Sunday, November 30, 2014

Preventing Infection by Shutting Down Host Cell Receptors?

While most anti-virals tend to target the virus itself, as in the case of influenza virus where there is rapid mutation, viruses are capable of finding ways to render the drug ineffective. If attacking the virus directly doesn't work, what could be another way of halting viral infection?

If we remember from class, viruses have tropogens which interact with host cell receptors to allow it to enter and infect the host cell. Since tropogens are easily mutated, drugs which target the other face of the coin, the host cell receptor, can be an effective way of preventing infection by viruses.

Researchers at the University of Wisconsin-Madison have taken just this approach when it comes to studying influenza infections. Rather than attack the virus, these researchers are testing the effect of silencing host cell genes - not just ones that code for proteins on the surface of the cell, but also proteins that can help the virus replicate inside the cell. By doing a wide screen of different genes that could possibly play a role in infection, the researchers were able to silence specific host cell genes to determine which ones are 1) the most important in infection and 2) non-essential and non-toxic to the host cell when silenced. After determining which genes are important, the scientists were then able to determine the role of the host cell protein during infection.

By studying these aspects of the interaction between host cell and virus, the researchers are able to look into drug prospects by choosing drugs which inhibit viral targets and look into the development of newer drugs that can inhibit other targets on the host cell.

Hopefully this is good news for the improvement of anti-viral drugs and anti-viral treatments!

-Anna

http://medicalxpress.com/news/2014-11-halting-hijacker-cellular-thwart-influenza.html

Bats vs Humans - Genome Data Crunching for Hendra Viral Infection

Since the advent of genome mapping, the use of computers for data crunching and analysis has been extremely important in many different aspects of biology. Better understanding of viruses is just one way computers can help us process data quickly and efficiently.

Recently, the bat's genome has been sequenced. One reason why this is interesting and relevant to our studies of viruses is that bats are often the reservoirs for diseases that can infect humans. How are bats able to remain unaffected by these viruses that they carry and transmit? Using a supercomputer, researchers at Bristol University were able to map around 6000 important bat genes and determine how these genes are regulated in the presence of Hendra viral infections.

While bats can carry and transmit Hendra virus, they are not themselves affected by this infection. In humans, while infection is rare, the virus has a high mortality rate. By comparing how human cells and bat cells respond to the virus side by side, the researchers were able to pinpoint differences in response to infection by the cells. While the bat cells have a quick response time, human cells are not as efficient at fighting off the infection, which could be the reason that the virus is so much more problematic in humans.

Hopefully, in comparing differences in the genomes of bats and humans, the researchers will be able to pinpoint exactly what genes and proteins provide this ability to respond to the virus in a quick, efficient matter. Perhaps this research can then further be applied to other diseases which bats harbor and transmit to humans, but are not affected by themselves.

-Anna

http://horsetalk.co.nz/2014/11/25/supercomputer-data-dangerous-hendra-virus/#axzz3Kceb8WN9

Norovirus: A Friendly Virus?

Many Stanford students can remember the norovirus outbreak that struck our campus last year.  First it was FloMo hall, then it was Theta house, and then the freshman dorms were hit.  Before we knew it single handicapped bathrooms were devoted to students suffering from the telltale signs, diarrhea and vomiting, and individual meals were prepackaged at the dining halls.  Although most people see this non-enveloped single-stranded RNA virus, in the family Caliciviridae, as the bad guy, could there be a beneficial role for norovirus in our lives?
A small percent of the bacteria in our bodies is harmful. The remaining bacteria are largely beneficial, and a substantial portion of these bacteria resides in our gastrointestinal tract performing a multitude of functions keeping us healthy.  This population of bacteria is included in our microbiome.  Recent studies suggest that there is an equally important microvirome that performs similar functions in our bodies.  A recent experiment aimed to evaluate the effects that Murine Norovirus (MNV) infection had on germ-free and antibiotic treated mice. The results showed the MNV infection preserved normal GI morphology and immune system conditions without causing symptoms in the mice.  Germ-free mice were used to see whether or not MNV could mimic the functions of bacteria.  Persistent MNV infection in these germ-free mice showed the restoration of normal intestinal physiology as well as increased immune response measured by T cell count, lymphocyte differentiation, and interferon expression.  These observations were recorded across several populations of germ-free mice and provided sufficient evidence that MNV could mimic the effect of commensal bacteria in the gut.
The study also looked at MNV infections in mice being treated with antibiotics.  This was a population of concern because many people being treated with antibiotics often suffer from vomiting, diarrhea, and abdominal cramps due to the elimination of gut bacteria.  Mice were treated for 2 weeks with antibiotics and had the same abnormalities as germ free mice.  After the 10th day of infection in these antibiotic treated mice, the villus width increased, T cell count increased, Paneth cell granules increased (the main cell type in the epithelium of the small intestines), and interferon expression in T cells increased.  Basically infection with MNV could prevent the unwanted side effects of antibiotic use.

