Cool Tools’. We hope that this section will enable others to tell the story behind the creation of radically new ways to use and visualise research.

Finally, how the authors coordinated the launch of the site, with the publication of the article, a You Tube video and a dedicated twitter feed also provides a powerful example of how scientists can effectively communicate their research.


 

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Marking the passing of time

By Jane Alfred and Ruchir Shah
Posted: October 30, 2012
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Traffic light countdown. Image source Sir James

We are constantly tracking the passage of time, from waiting for our kettle to boil to monitoring traffic lights. The ways in which we perceive time usually depend on the timescale involved, ranging from minutes to hours to days. Interestingly, it seems that we and other animals can estimate the duration of very small intervals of time with remarkable accuracy. But how does the brain do this? This is the question explored in a recent PLOS Biology article by Blaine Schneider and Geoffrey Ghose, which is also discussed in an accompanying Primer by Eric Cook and Christopher Pack.

Neuroscientists and psychologists have long been interested in studying the perception of time, because accurate timing serves as the basis for many behaviors, from foraging strategies in birds to performing music. From an evolutionary standpoint, one can imagine that as a prey, it’s important to gauge how long you have before your predator becomes hungry again. And in a more “real-world” example, you could also imagine why it’s important to have an accurate internal sense of time when trying to cross a busy street. You have to use visual information to estimate motion trajectories, but you also have to use past experiences (like how fast you can run!) to estimate your future position.

As Cook and Pack discuss, however, the picture becomes altogether more complicated when our brains attempt to estimate time over much smaller time scales. This process involves multiple brain areas – including the parietal cortex and cerebellum, to name but two –  all of which display neural activity correlated with time perception.

Many recent studies of non-human primates have found neuronal activity that correlates with time perception in a region of the parietal cortex called LIP. Traditionally, LIP activity has been linked to the generation of eye movements called saccades. These studies found that LIP activity increases when an animal is waiting to saccade and further increases just before the actual saccade.

A previous study of time perception by Matthew Leon and Michael Shadlen used a task in which monkeys had to make a saccade based on their own measurement of time. These researchers confirmed that LIP activity correlated with the saccade, as previous work had shown, but they were also able to show that LIP activity increased steadily in trials of a longer duration. Combined with other results, Leon and Shadlen concluded that LIP activity is related to internal time perception, and that increases in LIP activity may be the neural substrate for how the brain measures time.

But is this the whole story? As explained in the Primer by Cook and Pack, there are some interesting caveats here that Schneider and Ghose explored in their PLOS Biology paper. One important aspect of the task designed by Leon and Shadlen was that saccades were always associated with a reward. So what Schneider and Ghose did in this study was to eliminate external cues from their task design, including the correlation between saccades and rewards. They did this by training monkeys to move their eyes consistently at regular time intervals without any external cueing or expectation of an immediate reward.

Surprisingly, when they used this task, they found the opposite result to Leon and Shadlen. LIP activity actually decreased at a steady rate when monkeys prepared to make saccades. Clearly, some aspect of their new task design changes how LIP activity responds during saccade timing. The predictability and anticipation of the reward is one of the key differences, and an interesting hypothesis to explore in future studies.

So why do our brains perceive the passing of small time intervals, at the level of seconds or even subseconds? One possible reason is that it helps us to integrate information over these small time scales, allowing us to evaluate how sensory inputs change multiple times a second and to keep track of our own movements. Whether LIP activity is causally related to this process, and how other neural circuits are involved, are still open questions. But given the philosophical implications for how we measure time, and how this relates to our perception of “free will”, there’s no doubt we have some exciting results to look forward to from this field.

 

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Open access: Delivering on its potential

By Jane Alfred and Bryan Ghosh
Posted: October 24, 2012
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This week, October 22-28, marks Open Access Week, a global event that brings various parties together to discuss, publicize and advocate for open access. On October 23, leading open access journal PLOS Biology publishes an editorial that aims to direct this year’s discussion towards the need to focus on the re-usability of, and not just access to, the research literature.

With the incredible rise in the number of open access research papers available online, it is now time to focus on ensuring that we can make the most out of that access, argues Cameron Neylon, Advocacy Director at PLOS and author of the editorial.

