Today we published the article,Willingness to Share Research Data Is Related to the Strength of the Evidence and the Quality of Reporting of Statistical Results, by Wicherts et al. In the manuscript, the authors show that weaker evidence in a psychology paper published in a journal requiring signed agreements to share data is associated with a failure to comply with this signed agreement to share.

Rochelle Tractenberg

In the following opinion piece, Rochelle Tractenberg, the academic editor who handled the peer review of Wicherts et al., discusses the ways in which “research ethics” and the “responsible conduct of research” go beyond human subjects protection, to include data sharing, professional conduct, and the careful, correct and complete reporting of all analyses in published research.  Rochelle is a biostatistician and research methodologist at Georgetown University.

The article by Wicherts et al. describes their study of 1148 “statistically significant results” that were published in 49 different papers within two psychology journals. As it was being reviewed and revised, this paper sparked a vigorous debate among PLoS ONE editors and reviewers for two very different, ethics-oriented, reasons. These reasons were:

1. Disciplines differ in their requirements that data analyzed and published should be made available to any scientist that requests the data. In some cases, the data cannot be properly de-identified, which violates a key feature of human subjects protections that all scientists are supposed to commit to whenever they carry out scientific work involving living persons. The Ethics Committee of the authors’ institution explicitly required them NOT to publicize the authors who refused to share data – and whose work was identified as being weak in terms of evidence and/or quality of results.
2. The readers of published work are totally dependent on the quality and accuracy of the statistical results presented –and described – in any manuscript they wish to utilize as evidence in their own argument or scientific endeavor. The option to re-analyze data is critical to check the reliability of published designs, results, or conclusions. Time is a precious commodity; knowing what work is most likely to require replication prior to its use would limit our reliance on work likely to include mis-analyzed data, misinterpreted results, or both.

These considerations highlight diverse conceptualizations of the “responsible conduct of research”: in the first conceptualization, the protection of human subjects –the authors who did and did not share their data, whose published work was analyzed in this paper – is the sole concern. The second conceptualization involves the responsibility of the authors of the reviewed published papers to fulfill their professional ethical obligations as well as their contractual agreements. Wicherts et al. did obtain permission from their Ethics Committee to provide a list of authors who failed to share data – if specifically requested, but are NOT permitted to identify which authors were compliant and defiant within their paper, nor to place their data file, as is, into a public archive. Wicherts et al. analyzed the contents of published articles, and then requested the data these papers represented. The journals’ and APA ethics policies are public and require data sharing, so neither the requests nor the failures to comply with those requests can be considered privileged. In short, no feature of the data in this manuscript can be considered to be privileged. The responsible conduct of research is much more than protecting study subjects and obtaining informed consent, but the Ethics Committee did not act like it is.

As the editor shepherding this article through the review process, I applaud the effort by Wicherts and colleagues, and disagree with the Ethics Committee decision. I believe that every journal should document requests for data and the failures of authors to provide the requested data as part of the publication record. This compliance information should be accessible to all reviewers for journals and grants, and to scientists who look to the published literature for replicable, reliable, ethically obtained results.

A prior report by Wicherts et al. in 2006 found that, while journals published by the APA all require authors to sign an agreement to share their data, 73% of authors who were contacted for that study failed to do so. These 73% defied their written agreement, and professional obligation (see APA Ethical principle 8.05), to share their data. This is not responsible conduct of research; this is unethical behavior and every scientist is entitled to know whether or not an author is responsible in their conduct –and reporting – of their research. As critical as these features are to responsible conduct of research, the review of manuscripts and grants for “ethical considerations” cannot be limited to the inclusion of women and minorities, balance between male and female subjects, and properly obtaining informed consent.

Wicherts et al. conclude that policies for data archiving should be strengthened/more widespread, even though their 2006 findings that, in defiance of their signed agreements, the journals’ publishing policy, and the professional association policy on data sharing, nearly ¾ of APA published authors refused to share data when contacted. In their current study, the refusal rate was “only” 57%.

A survey of geneticists working at 100 universities in the US led to an estimate of 47% failure to share. The challenge is clearly widespread and has a prevalence rate in the 47-73% range. By contrast, in her survey of the prevalence of “unethical” or “questionable” scientific behavior, Fanelli arrived at far smaller estimates – possibly because of a lack of awareness among her respondents that a failure to share data or research resources constitutes irresponsible –not merely questionable – research practice.

A broader appreciation of how critical transparency and replicability are for good science could support the cultural shift necessary to promote the idea that the “responsible conduct of research” is not limited to properly obtained consent. A mechanism for documenting failures in these key features of responsible conduct of research would also support this shift. Every reviewer should have this information about the likelihood that an applicant or author will violate sharing policies and/or defy contracts they’ve signed and/or professional ethical science standards they should be held to.

The responsible conduct of research includes conscientious protection of human subjects. In the book, “Scientific Integrity”, Macrina  also notes, “(s)haring research materials published in the peer reviewed literature has been a traditional practice that follows from the expectation that scientific research must be amenable to replication” (p. 81) and that “…written communication is an essential part of scientific research.” (p. 83) (see also National Research Council, 1992; Board on Life Sciences, 2003). As such, these should be just as conscientiously executed as other aspects of the research enterprise. Refusals to share data harms science and constitutes violations of our obligations to be responsible conductors of research.

Rochelle Tractenberg has also written a companion piece to this article, which can be found in the comments section of the Wicherts et al. manuscript.  In the second piece, she interprets the association between weak evidence and failures to comply with data sharing requirements in a different way. Instead of supporting mandatory archiving of data, Dr. Tractenberg concludes that readers and reviewers of manuscripts and grant proposals should be notified of the author’s/applicant’s history of compliance with data sharing mandates and policies. She believes that such documentation will do more to change the culture towards one promoting science and data sharing than mandatory data archiving. To read this post, please click here.