Although this study focuses on mice, it is easy to see how this research applies to humans.  While Stanford students automatically think of ground zero FloMo when they hear the word “norovirus”, maybe we should think about all the friendly bacteria in our stomachs and how norovirus could become a friendly virus. 


-Nalani Wakinekona 

References

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13960.html

Lifelong Flu Vaccine?

How many of us LOVE getting shots? Let's be honest, lifelong vaccines would be amazing, especially against viruses that we are vaccinated against on an annual basis, like influenza.

Hope may be on the horizon for those of us who dread our annual flu shots. Dr. Sophie Valkenburg is currently looking into methods of extending the effectiveness of the flu vaccine. Current flu vaccinations induce an antibody response to influenza surface proteins. The problem with this approach is that due to genetic shift, the virus mutates at an incredible rate each year. The mutations often change which proteins are present on the outer surface of the virus. This renders the antibodies that the body produces less and less effective as the virus continues to mutate.

So how do we get around this problem? Apparently, the internal proteins of the influenza virus are relatively conserved. The vaccine that Dr. Valkenburg is working on targets both antibody activation and T cell activation. This differs from a sole antibody response because while antibodies typically only recognize surface proteins, the T cells are able to target the internal proteins of the virus. Because these internal proteins don't change much over time, the T cell response should be more effective for a longer period of time.

An added benefit of this potential new vaccine is that not only does it target the influenza strains that cause the yearly outbreaks of flu we are familiar with, but it also can target the newer outbreak strains that cause diseases such as avian and swine flu. These outbreak strains are more deadly because we do not have the natural immunity against them that we often have against the seasonal flu strains.

An interesting point to think about that Dr. Siegel brought up earlier in the course when we were discussing vaccinations was the fact that most of the vaccines we are given that theoretically give us lifelong protection actually may not provide protection for as long as we think they do. Do you think lifelong vaccinations exist?

-Anna

http://www.scmp.com/lifestyle/health/article/1651744/hong-kongs-dr-sophie-valkenburg-part-team-working-lifelong-flu-shot

MuPIT, Ebola Edition: Johns Hopkins and UCSC Team Up to Fight Ebola on the Bioinformatics Front

Fig. 1: MuPPET, Ebola Edition

Last week, John Hopkins University's Karchin Lab released "MuPIT: Ebola Edition," and extension of their 3-Dimensional protein mutation visualizer MuPIT. The public availability of all information on the browser, coupled with the robustness of its software and versatility of interaction, means that we can expect this development to be a massive boon to the Ebola research community. Most Ebola treatments to date have been based on antibody development, and being able to anticipate changes in Ebola's protein structure due to mutation is key to maintaining an effective arsenal against Ebola. MuPIT allows scientists worldwide to do this – when applying this to Ebola, we open up the realm of drug development to many, many more scientists, and thus accelerate curative (and perhaps someday soon, prophylactic) treatment of this terrible disease.

What's more, MuPIT, Ebola Edition was designed to integrate with the UCSC Ebola Genome Browser, allowing researchers to make direct correlations between genomic data and said data's manifestation in the structural/physical world. Researchers can now interpret the functional implications of mutations in the Ebola genome, and examine on a structural level how they might evolve over time.

With the advent of bioinformatics, the emergence of big data, the ability to sequence virtually any genome at a constantly plunging cost, and the ability to cross-examine all of the above data through online sources such as MuPIT and the Ebola Genome Browser, the world of disease research has been continually revolutionized, and with every revolution, this world has become more integrated, more connected, more encompassing. While one or two decades ago the concept of researchers collaborating on a massive scale worldwide, in realtime, on a given problem would have seemed absurd, now this is becoming commonplace. The gestalt implication of this is the emergence of an analytic hive mind, capable of solving problems that its individual units would find impossible. To quote a particular association of bow-tied comedians... "YAY, SCIENCE!!!"