“If we are to exploit the potential that open access provides,” writes Neylon, “we must look beyond just making research findings accessible to ensuring that they are legally and technically available for re-use.” Many journals that currently claim to publish ‘open access’ research actually withhold rights such as re-use, particularly commercial re-use, under the terms of their license. This, says Neylon, is at odds with the idea of open access, and must be addressed if we are to make full use of open research. “Mere access is not enough to deliver on the promise of a truly network-enabled research communication system,” he says.

The scientific community is at a point where more research is accessible than ever before, and this is only going to continue growing as funders, policy-makers and institutions across the world are enacting their own open access initiatives. Being able to build upon this research, to gather data, and to refine results is key to scientific progress, and is the only way to ensure that science can advance at the speed of which it is now capable thanks to the growth of the Internet, the editorial explains.

There have already been many examples of how research can progress when resources and information are fully shareable and useable thanks to worldwide networks, and there can be countless more if a system is built that enables scientists to fully and easily build on each other’s work, argues Neylon. As he explains, “Making things accessible is a necessary step to make this happen, but it is not sufficient.”

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Muscular dystrophy and vitamins

By Roli Roberts
Posted: October 23, 2012
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NAD (nicotinamide adenine dinucleotide); the cell makes the bit at the top out of vitamin B3 (Credit: Benjah-bmm27, Wikimedia Commons).

 

Therapy for muscular dystrophy?

A new study in PLOS Biology raises the possibility that vitamin B3 might be worth assessing as a therapy for muscular dystrophies. This is tantalising, because this group of human genetic diseases includes some severely disabling and ultimately lethal forms, including Duchenne muscular dystrophy (DMD), which affects one boy in every 3000 born. However, the study rang a faint bell in a dusty 20-year-old room…

Back in the early ’90s as part of my PhD thesis on DMD, I wrote a section for the introductory chapter in which I catalogued all the attempted therapeutic interventions that I could dig out of the literature. There were a large number, many based on rather questionable rationale, and most with no demonstrable effect, but then desperate diseases warrant desperate measures. Among them I recall several studies that involved dietary vitamins – E and Q10.

Nowadays most therapeutic efforts for DMD seem to be aimed at rectifying the underlying genetic defect in muscular dystrophy, whether at the DNA level (gene therapy), RNA level (antisense oligonucleotide-induced exon-skipping) or protein level (translational read-through); mercifully, several of these approaches are at last a source of some genuine optimism.

But a new study just published online in PLOS Biology by Michelle Goody, Clarissa Henry and colleagues (and discussed in an accompanying Synopsis by Richard Robinson) hints at a potential parallel route towards improving the symptoms of muscular dystrophies, rather than tackling the root genetic cause. And it involves another vitamin…

 

How muscular dystrophies work

To appreciate this, you need to know a little about how muscular dystrophies are thought to work. The most generally accepted idea is that this group of diseases, which arise from a variety of genetic mutations, share a common disastrous effect on the robustness of muscle cells.

Cells, and the gossamer two-molecule-thick membranes that enclose them, are shockingly fragile things, but next time you’re pumping iron (no, I don’t either, but bear with me) just think of the forces that muscle fibres are subjected to. How do they cope with this? The short answer is that they’re each enclosed within a tough tube of extracellular matrix, and that minuscule but crucial protein clusters anchor the cell membrane to the tube. It’s these protein anchors that go wrong in muscular dystrophies, with devastating consequences for the patients.

 

The new study in PLOS Biology

I won’t go into the science much here (see the Synopsis if you want more detail), but building on a previous paper of theirs, the authors checked out their hunch that boosting levels of a common cellular chemical, NAD+ (see picture at top), could help organise and strengthen the extracellular matrix in zebrafish that have a severe (congenital) form of muscular dystrophy. This might enable any remaining protein anchors (there are several different types, some affected, some spared, by the mutation) to rescue the fish from the disease.

Normal (blue) and dystrophic (red) cells transplanted into zebrafish muscle (green) Credit: Clarissa Henry.

To cut to the chase, the results are quite spectacular, with NAD+ significantly improving not only the state of the animals’ muscles, but also enhancing their swimming performance. The authors also start to tease apart the mechanism by which NAD+ might be having these effects. As an extra twist, because cells make NAD+ out of vitamin B3 (niacin), the authors took the bizarre step of adding a proprietary B3-rich vitamin supplement (Emergen-C) to the fishes’ environment. Incredibly, this also seemed to work.

 

But…?