References

Board on Life Sciences (2003). Sharing Publication-Related Data and
Materials: Responsibilities of Authorship in the Life Sciences.
Washington, DC: National Academy Press.

Campbell, E. G., Clarridge, B. R., Gokhale, M., Birenbaum, L.,
Hilgartner, S., Holtzman, N. A., et al. (2002). Data withholding in
academic genetics: Evidence from a national survey. Journal of the
American Medical Association, 287, 473–480.

Fanelli D (2009) How Many Scientists Fabricate and Falsify Research? A
Systematic Review and Meta-Analysis of Survey Data. PLoS ONE 4(5):
e5738. doi:10.1371/journal.pone.0005738

Macrina FL. (2005). Scientific Integrity: Text and Cases in
Responsible Conduct of Research, 3E. Washington, DC: American Society
for Microbiology Press.

National Research Council (1992). Responsible Science, Vol 1: Ensuring
the Integrity of the Research Process. Washington, DC: National
Academy Press.

Wicherts JM, Borsboom D, Kats J, Molenaar D (2006) The poor
availability of psychological research data for reanalysis. American
Psychologist 61:726-728.

Wicherts JM, Bakker M, Molenaar D (2011) Willingness to Share Research Data Is Related to the Strength of the Evidence and the Quality of Reporting of Statistical Results. PLoS ONE 6(11): e26828. doi: http://dx.plos.org/10.1371/journal.pone.0026828

We’d like share with you their stories as examples of how three scientists at very different places in their careers use social networking tools to gain influence in their field.

Dr. Heather Piwowar (Postdoctoral Research Associate at Duke University, co-funded by DataONE, NESCent, and Dryad)

Courtesy of H. Piwowar

In the world of scientometrics, there are few young researchers these days making as many waves as Dr. Heather Piwowar. How do I know that? As a fellow junior researcher interested in scientometrics, I’ve found that there’s no better way to receive up-to-the-minute recommendations on interesting white papers, insider’s information on invitation-only conferences like #scifoo, and thought-provoking observations than by following Heather on two online services where I already spend a lot of time: Twitter and Google Reader.

What’s notable about Dr. Piwowar’s use of social media is that she very rarely indulges in self-promotion. Rather, she uses social media to engage other researchers: “Tweeting, blogging, friendfeeding, creating public Mendeley groups, etc. helps me find and be found by some of the most enthusiastic, engaged people in my area.  I learn what they think, what they are working on, and sometimes a bit about who they are.  They get to know me and what I do.  As a result, I do better work and my work gets more exposure.”

Piwowar also points out that social media, as an engagement and networking strategy, is strong in two areas where traditional forms of academic feedback are weak: timeliness and connecting far-flung researchers.

She notes, “Data finds data then people find people” is really true… when you start sharing information about your research passions and seeking other shared info relevant to your work, all of a sudden you find new groups of people who are about the same things you do.  Some of them turn into collaborators, and a few into friends.

Time well spent, no doubt about it.”

Blog | LinkedIn | Twitter | Mendeley

Dr. Alistair Dove (Senior Scientist at the Georgia Aquarium Research Center)

Courtesy of A. Dove

Dr. Alistair Dove, a Senior Scientist at Georgia Aquarium Research Center—the world’s largest aquarium—is what could be called a “trust agent,” imparting insights into his deep-sea research via Twitter and his blog, Deep Sea News, while engaging the public in science.

Dove explains, “If you have, say, a thousand followers on Twitter, that’s like talking to a large auditorium every time you tweet something about your science: a powerful tool indeed.  A direct line like that means the scientist can ensure that their science is accurately portrayed and that they have an opportunity to share with the public the personal passion that drives them to science in the first place.” A great side effect of all this communication with the public? If you do it well, recognition of your name and your contributions to research will increase among your colleagues, as well.

[Facebook and Twitter] are legitimate, powerful communication tools and scientific funding agencies want to see that you are considering them (and Apps, and Google Earth and all the other tools) as part of the plan for sharing science with the public.  Social media can help you get funded, help popularise your work, and help educate, entertain and inform the public, and I reckon that’s what it’s all about.

Blog | LinkedIn | Twitter

Dr. Jonathan Eisen

I believe in making it easy for people to find information and stories and such.

Courtesy of J. Eisen

Eisen explains, “I emailed the paper to a few contacts who are reporters (Carl Zimmer, for example) and told them I would be posting more information about the story behind the paper on my blog.  Then I wrote the detailed background story on my blog and when the paper came out of its embargo, I made the blog post live and then emailed a bunch of people the link to the paper and the blog post.”

He continues, “I posted these links to Facebook and twitter and my blog too — and since I have been working to build up my social networks for many years this at least got the message out to a few people.   One of those fortunately was PZ Myers, who writes the Pharyngula blog, and he posted a little discussion of how I had avoided a press release and that generated enormous web attention.  This, along with the article in the Scientist and on Carl Zimmer’s blog, was enough to get some attention around the web.  I think this helped convince others to write about it, including The Economist, which wrote a story for their online and print editions.”

Eisen’s experience shows that having a well-cultivated and engaged circle of social media friends and followers can help expand the impact of your work, even if you don’t follow traditional routes to publicize it.

Blog | LinkedIn | Twitter | Mendeley

If you are interested in learning more about how to collaborate and spread your own scientific messages using social media, check out the following links:

• How scientists can reach out with social media, by Jennifer Rohn
• Social Media for Scientists Part 1: It’s Our Job, by Christie Wilcox
• Top Twitter Tips for Academics, by Mark Reed and Anna Evely

To mark this occasion, we’ve asked Dr. Brian Oliver and Dr. Stephen Liggett, authors of the 20,000^th manuscript, b2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D to tell us a bit about their article, their background, and their research via email.