SOURCES:
http://hub.jhu.edu/2014/11/21/ebola-software
http://www.imperialvalleynews.com/index.php/news/health-news/329-new-online-3-d-tool-seeks-possible-targets-to-disable-ebola-virus.html\
http://www.ncbi.nlm.nih.gov/pubmed/23793516
Doctors Without Borders Stretched to its Limits with Ebola

David Villars calls Doctors without Borders the “most functional outfit in a dysfunctional global health system” and the “one-stop shop for West African governments seeking quick solutions to the Ebola crisis" in his Wall Street Journal article, “Ebola Crisis Stretches Doctors without Borders’ Means.” How functional is this unit? Doctors without Borders has treated more than 60% of all Ebola patients in West Africa as of the end of October, built many treatment clinics, recruited 3,400 people to work on the crisis, helped run several clinical trials of experimental drugs in its West African treatment centers. As a result, 24 of the NGO’s workers have been infected with Ebola and 13 have dies.

What factors drive its functionality? It received $1.3 billion in funding from various foundations, individuals, and governments. Furthermore, it’s functioning for 43 years gave it more experience and logistical expertise than other organizations have to deal with Ebola. While many NGO’s have been too overwhelmed and have failed to accomplish their objectives, this NGF has powered through for eight months.

Despite its achievements in confronting the emergency, dealing with the crisis has put a to of burden on the organization.  The Ebola outbreak is nothing that the organization has dealt with before. Marc Poncin, head of the NGO’s Ebola mission in Guinea admits that it’s been extremely challenging, “We’ve had to fill the vacuum, but fixing Ebola is too big for us.”

To read this article, go to

http://online.wsj.com/articles/ebola-crisis-stretches-doctors-without-borders-means-1417219277

Your Ebolaphobe,
~Mariam

Early Timing of Antiretroviral Therapy Associated With Immune Restoration

Digital Representation of The HIV Virion
A report published online by JAMA Internal Medicine suggests that early initiation of antiretroviral therapy (commonly referred to as ART) is correlated not only with decreased viral load, but also with immune recovery and reduced AIDS risk. The best results were seen when ART was begun within 12 months of seroconversion, which means the point at which antibodies against a pathogen are detectable in the blood. The researchers defined immune recovery as CD4+ T-cell counts in infected patients that were comparable to uninfected individuals.

After measuring the CD4+ T-cell counts of healthy individuals, researchers identified ≥900 cells/microliter as the normalized cell count, and they predicted that patients that achieved counts closer to this value would have (1) a greater T-cell response to chemical messengers that maintain immunological homeostasis (2) a decreased risk for developing AIDS and (3) lowered T-cell over-activation, which can exacerbate disease.

Data for the study was obtained retrospectively from the US Military HIV Natural History Study, an observational study of military men and women and their partners, and it supported the researchers’ hypothesis.

To provide context, ART given to patients with HIV-1 infection tends to be administered with the sole purpose of diminishing viral load. In the past, this objective has been acceptable, for viral load is correlated with poor recovery. Now, however, researchers acknowledge that decreasing HIV-1 viral load is achievable when antiretroviral therapy is prescribed and taken successfully. Thus, clinical attention is changing, focusing more on restoring the immune system of immunocompromised individuals in addition to decreasing viral load.

The report provides strong evidence to support initiatives for early testing and improved drug access. In the United States, the wholesale cost of antiretroviral therapy can range from $300 to over $3000 per month.1 Infected individuals can receive help in obtaining treatment from Medicaid, Medicare, The Ryan White Program, and the AIDS Drug Assistance Program,2 but these programs have income requirements that may still exclude individuals that need help obtaining care.

If the best results for immune restoration occur if ART is administered within 12 months of seroconversion, it is imperative that infected individuals become aware of their HIV status early, so they can begin drug therapy sooner rather than later. Moreover, drugs must be affordable and available—knowing that you’re HIV positive is far less tolerable if you don’t have access to treatment.

We need studies like this to provide (almost self-evident) support for public health campaigns that can improve health outcomes when they provide appropriate interventions. More importantly, it’s important to acknowledge that this research underscores the inequities that exist in the United States’ health care system.