Science, and especially translational science, tends to progress in a series of steps; some in the right direction, and others not so fruitful, so I’ll end this piece with a list of caveats. In terms of a rationale on which to base further investigations, the results of this study look much more promising than the historical trials with vitamins E and Q10. But here are three reasons not to reach for the B3 supplements just yet:

  • Humans and zebrafish last shared a common ancestor 500 million years ago; what happens in one animal may not happen in the other.
  • The study addresses young developing fish, and presumably the authors will go on to see whether these findings can be replicated in older animals. Most human muscular dystrophy patients are not diagnosed until after birth, and (depending on the type of muscular dystrophy) often much later in life. We can’t assume that this treatment would work if it were to be initiated long after the extracellular matrix has been made.
  • The study looks at the very severest types of muscular dystrophy – the congenital ones. It may be that the commonest form of muscular dystrophy, Duchenne, which is less severe (but still deadly), is not significantly improved by this treatment.

So my pressing question for the future is: “This works (spectacularly well) for fish embryos with congenital muscular dystrophy; will it work for a five year-old boy who’s just been diagnosed with Duchenne muscular dystrophy?” Only time and future research into these promising findings will tell.


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Why I love the H-index

By abateman
Posted: October 19, 2012
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The H-index – a small number with a big impact.  First introduced by Jorge E. Hirsh in 2005, it is a relatively simple way to calculate and measure the impact of a scientist (Hirsch, 2005). It divides opinion.  You either love it or hate it. I happen to think the H-index is a superb tool to help assess scientific impact.  Of course, people are always favourable towards metrics that make them look good.  So let’s get this out into the open now, my H-index is 44 (I have 44 papers with at least 44 citations) and, yes, I’m proud of it! But my love of the H-index stems from a much deeper obsession with citations.

As an impressionable young graduate student, I saw my PhD supervisor regularly check his citations.  Citations to papers means that someone used your work or thought it was relevant to mention in the context of their own work.  If a paper was never cited, and perhaps therefore also little read, was it worth doing the research in the first place? I still remember the excitement of the first citation I ever received and I still enjoy seeing new citations roll in.

The H index: what does it mean, how is it calculated and used?

The H-index measures the maximum number of papers N you have, all of which have at least N citations. So if you have 3 papers with at least 3 citations, but you don’t have 4 papers with at least 4 citations then your H-index is 3. Obviously, the H-index can only increase if you keep publishing papers and they are cited.  But the higher your H-index gets, the harder it is to increase it.

One of the ways in which I use the H-index is when making tenure recommendations. By placing the candidate within the context of the H-indices of their departmental peers, I can judge the scientific output of the candidate within the context of the host institution. This is a useful because it can be difficult to understand what is required at different host institutions from around the world.  It would be negligent to only look at H-index and so I use a range of other metrics as well,  together with good old fashioned scientific judgement of their contributions from reading their application and papers.

The m value

One of those extra metrics I use was also introduced by Hirsch, and is called m (Hirsch, 2005). M measures the slope or rate of increase of the H-index over time and is, in my view, a greatly underappreciated measure.   To calculate the m-value, take the researchers H-index and divide by the number of years since their first publication. This measure helps to normalise between those at the early or twilight stages of their career. As Hirsch did for physicists in the field of computational biology, I broadly categorise people according to their m value in the table below.  The boundaries correspond exactly to those used by Hirsch.

m-value – H-index/yr Potential for Scientific Impact
<1.0 Average
1.0-2.0 Above average
2.0-3.0 Excellent
>3.0 Stellar

So post-docs with an m-value of greater than three are future science superstars and highly likely to have a stratospheric rise. If you can find one, hire them immediately!

The H-trajectory

The graph below shows the growth of the H-index for three scientists  - A, B and C – who respectively have an H-index of 12, 15 and 16.  I call these curves a researcher’s H-trajectory.

If we calculate their m-value, then we find that A has a value of 0.5, B has 0.94 and C a value of 1.67. So while each of these researchers has a similar H-index, their likelihood for future growth can be predicted based on past performance. Recently, Daniel Acuna and colleagues presented a sophisticated prediction of future H-index using a number of several features, such as number of publications and the number in top journals (Acuna et al. 2012).

As any serious citation gazer knows, the H-index has numerous potential problems. For example, researcher A who spent time in industry has fewer publications, people with names in non English alphabets or very common names can be difficult to correctly calculate, different fields have widely differing authorship, publication and citation patterns. But even considering all these problems, I believe the H-index is here to stay.  My experience is that ranking scientists by H-index and m-value correlates very well with my own personal judgements about the impact of scientists that I know and indeed with the positions that those scientists hold in Universities around the world.