To begin, give us a summary of your research?

Dr. Brian Oliver

BO: In our research, we have been examining how the drugs, which relax bronchial air passages of people with asthma, work.  These therapies bind to, and activate the ß2 receptor. This receptor induces the formation of cAMP, which initiates muscle relaxation.  In turn cAMP is regulated by an enzyme phosphodiesterase 4 (PDE4D).  We have discovered that airway smooth muscle cells from people with asthma have increased phosphodiesterase 4.  As phosphodiesterase 4 degrades cAMP, our research has important implications for the treatment of asthma.

SL: We found that airway smooth muscle cells derived from asthmatics are “hard-wired” to have a defect in signaling by the beta-2 adrenergic receptor. This defect is an enhanced phosphodiesterase activity, essentially leading to rapid metabolism of intracellular cAMP, rendering the asthmatic smooth muscle cell with a depressed response to beta-agonists. Beta-agonists are the major drugs used to relax airway smooth muscle and open airways in asthma. The hard-wiring part is quite intriguing. It has been generally thought that inflammation in asthma leads to signaling defects, at both the relaxation side (such as with beta-2 adrenergic receptors) and the exaggerated bronchoconstrictive receptors such as the M3 muscarinic receptor. However, these cells were kept in cell culture media and passaged multiple times, and obviously removed from the inflammatory environment in the asthmatic patients. So, this is either a genetic or epigenetic effect.

When did you become interested in studying asthma?

BO: Before starting my PhD, I realized that asthma is a disease which effects a large proportion of the population (at least 10%), and is also a disease in which there is a need to develop better therapeutics.  I was fortunate to be employed at the National Heart and Lung Institute,UK where I examined basic science mechanisms underpinning asthma, and I realized that this is where my future career would be.  I then travelled to Australia to undertake my PhD with Professor Judith Black who is one of the leading experts in airway smooth muscle biology, and as they say I have never looked back.

SL: I was a post doc at the HHMI with Robert Lefkowitz during the cloning and initial characterization of the adrenergic receptors, and my lab studies basic structure/function relationships. But I have always been drawn to the translational aspect of understanding how G-protein coupled receptor signaling is so aberrant in asthma. And, I have persistent asthma myself, so there is a personal interest in further understanding these issues. Actually, I am wondering if this has been a driving force for longer than I might realize. I got irritated that we knew so little about human rhinoviruses (a major cause of asthma exacerbations), so we just sequenced every known common cold strain to get a handle on that. And we have made dozens of transgenic mice aimed at understanding smooth muscle signaling, all pointing towards asthma. So as it was with this study, we went against some old dogma and just pushed on. Studying human cells derived from affected and unaffected individuals is hard, but it must be done if we are to crack this nut.

Your manuscript has several figures in it. Which one do you think is the most important for people to pay attention too?

BO: Figure one represents the initial finding which led to this study, however this for me is not the most important figure.  Figure two is.  In figure two we measured phosphodiesterase activity in asthmatic airway smooth muscle cells, and found increased activity in the asthmatic cells.  To investigate which phosphodiesterase was increased we used a series of phamalogical inhibitors and were able to demonstrate that PDE4 activity was specifically increased in the asthmatic cells.

During the course of your research for this paper, did you find anything unexpected?

BO: Our initial finding was that ß2 agonist induced cAMP was lower in the asthmatic cells.  There are several reasons described in the literature as to why this could occur.  However increased PDE4 activity was not one of these.

SL: The hard-wiring aspect, and where the defect was. I figured that it would be upstream of adenylyl cyclase.

What’s next? Where would you like to go from here?

Dr. Stephen B Liggett

BO: In asthma, virus infection precipitates exacerbations (bronchial contraction) in which ß2 agonist don’t work as well as they do at other times.  As we have now shown that PDE4 activity is increased in asthma we want to investigate the role of PDE4 in virus-induced exacerbations.

SL: Now that we have this identified, we would like to devise a “workaround” strategy, that will allow for effective bronchial dilatation by beta-agonists (or another receptor), so as to provide more effective treatments.

What made you decide to submit to PLoS ONE?

BO: There are several factors to consider when submitting a paper to a journal.  Amongst the most important are: journal prestige, length of review process, and the accessibility of the paper post publication.  PLoS ONE is a good journal by all measures, and based upon our previous experience we knew that we would receive a quick and fair review.  Also, being open access allows anyone with internet access to see our paper and, as such, allows us as scientists to share our findings with the world.

SL: The general readership is a big plus. As we all know so well, these pathways and proteins are in many cell types and we wanted investigators from many fields to be aware of what we found, so that there can be more “collective thinking.”

In this author spotlight, Sara Maxwell, a Postdoctoral Fellow with Marine Conservation Institute and the University of California, Santa Cruz, answers questions about her background, her research and her PLoS ONE manuscript, Using Satellite Tracking to Optimize Protection of Long-Lived Marine Species: Olive Ridley Sea Turtle Conservation in Central Africa.

First, a bit of background – how did you become interested in studying migratory patterns of large pelagic animals?

My interests have always centered around conservation primarily.  In my mid-20s as I was considering going back to graduate school, I knew I wanted to study a system that would interest me over the course of an entire career – and a system where my science could make a difference.  The migratory patterns of marine mammals fit the bill well, and turtles in particular have always been particularly special to me. During my undergraduate career, I spent a summer working with sea turtles at Duke University’s Marine Laboratory and it was ultimately the turtles that drew me into marine biology and conservation.  When the opportunity to work with turtles in Gabon arose, I didn’t think twice!