Access to treatment and testing is limited in impoverished communities of low socioeconomic status—a stark contrast to the military men and woman involved in the study detailed above, all of whom have access to free or subsidized and routine medical care. In fact, the incidence of HIV continues to be higher among low-income communities in the United States.3

As research and treatments become more sophisticated, our delivery systems must follow suit. Admittedly, sustainable sources of funding have to be identified and secured if treatment for HIV is to become even more widely accessible, but to fail to do so—and do so in earnest—is to concede defeat in the struggle against health disparities in the United States.

-Luis Garcia

References:
1.     Cost of ART: 
2.     Programs that help pay for drugs:
3.     CDC Reports on Poverty and HIV Incidence:
4.     The JAMA Report:
5.     Graphic Link:

a.     http://eng.spb-venchur.ru/news/7437.htm



Obama's Global Health Agenda

“Make Sure We're Not Caught Flat-footed”
President Obama made this statement in September about the need to revamp the world’s preparedness to deal with epidemics in the future. On September 16, the White House released the fact sheet on the US response to Ebola that not only contained information about the actions the US will take about Ebola, but about the actions it will take to build the capacity of other nations to deal with the outbreak. The fact sheet indicates, "Over the next five years the United States has committed to working with at least 30 partner countries to invest in model systems to advance the Global Health Security agenda. CDC and DoD will work with other U.S. agencies and partner countries to establish emergency operations centers, build information systems, and strengthen laboratory security to mitigate biological threats and build partner capacity.”

In February 2014, before the Ebola crisis had occurred, the US government had already initiated a global health security project. The goal of this project was to assist 30 countries build a network of physicians and health care professionals, increase local disease prevention and monitoring, improve the laboratories,  and ensure the preparedness of local health care facilities to deal with emergencies.  While the objectives the White House and the CDC make seem to be similar to the previous goals of the CDC, the authors of the Huffington Post article claim that this initiative differs from the previous system of having Western disease detectives investigate in that it relies on more international collaboration and local participation. In the video of the GHS Agenda Launch of February, 2014, the speakers indicate their goals of making progress in developing and delivering measurable commitments. Information about the global health security agenda, including action packages, a fact sheet, President Obama’s remarks, and videos of the GHS Agenda Launch in February, 2014 can be found on the CDC website. It seems that the timing of the Ebola outbreak was just right in showing the desperate need for the amelioration of emergency outbreak preparedness worldwide. While the commitment to global health security preceding the Ebola  outbreak seems clairvoyant, it just highlight the need for the improvement of health systems around the world. 

I was curious to find out what concrete steps the CDC has taken to make their dream of global health security into reality.  I tried to find how much money the US government is giving towards this initiative. Surprisingly(or maybe not since almost anything can be found on the Internet), all information on allocations to global health was available online on the Kaiser Family Foundation website. Check it out! Some progress has been made in terms of funding from last year, and the FY2015 budget request includes a 45 million increase in funding from FY2014. I found that the allocation of funding on prevention research centers, healthcare surveillance, and public health system research has seen a total increase of 63000 from 2014, and around $20000 from 2013.  There is an increase in funding for emerging and zoonotic infectious diseases and public health scientific services. There is a slight decrease in funding for immunization and respiratory diseases. I am not sure if the numbers I found are correct, because it seems odd that the increase would only be in the thousands, but that was the data I pulled from Tom Friedan’s request for CDC 2015 funding. Apart from increasing funding, the CDC is working on increasing the collaboration between countries. They invited health leaders from different parts of the world to the white house and had numerous conferences and events during the past months. In fact, you can see a Flickr photo album of a meeting in Indonesia in August.

CDC’s president Tom Frieden stated: "The world would be a very different place today if Liberia, Guinea and Sierra Leone had had those systems in place a year ago. They could have contained this outbreak.” While this statement seems intuitive, it also brings back a recurring theme: "should it be the responsibility of the US to take care of the health systems around the world?"