Alex Bateman is currently a computational biologist at the Wellcome Trust Sanger Institute where he has led the Pfam database project. On Novembert 1st, he takes up a new role as  Head of Protein Sequence Resources at the EMBL-European Bioinformatics Institute (EMBL-EBI).

References

J.E. Hirsch. An index to quantify an individual’s scientific research output. Proc. Natl. Acad. Sci. 102, 16569-16572.

D.E. Acuna, S. Allesina & P. Konrad. Predicting scientific success. Nature 489, 201-202.

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Future Directions at PLOS Computational Biology

By Rosemary Dickin
Posted: October 5, 2012
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This week PLOS Computational Biology publishes a pair of Editorials by Philip E. Bourne and Ruth Nussinov, who outline some important leadership shifts and point to exciting new developments in a journal that has both influenced and been influenced by the emergent field of computational biology. These developments will reflect an even richer collection of research articles and even more innovation in scholarly communication.

After seven years as the sole Editor-in-Chief, carrying much of the unseen day-to-day editorial work of running a community journal, Phil Bourne is transitioning to the new role of Founding Editor-in-Chief.

Image: .v1ctor. on flickr

Phil will continue to provide guidance and direction to PLOS Computational Biology’s senior leadership, as well as managing innovative projects such as Topic Pages, a move towards data publishing, and our popular Ten Simple Rules series.

We’re delighted to welcome Ruth Nussinov to her new role as Editor-in-Chief. Ruth has been a crucial and enthusiastic member of the senior editorial board since 2008 and, as Deputy Editor-in-Chief since 2010 has worked in partnership with Phil to create the journal we see today. In the past few months the ranks of our senior editorial board have been boosted by the promotion of Arne Elofsson, William Stafford Noble, Jason Papin and Rob de Boer to Deputy Editors.

In response to discussions among the editorial board and the community, PLOS Computational Biology is taking this opportunity to expand the journal’s scope by including papers describing outstanding methods of exceptional importance that have been shown to, or have the promise to provide new biological insights. We also plan to enhance the journal’s Reviews section, with the aim of publishing thought-provoking, unmissable Reviews in key topics in computational biology.

As a community journal, PLOS Computational Biology is your journal, and we want to know what you think. Please send your thoughts to ploscompbiol[at]plos.org or add them as comments to this blog post. We’re always happy to hear from you.


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Tracking Coverage of the Radar Tracked Bees

By Rachel Jarmy
Posted: September 26, 2012
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In a recently published PLOS Biology Research Article, by Prof Lars Chittka and colleagues, (and an accompanying Synopsis), the authors revealed how bumblebees quickly find the shortest route to feed from numerous flowers. In this PLOS Biologue post, we take a look at some of the media interest in this article.

Image: Dr Stephan Wolf

The Telegraph

Environment Correspondent Louise Gray summarises the study, and how it could help farmers identify the best ways to grow crops to ensure faster pollination.  “The results showed that the bees would try a number of different routes to a flower and between plants in order to work out the quickest way to and from a food source. Within hours or even minutes, the apparently random ‘flight of the bumblebee’ is an efficient and learned route.”

The Huffington Post

The online newspaper goes into further detail of the methods used by Prof Chittka and his team, including arrangements of the flowers in the wild, and the average  amount of time the bees took to learn the fastest route.  “Scientists tracking the flight of the bumblebee have been astonished by the power of the insects’ tiny brains. Let loose to find their way among five artificial flowers in a one kilometre-wide field, the bees quickly learned which routes were the most efficient.”

BBC Radio Four’s Material World

In this episode of the weekly radio programme, Quentin Cooper interviews the lead author about the study and the high tech methods used by the team;  “We glued little radar antennae on the backs of bees when they left the hive” explains Prof Chittka. “They don’t necessarily like being manhandled and having an antenna on their back, but we’re stronger.”

Image: Dr Stephan Wolf

Scientific American

Associate Editor Katherine Harmon explains the differences between the cognitive behaviour of these bees compared to larger brained animals. “Although this navigation seems to be a no-brainer for the bees, we humans needed mathematical algorithms to analyze and understand the elegance of their behavior.”