In the manuscript, it mentions that sea turtles are “excellent candidates and models for protecting vulnerable, discrete breeding areas.” Why is this so?

Sea turtles are a highly migratory and dispersed species throughout most of their lives, but during the breeding and nesting season, they come together in large concentrations – and for fairly long stretches of time.  Breeding and nesting areas are relatively close together. Olive ridley sea turtles, for example, nest every year to three years.  Female turtles stay in the breeding-nesting grounds for several months while they mate and lay up to three clutches of eggs, and breeding males are found in the same areas.  Breeding and mating areas, however, are close to shore – so closer to humans, fishing and other threats – but because they are in a small area for a specific period of the year and during an important life history stage, it makes protecting them easier and more politically and socio-economically feasible.

Mayumba National Park is a marine protected area just north of the border of the Republic of Congo. The area is home to leatherback and olive ridley sea turtles but of the two turtles, olive ridleys make up 59 to 95 percent of the dead turtles that wash up on shore.  Is there a reason for this and how does tracking via satellite help to minimize the number of stranded olive ridley sea turtles?

We understand the situation in Mayumba a lot better than we did before this study but it is still a bit of a thousands of leatherbacks sea turtles nesting in Mayumba every year but only a few hundred olive ridleys – yet the olive ridleys are dying in much greater numbers.  We used satellite tracking to determine where the turtles were going in relation to the park that was created to protect them. We found that they are spending a lot of time outside the park boundaries where they are exposed to fishing nets and drowning.  Leatherback movement patterns are somewhat similar; however we don’t see the same number of dead animals washing ashore.  This could be because leatherbacks are heavier and their bodies sink instead of washing ashore or they don’t encounter fishing nets as frequently because they are in deeper waters or have different diving behavior.  There are lots of things we still don’t know, but what we do know is that creating a larger park – one that is in both Gabon and the Republic of Congo – will protect both species better more from fishing nets.  Satellite tracking has been the key tool that brought us to that conclusion, through this study and another great study by Matthew Witt and colleagues published in Oryx in 2008.

One of the three elements you mention, as being necessary to provide protection to breeding females, is the level of confidence in tracks given the limitations of satellite telemetry. How accurate is satellite telemetry and what was done to eliminate location error of internesting movements?

Satellite tracking is an incredibly powerful technology – but it can be tricky too!  We were focused on a fairly small area of the world in this study (approximately 1500 km2), and like all measurements, satellite telemetry locations have error associated with them.  In the case of telemetry, however, this error can be tens of kilometers which could have a significant impact on the conclusions we were making about where turtles are found in relation to park boundaries.  To help counter this, we used a technique called state-space modeling that has been fairly recently applied to animal movement.  State-space models allowed us to assign the Bayesian equivalent of confidence intervals to every track location.  By doing this, we could calculate error estimates for how animals are using park boundaries – and recommend changes in the park boundaries that take this uncertainty into account.

You have included a few figures in the manuscript. Of them, which one is the most important and why?

This is a difficult question!  I think Figure 3, (above figure) which shows the key areas that the olive ridleys are using along with the outer bounds for our error estimation, is critical in showing what we learned from the study – and what we are still uncertain about due to satellite telemetry error. Figure 4 is important as well because it shows the olive ridley and leatherback sea turtle distributions together.  Though the analytical techniques were different, this figure shows that the proposed park boundaries (which extend into both Gabon and Congo as well as further offshore) are really on target to protect BOTH of these species – this was a really exciting finding, and one in which is already helping to guide management in the area.

Did you find anything surprising or unexpected while conducting your research for this paper?

One of the most critical things that we learned from conducting this research is not in this paper – and is critical to protecting the olive ridley population.  There is a substantial nest monitoring effort that goes on in Gabon and in Mayumba National Park but most of the monitoring has focused on leatherback sea turtles.  Olive ridleys, however, nest earlier in the year, and in the most remote part of the park.  We were on this remote part of the beach earlier in the year, both to deploy our satellite transmitters and to monitor the nests.  As a result we discovered that almost 100% of the nests being laid by olive ridleys were being predated upon by natural predators such as crabs and mongooses. Olive ridley nests are not as deep in the sand as leatherbacks, so predators could reach the eggs and none of the eggs being laid were hatching.  This obviously will have a huge impact on the population. As a result of what we learned, however, over the last three years, with support from the US Marine Turtle Conservation Fund, Mayumba National Park has started a hatchery where they incubate the eggs in a protected area of the beach to ensure that the eggs are safe and hatchlings are born.

What’s next?  Where do you hope to go from here?

The directions are endless!  But there are several directions we are actively working towards.  We are working to combine not just the satellite tracks from olive ridley and leatherback sea turtle data but also humpback whales.  The goal is to have a comprehensive understanding of how key species in the region are moving in relation to both park boundaries and also other human activities such as fishing and oil and gas development.  We have begun modeling the at-sea habitat olive ridleys use during the nesting season in relation to the physical and oceanographic environment.  The goal is predicting where ridleys are likely to be found in relation to other nesting beaches where we weren’t able to deploy satellite tags.  Finally, we are also collaborating with scientists from Pendoley Environmental who have tracked olive ridleys from another nesting beach in Angola.  We are finding that the turtles have similar migratory patterns and are focusing on the same foraging grounds and oceanographic features. All of these efforts are focused on how can we better understand and protect the turtles.