As usual, I welcome your feedback!
Virologically yours,
~Mariam


Sources 
http://www.huffingtonpost.com/2014/11/24/cdc-global-epidemic-_n_6212990.html
http://www.cdc.gov/fmo/topic/Budget%20Information/appropriations_budget_form_pdf/FY2015_CJ_CDC_FINAL.pdf \http://www.modernhealthcare.com/article/20141123/NEWS/311239998
http://www.whitehouse.gov/the-press-office/2014/09/16/fact-sheet-us-response-ebola-epidemic-west-africa
http://www.whitehouse.gov/the-press-office/2014/09/16/fact-sheet-us-response-ebola-epidemic-west-africahttp://kff.org/global-health-policy/issue-brief/the-u-s-global-health-budget-analysis-of-the-fiscal-year-2015-budget-request/http://www.cdc.gov/globalhealth/security/

Saturday, November 29, 2014

Why (B)Eating a Dead Horse isn't a Good Idea in the Phillippines

Recently, the Philippines has banned the butchering and eating of dead horses due to the reported deaths of people who contracted Nipah virus in two villages in the southern Philippines in April, though the ban has only recently been reported to the public. Originally, Manila’s health department did not formally announce the suspected outbreak of Nipah Virus-related cases when it occurred in Sultan Kudarat. It has since been found that the horses were initially contaminated by fruit bats that belong to the family Pteropodidae, endemic in one of the two affected villages and a known natural reservoir of Nipah Virus.

Along with the horses, human residents --as well as local cats and dogs, which also died after eating contaminated horse meat-- have also been infected with Nipah virus in Tinalon and Midtungkok villages. This has been reported by a paper published in Emerging Infectious Diseases, written by a team of 17 authors, led by Paola Katrina Ching, a hospital staff nurse at Dr Jose N. Rodriguez Memorial Hospital, and a second-year fellow in the Philippine Field Epidemiology Training Programme of the health department’s National Epidemiology Centre.

According to the report, the outbreak began with the reported deaths of humans due to the disease in two villages in April. Early reports say the victims experienced vomiting, stomach pain, and diarrhea after eating horse meat in Barangay Tinalon on Wednesday. Municipal health officer Maricris Idio said more victims were rushed to the municipal hospital, but they have to transfer those in serious condition to the provincial hospital. Of the 17 cases so far reported, 82% have died after developing acute encephalitis syndrome. Others have experienced residual severe cognitive impairment, motor weakness, and ataxia.



References:

 http://gulfnews.com/news/world/philippines/philippines-bans-eating-meat-of-dead-horses-over-nipah-virus-cases-1.1419512

http://www.philstar.com/nation/2014/04/06/1309254/horse-meat-downs-70-more-kudarat


 By Kasiemobi Udo-okoye

Ebola Pathogenesis: GP Protein Shedding

Research published in PLOS Pathogens clarifies the mechanism by which Ebola is able to cause excessive bleeding and inflammation in human hosts. The research, conducted using tissue culture, involved human cells that were exposed to GP proteins isolated from infected cells, and it suggests novel possibilities for drug therapy against Ebola.

Figure 8 from the research paper.
The study suggests that infected cells shed glycoproteins after they are cleaved from surface membranes by a cellular protease called TACE. After cleavage-induced shedding, GP proteins encounter and stimulate dendritic cells and macrophages that produce a diverse combination of inflammatory cytokines. In turn, these cytokines activate other dendritic cells and macrophages that also release immunological messengers, ultimately prompting widespread inflammation.

Additionally, shed glycoproteins stimulate endothelial cells (blood vessel cells) to increase permeability and reduce coagulation (which facilitates bleeding), and shed GP proteins bind to antibodies, preventing them from neutralizing the actual virus. Inflammation and permeability improve the virus’s ability to access and infiltrate target cells; after macrophage and dendritic cell infection, viral replication intensifies in liver cells (hepatocytes) and white blood cells purified in the spleen (splenocytes), leading to organ failure.

Together, these factors contribute to the pathogenicity of Ebola virus.

The researchers continued their investigation by treating macrophages and dendritic cells with antibodies against TLR4—a human toll-like receptor that is previously known to mediate the immune response and be activated by shed GP proteins. After treatment with the antibodies, shed glycoprotein bound dendritic cells and macrophages less successfully.

The results of this study clarify the pathway by which the Ebola virus triggers disease, and it points to TLR4 as a potential drug target for attenuating the pathogenic effects of Ebola. Future avenues of study include validating these results within an animal model and, if successful, in clinical trials. 