Wired

Virginia Morrell from ScienceNow looks at the study from a mathematical perspective, by homing in on the well known ‘traveling salesman’ problem.  “Bumblebees foraging in flowers for nectar are like salesmen traveling between towns: Both seek the optimal route to minimize their travel costs. Mathematicians call this the ‘traveling salesman problem,’ in which scientists try to calculate the shortest possible route given a theoretical arrangement of cities.”

And here is a snippet of the reaction from Twitter users following the recent PLOS Biology publication from the Chittka Lab, showing how bumblebees quickly find the shortest route to feed from a selection of flowers.


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Bumblebee orienteering

By Roli Roberts
Posted: September 20, 2012
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Bumblebees (also quaintly known as dumbledores, long before the wizard was a twinkle in JK Rowling’s eye) have an image problem. Their fat and furry bodies, their ridiculous name(s), our preoccupation with their theoretical inability to fly – it just isn’t very rock’n’roll. Indeed, it’s all a bit Rimsky-Korsakov.

The humble bumblebee (Tony Wills, Wikimedia Commons)

But a research article just published in PLOS Biology (also discussed in an accompanying Synopsis) highlights a very different side of this animal. In contrast to the apparently shambling figure that seems to tumble chaotically from flower to flower, the bumblebee emerges from this study as a shrewd navigator walking an energetic tightrope. Critically dependent on the balance between the energy that it expends on foraging and the energy that it can acquire from these ventures, the bumblebee must be ever-conscious of economising.

Although a fair bit was already known about bee navigation, in the latest paper Lars Chittka and his co-workers go one step closer to how the animal performs route-optimising calculations in the wild. Chittka works at Queen Mary, University of London, and uses a combination of field studies, experimentation and computer simulation to tease apart the mechanisms that underlie insect behaviour.

A bumblebee visits one of the artificial flowers used in this study; a webcam keeps watch from above (Lihoreau et al., PLOS Biology 2012).

He and his colleagues glued tiny radar transponders to the backs of seven bumblebees and released them into an open field in bleak mid-autumn when natural food sources are rare. Here they placed five artificial syrup-filled “flowers”, each monitored by a motion-sensitive webcam (as you can see from the picture, realism wasn’t top of the agenda; instead the bees were pre-trained to recognise them as food sources).  The flowers were placed far enough apart that the bees couldn’t see one from another, forcing the naïve insects to figure out where the flowers are and to optimise their route between them.

Using the combination of radar tracking and video footage the authors were able to monitor the bumblebees’ learning curve over many forays, allowing them to guess at the bees’ optimisation strategy. And just when the bees thought they knew how the land lay, the authors messed with their little brains by removing some flowers and adding new, more distant ones to see how the bees adjusted and re-optimised their route.

From their data, the authors are able to deduce that the bees use a simple trial-and-error strategy, calculating, memorising and comparing the lengths of routes attempted, and choosing the shorter of the two each time. The authors could model this process and its reiteration, finding a good fit with the real bees’ performance. Just how bees are able to calculate distances traveled, incidentally, is the subject of an earlier PLOS Biology paper (and an accompanying Primer by Lars Chittka).

The new study extends the authors’ previous findings from artificial enclosed environments to the more realistic open field, but the greater distances seem to sharpen the bees’ need to optimise. The authors note that the strategy taken by individual bees, which depends on local vectors rather than a map-like representation of the environment, is reminiscent of the collective navigation tactics of ants, and wonder whether other foraging animals such as hummingbirds, bats and primates might take a similar tack.

 

 

 

 

 

 

 

 

 

 

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PLOS Biology roundup

By Jane Alfred
Posted: August 24, 2012
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In our latest PLOS Biology Roundup, we offer you a taste of the range of topics covered in our recently published articles, from how to prune the brain’s vasculature and drug discovery in yeast, to new insights into the internal workings of the body’s circadian clock.

Blood flow gets the brain’s vasculature into shape

The not inconsiderable activities of the vertebrate brain are supported by its vasculature – an elaborate network of blood vessels – that provide it with the oxygen and nutrients it needs. Because the architecture of this network is important for meeting the brain’s energy demands, and because disruptions to it can cause serious neurological problems, there is considerable interest in understanding how this vascular network develops.