To read more about Sara’s experience in the field, please see her posts on Turtling in Africa in the On TOPP of the World Blog and to view the satellite tracks online, visit the SEATURTLE.ORG tracking page. The paper Using Satellite Tracking to Optimize Protection of Long-Lived Marine Species: Olive Ridley Sea Turtle Conservation in Central Africa is freely available to rate, comment on, and share.

Today is World Malaria Day —a time to reflect upon and commemorate the global efforts to fight this deadly mosquito-born disease found throughout the tropical and subtropical regions of the world. Given the day, we thought it would be a good opportunity to highlight some of the recent malaria research published in PLoS ONE and PLoS Pathogens, as well as have the authors discuss their work.   Many thanks to the authors and academic editors who agreed to participate in this post.

PLoS ONE

Earlier this month, the Head of Malaria at the Foundation for Innovative New Diagnostics (FIND) in Geneva, Switzerland,  David Bell, and colleagues from the Ministry of Health of Senegal, FIND and WHO published a paper on the Major Reduction in Anti-Malarial Drug Consumption in Senegal after Nation-Wide Introduction of Malaria Rapid Diagnostic Tests.

According to Bell:

This paper demonstrates the tangible impact that can be achieved through the well-managed rollout of malaria rapid diagnostic tests (RDTs) nationwide. In particular, the article shows that:

• rolling out a high quality nation-wide RDT programme is feasible even in low-income countries
• a carefully planned and implemented rollout results in good adherence to diagnostic results by clinical staff
• the widespread use of quality diagnostics can lead to a significant reduction in the number of anti-malarial drugs prescribed, which is both a public health gain and results in significant savings in ACT procurement (the Global Fund was able to retain €1.2 million from its Malaria grant to Senegal, available for use in other projects)
• Senegal now has solid evidence of its “true” national malaria rates, allowing for more accurate targeting of malaria interventions and resources, essential if elimination is eventually to be achieved.
  

  Figure 2. Evolution of parasite based diagnosis of malaria in Senegal public health services 2007–2009.

While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in smaller-scale interventions some settings, with little impact on anti-malarial drug consumption. The experience in Senegal shows that this need not be the case, and that the well-managed use of quality diagnostics can have a dramatic positive impact on the management of malaria and febrile disease.

In the paper, Malaria Prevalence, Risk Factors and Spatial Distribution in a Hilly Forest Area of Bangladesh,  Ubydul Haque, a PhD student currently at  the Department of International Health, Institute of Tropical Medicine (NEKKEN) and the Global Center of Excellence Program in Nagasaki, Japan, along with colleagues from the International Center for Diarrhoeal Disease Research  in Bangladesh, and the  Johns Hopkins Bloomberg School of Public Health evaluate early stage malaria interventions in Bangladesh.

From the authors:

Figure 2. Land cover classification in Rajasthali

Malaria is a major public health concern in Bangladesh and it is endemic in the Chittagong Hill Tracts where prevalence was 11.7% in 2007. One sub-district, Rajasthali, had a prevalence of 36%. Several interventions were introduced in early 2007 to control malaria with the support of Global Fund. This study was undertaken to evaluate the impacts of these intensive early stage interventions on malaria in Bangladesh. The study result confirmed the malaria prevalence dropped to 11.5% in 2009. Sex, age, number of bed nets, forest cover, altitude and household density were potential risk factors. Statistically significant malaria clusters were identified. Significant differences among risk factors were observed between cluster and non-cluster areas. Malaria has significantly decreased within 2 years after onset of intervention program. Both aspects of the physical and social environment, as well as demographic characteristics are associated with spatial heterogeneity of risk. The ability to identify and locate these areas provides a strategy for targeting interventions during initial stages of intervention programs.

The findings are important since the prevalence rate sharply declined although malaria cluster effect still remains.

In another paper published this month called, Determinants of the Cost-Effectiveness of Intermittent Preventive Treatment for Malaria in Infants and Children, Amanda Ross a statistician at the Swiss Tropical and Public Health Institute and first author of the manuscript writes:

With finite resources, a rational basis is needed for choosing between malaria control strategies. The potential strategies, intermittent preventive treatment in children (IPTc) and infants (IPTi), are under consideration. IPT aims to deliver anti-malarial treatment to the target age group at specified time points whether or not they are known to be infected with the aim of reducing morbidity and mortality.

Field trials have provided information on the effectiveness of IPT on clinical episodes in a number of settings. It is not practical, however, for the trials to include the very large numbers of children required to estimate the effectiveness on the less frequent but important outcomes of severe malaria (requiring hospitalisation) and death, neither is it feasible to carry out large numbers of trials for many different setting nor implementation characteristics.

Figure 5. Predicted effects and cost-effectiveness of IPT depending on timing of first dose in seasonal settings.

This paper uses a comprehensive model of malaria epidemiology together with economic data to provide predictions of the impact and cost-effectiveness of IPTc for different settings, drugs and implementation characteristics, and to investigate the limits where IPT is no longer cost-effective. These predictions contribute to a growing database of the likely effectiveness, including cost, of different malaria control strategies generated using this common simulation platform. These predictions, taken together with other considerations, can aid decision-makers.

Our final PLoS ONE malaria highlight comes from Francesco Dieli, a Professor of Immunology and Director of the Division of Immunology and Immunogenetics at the University of Palermo, Italy.  As the Academic Editor for the recently published paper, Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria, by Charles Arama et al., he writes:

Half of the world’s population remains at risk of contracting malaria. During 2008, malaria was estimated to be responsible for 767,000 deaths in Africa alone, mostly in children below the age of 5 years. There is substantial evidence that host genetic factors play a major role in determining the outcome of infection with Plasmodium falciparum (P. falciparum), the ethiologic agent of malaria, but in humans, this genetic trait is complex. Several epidemiological approaches can be applied in the study of the genetic susceptibility to malaria, amongst which is inter-ethnic comparative analyses among populations with different genetic backgrounds, exposed to the same epidemiological context and showing different susceptibility to the disease.  The combination of such epidemiological studies, together with linkage analyses in a rural area in Mali have clearly shown different genetic innate susceptibility to P. falciparum between two ethnic groups, the Fulani and the Dogon. These populations live under similar social, cultural and geographic conditions and are exposed to identical malaria pressure. However, the Fulani are better protected against Plasmodium falciparum malaria as compared to the Dogon and this has been associated to the development of robust anti-malarial immunity.