-Luis Garcia


References:


Cases of the Tourists' Virus Skyrocket in the UK

On Friday, Public Health England has reported close to 200 new cases of the virus chikungunya. Public Health England reports that 197 British tourists have been diagnosed with chikungunya in 2014.  This is an increase of 432 per cent increase from September 16, when just 37 cases had been reported in the UK. The chikungunya virus, transmitted through infected mosquito bites, has spread to more than 30 Caribbean nations since it was first reported by the World Health Organization in December 2013, when the first case was discovered in St Martin, a French overseas territory. There are now more than 700,000 suspected cases and approximately 120 deaths reported. Additionally, in the U.S., the Centers for Disease Control and Prevention (CDC) reported more than 1,600 cases of chikunguya among returning travelers as of November 4th, and there has been in a significant surge in the number of cases in Canada as well. Meanwhile, the number of cases in Caribbean countries continues to increase, with the Dominican Republic, Guadeloupe, Haiti and Martinique bearing the greatest burden of new cases.

 According to one official at Public Health England, Dr. Tim Brooks, "Chikungunya is now a common infection in travelers from the Caribbean, and is 
currently reported more frequently than dengue."

Read more here: http://www.dailymail.co.uk/travel/travel_news/article-2853247/Mosquito-virus-cases-soar-432-UK-holidaymakers-return-Caribbean-major-chikungunya-outbreak-spreading.html

By Kasiemobi Udo-okoye

Friday, November 28, 2014

The Slow Track of the Host-Pathogen Arms Race: Human Evolution in Response Pathogen Pressures

Mutation and evolution are inescapable considerations in the study of infectious disease.  Microbes have comparatively small genomes and short replication times so they mutate quite frequently and favorable mutations are selected for and come to pervade the population quickly.  Hosts have developed ways of circumnavigating this rapid mutation.  One example would be the encoded and recombinate diversity of human T and B cell specificity in the human immune system.  Even if a microorganism mutates away from one immune-detected epitope the host can generate immune cells with specificity to the new epitope.

Because the timescales of host and pathogen replication and evolution are so different, the evolution of hosts in response to pathogens is less frequently investigated.  Not all researchers, however, shy away from such questions.  One research team, based at Harvard and led by Dr. Pardis Sabeti, is leveraging large datasets of human genome sequences and the computational tools of bioinformatics to investigate how the Lassa fever virus has influenced conserved changes in the human genome in regions where the disease is endemic.

Lassa fever virus, a member of the Arenaviridae family, is endemic to west Africa.  Although it rarely appears beyond that area, within west Africa Lassa fever generates a substantial disease burden.  According to the CDC, the virus infects about 200,000 individuals per year, kills about 5,000 and is present in about 10-16% of individuals admitted to hospitals in the area.  The virus has a rodent reservoir, the multimammate rat," which sheds the virus in urine and feces.  Humans are most commonly infected when they inhale or ingest the excretions of an infected rat, but can also be infected through contact with infected humans as well.  Most infected individuals (80%) present with a mild feverish malaise after an incubation period 1-3 weeks long.  In the remaining 20% of cases, severe symptoms develop that can include hemorrhaging, vomiting, respiratory distress, and shock and can result in death from multi-organ failure.

Sabeti's team, in a paper published in Nature in 2012, hypothesized that the endemicity of Lassa in west Africa might have placed a consistent pressure on human evolution in the region to favor the retention of alleles that confer resistance to Lassa or improve disease outcomes.   Using human full-genome sequence data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, these researchers identified conserved changes in two regions, a gene called LARGE and the gene encoding immune mediator interleukin-21, that had been determined through previous work to be involved in the infection of a host with Lassa and the development of immunity against Lassa.  These findings, like most in science, generated as many questions as they answered, particularly with respect to the physiological implications of these genetic changes.  However, the team was able to posit that the positively-selected variants of these genes were associated with increased alternative splicing and differential gene expression.  The implications of these findings extend beyond the particular disease of Lassa fever, however, because these results pave the way for similar investigations into the effects of related pathogens on human evolution.  However, pathogen influence on human evolution will likely be substantially less challenging to uncover for diseases that have a consistently strong presence over time and localized endemicity, like Lassa fever.

--Laurie Rumker

Check out the full published paper via DOI: 10.1098/rstb.2011.0299