During the early stages of brain vasculature formation, new brain blood vessels sprout off an existing vascular structure and then invade the brain. In a recent paper in PLOS Biology, Qi Chen and colleagues sought to understand how these early sprouts evolve into the elaborate blood vessel architecture that meets the brain’s energy needs. They investigated this process using the embryos of zebrafish, which are naturally transparent and develop outside of the mother’s body. Using transgenic zebrafish in which vascular endothelial cells are marked with fluorescent labels, they monitored changes in brain vasculature in the midbrain of live animals during the first few days of development. They observed that new blood vessel sprouts appear on day one post-fertilization, which transform into an intricate network of vessels by day two. As they carried on monitoring, they noticed over time that while vessel growth continued the degree of complexity and interconnectedness between vessels in the network decreased.

Why might this be? The authors hypothesized that the blood vessels that are pruned away may be redundant and that their pruning increases the efficiency of blood flow within the brain. Does blood flow itself contribute to this pruning process? Yes, say the authors: they show that the local blocking of blood flow triggers vessel pruning. They also show the mechanism by which pruning occurs – preferentially at loop-shaped vessel segments via the migration of endothelial cells to adjacent unpruned segments.

Together these findings show how hemodynamics contribute to a simpler, more efficient vasculature in better shape to meet the energy demands of the brain.

Interested in finding out more about this study? Take a look at the paper itself and the accompanying synopsis by Caitlin Sedwick.

 

An evolutionary approach to drug discovery

One of the great insights to come from the Human Genome Project was the realization that evolution loves to conserve resources. Complexity in humans comes not from adding more and more genes, but from finding new ways to express them. Ancient gene modules used in new combinations pave the way for new traits. That’s why such distant relatives as yeast and humans share so many genes. And that’s why some researchers are taking an evolutionary approach to drug discovery.

The hope is that by identifying human disease genes (and their protein products) with counterparts in workhorse model organisms like yeast and mice, they can use the lab models to screen and test drug candidates for human disease. A new study published in PLOS Biology takes this approach to show that even though a given pathway serves different functions in yeast and humans, it might still prove a useful therapeutic target.

The pathway in the study helps maintain cell wall structure in plants and blood vessel formation (angiogenesis) in humans. The study shows that the fungicide thiabendazole, long used to control crop diseases, can also inhibit angiogenesis, an important factor in tumor growth and metastasis. This suggests that thiabendazole, already approved as safe for human use by the US Food and Drug Administration, might have therapeutic potential in treating cancer, a possibility to consider in future research.

In a comment on the paper, @eperlste points out that a pharmacological approach would have included other targets: “…there is already strong genetic and biochemical evidence demonstrating that benzimidazole family members can target at least tubulin, and, in the case of thiabendazole, potentially other targets given the high drug concentration required (250µM) to see anti-angiogenic effects.”

We encourage you to join the discussion on the paper by clicking on this link

 

Degrading the tick tock of the body clock

Circadian clocks are the means by which organisms adjust their physiology and behaviour to the daily cycle of day and night. Some of the internal workings of these clocks rely on molecular feedback loops that generate daily peaks and troughs (oscillations) in gene activity.

In the Drosophilafruit fly, two proteins called PERIOD (PER) and TIMELESS (TIM) coordinate the fly’s circadian clock– they accumulate during the night, form a complex, and then repress their own gene expression early in the morning. The temporal control of this

By Nargilé, via Wikimedia Commons

oscillation involves the degradation of the PER and TIM proteins by various means, including their being marked for destruction by phosphorylation and ubiquitination. One protein called SLMB is known to play a key role in controlling the degradation of phosphorylated PER and TIM. Now, Brigitte Grima and colleagues report  - in a study recently published in PLOS Biology - that another  protein called  CUL-3 is also involved in the workings of this clock. These authors found that when they inhibited the activity of CUL-3, the oscillations of PER and TIM flattened out and the normal rest and activity rhythms of flies were abolished.  This lead to their discovering that CUL-3  forms a complex with a lightly phosphorylated form of TIM when PER is not present; this complex allows this version of TIM to accumulate during the night. But when PER is present, SLMB preferentially interacts with this phosphorylated TIM, favoring its degradation.

From these findings the authors propose that CUL-3 and SLMB share the task of keeping the internal workings of this clock – the control of the oscillations of PER and TIM  - in time with the day/night cycle.

If you’re interested in the workings of the circadian clock, you might also want to check out these other recently published PLOS Biology articles on this subject:

A Blind Circadian Clock in Cavefish Reveals that Opsins Mediate Peripheral Clock Photoreception

Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver

Circadian-Related Heteromerization of Adrenergic and Dopamine D4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland

 

 

 

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