Nevertheless, little is known about the functionality of innate immunity in Fulani and sympatric ethnic groups and how this branch of immunity influences susceptibility to malaria infection. This aspect is of crucial importance to fully understand the immunological mechanisms of susceptibility/resistance to malaria, as innate immunity both rapidly inhibits parasite growth, thereby limiting the onset of disease, and instructs specific adaptive immunity

The paper by Arama and colleagues clearly demonstrates that important differences exist between the Fulani and Dogon groups at the level of innate immune response, which involve the function of dendritic cells (DCs): P. falciparum infection impairs the phenotype of DCs and alters their responses  to TLR agonists in Dogon, but not in Fulani children, and this has an important consequence on the outcome of subsequent adaptive immunity to P. falciparum, as documented by differential IFN-γ release in the two ethnic groups.

While evaluation of a larger cohort of patients is required to confirm these results and to analyze the potential occurrence of distinct TLR polymorphisms in these two ethnic groups, this paper clearly indicate that understanding of innate immune responses to P. falciparum in naturally exposed children may yield important insights in the development of immunity to malaria, with particular regard to the definition of robust correlates of susceptibility/resistance to infection, and to the development of novel vaccination strategies.

PLoS Pathogens

Dr. Anthony James, a Distinguished Professor of Microbiology & Molecular Genetics at the University of California, Irvine School of Medicine, writes about his recently published article, Engineered Resistance to Plasmodium falciparum Development in Transgenic Anopheles stephensi.

Figure 1. A model of the modified scFv transgenes.

Malaria eradication will require vector-control strategies that are both self-sustaining and not affected by migration of infected humans and mosquitoes. Replacement of wild malaria- susceptible mosquito populations with transgenic strains refractory to parasite development could interrupt the cycle of disease transmission and support eradication efforts.

Production of P. falciparum-resistant mosquitoes is a necessary first step towards investigating the population replacement strategy. Alison T. Isaacs and colleagues engineered Anopheles stephensi to produce P.falciparum-targeting effector molecules; these mosquitoes exhibit resistance to this important human malaria parasite. Two of the three effector molecules represent a novel combination of components derived from the immune systems of mosquitoes and mice. Transgenes with this design coupled with a gene-drive system could be used alongside vaccines and drugs to provide sustainable local elimination of malaria as part of a long-term strategy for eradication.

Author Franck Prugnolle writes about his team’s review article, A Fresh Look at the Origin of Plasmodium falciparum, the Most Malignant Malaria

Figure 2. Distribution of the different subspecies of chimpanzees, bonobos, and gorillas in Africa and representation of the spread of the different Plasmodium species in these subspecies.

Agent.

Until very recently, Plasmodium falciparum, the main malignant agent of human malaria, appeared phylogenetically isolated from the other Plasmodium species infectinghuman and non-human primates. Only one sister species, P. reichenowi from chimpanzees was recognised and molecularly characterised. In 2009 and 2010, thanks in particular to the use of new non-invasive methods to diagnose the presence of Plasmodium species in wild great apes, several studies have revealed the existence of a number of distinct new phylogenetic species infecting chimpanzees, bonobos, and gorillas. P. falciparum parasites were also found to naturally infect wild gorillas. In our paper, we discuss how these discoveries irrevocably changed our perception of the evolution and origin of P. falciparum but also how this opens vast new areas of research to explore the origin of these different species, their ecology and their evolution.

Dr. Christian Engwerda, an Associate Editor for PLoS Pathogens, edited the paper Dendritic Cells and Hepatocytes Use Distinct Pathways to Process Protective Antigen from Plasmodium in vivo by Cockburn et al., and offers his comments:

CD8+ T cells recognize intracellular peptide antigens presented on the cell surface by major histocompatibility complex (MHC) I molecules. In this way, CD8+ T cells can recognize and kill tumours and cells infected with intracellular pathogens. Malaria is

Figure 6. Pexel/VTS motifs are not required for the presentation of CD8+ epitopes in the CS protein.

caused when a female mosquito injects Plasmodium Spp. parasites while taking a blood meal. The parasites first infect hepatocytes in the liver, prior to establishing the blood stage of infection responsible for all clinical symptoms of malaria. Evidence to date indicates that the malaria liver stage is a good target for vaccine-induced CD8+ T cell-mediated protective immunity. However, CD8+ T cells first need to be activated by specialized antigen presenting cells called dendritic cells (DCs) in lymph nodes before they can migrate to the liver and kill infected hepatocytes, and hence much work has been devoted to studying parasite antigens presented via MHC I on DCs. However, malaria-specific CD8+ T cells must recognize parasite peptide antigens presented by MHC I on both DCs and hepatocytes.

Recently, Cockburn, Zavala and colleagues reported in PLoS Pathogens that DCs and hepatocytes use different mechanisms to process Plasmodium Spp. antigens prior to presentation by MHC I on the cell surface. Furthermore, they discovered that in hepatocytes, well-recognised parasite protein export motifs were not required for parasite antigens to leave the parasitophorous vacuole, where parasites reside in the cell, to enter the cell cytoplasm prior to antigen processing. These data are important because they show that the potential number of parasite proteins presented on MHC I molecules by hepatocytes may be much greater than previously thought, and importantly, suggest that identifying protective CD8+ T cell parasite antigen epitopes might best be achieved by looking for them in infected hepatocytes, the targets for CD8+ T cell-mediated killing, rather than restricting our search to those that can be presented by DCs. This information will help in developing a safe and effective malaria vaccine.

All together, PLoS ONE, PLoS Pathogens and PLoS Medicine have over 400 research articles focused on Malaria.  To browse more of the research, click here.  In addition, PLoS Medicine launched the malERA – a research agenda for malaria eradication collection earlier this year.  The collection contains 12 Reviews,  three reflective pieces, and nine research and development agendas. They have also posted on their Speaking of Medicine blog an interesting post by Nathan Ford, a medical coordinator for Médecins Sans Frontières (MSF), on improving treatment for severe malaria.

Many thanks to Mary Kohut, the PLoS Pathogens Publications Manager, for her assistance in this post.

First image shown in this post is courtesy of SomosMedicina.

In this media digest: your flaws are my pain, increased gold mining threatens the Peruvian Amazon and more.

The manuscript, Your Flaws Are My Pain: Linking Empathy To Vicarious Embarrassment, by Soren Krach et al., received media attention from: The Body Odd, Toronto Sun, Indian Express and US News & World Report. The featured image is from Figure 1 of this manuscript.

Jennifer Swenson and colleagues published a paper on, Gold Mining in the Peruvian Amazon: Global Prices, Deforestation, and Mercury Imports.  Their research was covered by Discovery News, Mongabay, and Treehugger.

In addition to the media coverage for the article, Antidepressants and Breast and Ovarian Cancer Risk: A Review of the Literature and Researchers’ Financial Associations with Industry from last week.  This paper was also covered by the Boston Globe.

Colored Motifs Reveal Computational Building Blocks in the C. elegans Brain by Jifeng Qian, Arend Hintze, and Christoph Adami1 was covered by Live Science.

Colin P. Groves, Prithiviraj Fernando, and Jan Robovský published a paper earlier this month called, The Sixth Rhino: A Taxonomic Re-Assessment of the Critically Endangered Northern White Rhinoceros. It has received coverage from Mongabay.

Partners with Bad Temper: Reject or Cure? A Study of Chronic Pain and Aggression in Horses by French researchers Carole Fureix, Hervé Menguy, and Martine Hausberger received coverage from Horsetalk and Horse Yard.

The manuscript, Getting the Grip on Nonspecific Treatment Effects: Emesis in Patients Randomized to Acupuncture or Sham Compared to Patients Receiving Standard Care was covered on About.com.

US News & World Report and Estonian Public Broadcasting covered the manuscript, Carotid Plaque Age Is a Feature of Plaque Stability Inversely Related to Levels of Plasma Insulin.

Diet-Independent Remodeling of Cellular Membranes Precedes Seasonally Changing Body Temperature in a Hibernator was covered by Xinhua and Cordis News.

The view from Helicon covered Ingroup-Outgroup Bias in Contagious Yawning by Chimpanzees Supports Link to Empathy.

Andrew Farke interviewed Josh Miller about his paper, Ghosts of Yellowstone: Multi-Decadal Histories of Wildlife Populations Captured by Bones on a Modern Landscape.  The interview can be read on his blog, The Open Source Paleontologist.

Researchers from Cancer Commons, a rapid learning community for Cancer, have created a Web-based app that uses information from Table 1 of a paper entitled, “A Melanoma Molecular Disease Model,” by Vidwans et al.  The paper, which published today, outlines a model for melanoma and was curated by a panel of researchers and clinicians.

Dr. George Lundberg, who is the Editor in Chief of Cancer Commons, discusses why the PLoS ONE article is noteworthy and how open access played a role in the development of the Targeted Therapy Finder application.

“Modern molecular biology supports the hypothesis that cancer is actually hundreds or thousands of rare diseases, and that every patient’s tumor is, to some extent, unique. Yet most patients are still treated using standard guidelines that are based not on their tumor’s molecular biology but on its organ of origin.  With hundreds of molecular diagnostics and targeted therapies in development, the time is ripe to develop a formal process for classifying cancer into molecular subtypes and developing proposed treatment guidelines for each subtype, including specific assays, drugs, and clinical trials. This process produces a formal ‘molecular disease model’ that can be used by clinicians to guide treatment decisions, and refined by researchers based on clinical outcomes and laboratory findings.

The Melanoma Molecular Disease Model (MMDM) lists the currently known molecular subtypes of melanoma, each hyperlinked to relevant pathways, diagnostic tests, approved and experimental (targeted) therapies, and clinical trials.  Its pages of tables, charts, literature references and supporting data pulls together, for the first time, information linking melanoma genomics and available targeted therapies previously dispersed across hundreds of publications, databases and websites.  The article is also noteworthy for three innovative ways it exploits PLoS’s open access publishing model to accelerate medical research in era of genomics and personalized medicine:  an open access knowledge base for computers as well as eyeballs; a living review article subject to continuous, incremental revision; and a rapid publication process, fast enough to save lives.

While valuable to cancer researchers, few practicing physicians or patients are likely to consult a very long document to guide treatment decisions.  They need user-friendly Web-based apps that help them rapidly identify relevant diagnostic tests, treatments and trials. To facilitate this, we are developing a family of such applications for melanoma and other common cancers.  The first such app is a Targeted Therapy Finder (TTF) for Melanoma. Using information from the MMDM, it guides patients and their physicians through a series of molecular tests to determine their tumor’s subtype, and then recommends the best available therapies and clinical trials.”

Screen shot of the Melanoma Targeted Therapy Finder app developed by CollabRx, Inc. based upon the Melanoma MDM. Selecting characteristics of a patient’s specific tumor and pressing “SEARCH” will report clinical trials and literature that are possibly appropriate for this individual patient.

“Given the rapidly evolving state of knowledge, the MMDM will need continuous revision to keep pace with the latest clinical and scientific findings. While the version of record will remain available on the PLoS ONE website, the latest version of the ‘dynamic’ review article will be available on the CollabRX website as a hyper-document and will be continuously updated based on input from the melanoma community, curated by the authors. The hyper-document can be rapidly navigated to find all information relevant to a given topic (e.g., subtype, test, drug or trial) as well as additional information on the Web. We are developing tools that will enable physicians and patients to report their clinical outcomes so that they can be factored into model revisions.”

The paper and the Target Therapy finder are free to read and use. To try the Target Therapy Finder you can go to http://therapy.collabrx.com.

Tomorrow is World TB Day—a time to reflect and recognize that tuberculosis is still an important epidemic across the world, causing the deaths of several million people each year, mostly in developing countries. It’s also a good time for us at PLoS to reflect upon and highlight the excellent research and analysis we’re recently published on tuberculosis.

Yesterday PLoS Medicine published a paper announcing the BCG Atlas, the first free online atlas of Bacille Calmette-Guérin (BCG) vaccination policies from around the world. The Atlas—developed by Madhu Pai and colleagues in Canada—is the first-of-its-kind, easy-to-use, searchable website that provides free detailed information on current and past TB vaccination policies and practices for more than 180 countries, thus providing useful information for doctors caring for patients with TB.

And since it’s 2011 an excellent YouTube video developed by the authors describes the Atlas further.

Other recent highlights in TB research @ PLoS are:

Scaling Up Towards International Targets for AIDS, Tuberculosis, and Malaria: Contribution of Global Fund-Supported Programs in 2011–2015

Antiretroviral Therapy Outcomes in HIV-Infected Children after Adjusting Protease Inhibitor Dosing during Tuberculosis Treatment.

The Prevalence and Drug Sensitivity of Tuberculosis among Patients Dying in Hospital in KwaZulu-Natal, South Africa: A Postmortem Study.

Combining Domestic and Foreign Investment to Expand Tuberculosis Control in China.

The Health Crisis of Tuberculosis in Prisons Extends beyond the Prison Walls.

Tuberculosis Incidence in Prisons: A Systematic Review.

Two papers, published today, have both sought to answer this question, but have come to seemingly different results.  In the first paper, Jasmine Grimsley, a post-doc fellow at Northeastern Ohio Universities Colleges of Medicine and Pharmacy, and her colleagues demonstrated changes during development of social vocalizations in mice, suggesting that some learning takes place.  In the second paper, Takefumi Kikusui from Azabu University and Kazuo Okanoya from the RIKEN Brain Science Institute, along with their colleagues conducted cross-fostering experiments that suggested that the songs are innate.

Given the two conclusions, we thought it would be interesting to find out a little bit more about the authors, their research and their opinions on each other’s research.  Drs. Grimsley, Kikusui, and Okanoya graciously agreed to answer the following questions for us via email.

First, a bit of detail on your scientific background – how did you become interested in animal behavior and evolutionary biology?

The Wenstrup Lab (from left to right) Grimsley, Anderson, Wenstrup and Gadziola

Grimsley: I am really interested in hearing research, and with the advent of midbrain auditory implants it has become increasingly important that we understand how higher order areas of the brain process complex signals, such as social vocalizations. For my PhD work at the Institute of Hearing Research in England, I compared how all eight areas of guinea pig auditory cortex respond to conspecific social vocalizations. I try to approach research from a neuroethological perspective; understanding the natural behavior of my animal model is fundamental to this. Currently, I am a postdoctoral researcher in Dr. Wenstrup’s lab at NEOUCOM, and our lab is interested in how the brain codes the meaning of social vocalizations in both mice and bats. We have recently started working with mice because of the opportunities to study genetic variants and disease models.

Authors (from left to right) Kikusui, Nakanishi and Mogi

Kikusui: I started my career with veterinary medicine when I was an undergraduate and belonged to the lab of Veterinary Ethology in the University of Tokyo. I learned a lot of animal behavior including behavioral problems in dogs and cats.  To solve the behavioral problems, we must understand the natural behavior of animals, that is, why the animals show species specific behavior (evolutionary biology, or genetic traits) and how the animals adapt to the environments, especially the social experience during the neonatal period of their lives (developmental biology, or acquired traits).  Gradually, my research focus has been sifting to the two big questions, one is social cognition in animals and the other is developmental impacts on social brain functions.

Your manuscript includes several different audio recordings of the mice you were studying.  Which audio file would you consider the most important and why?

Grimsley: We have compiled a library of the most typical example of each syllable from mice at each of the ages we tested. The “virtual mouse vocal organ” that is downloadable with the paper can produce bouts of mouse song that have patterns that are appropriate for mice of different ages. We hope that this will serve as a useful tool for other scientists interested in mouse communication.

Click here for  an example of a mouse pup song

Click here for an example of an adult mouse song

Kikusui: I would recommend the first two audio files; Audio S1 represents C57BL6 song, Audio S2 represents BALB/C song. Because the readers would understand how these two strains emit different songs by these files.

Click here to listen to Audio S1

Click here to listen to Audio S2

Spectogram of song from 13 day old pup

Dr. Grimsley: In your manuscript, you suggest that mice are capable of vocal learning. Dr. Okanoya: Your team suggests that mouse songs do not involve imitative learning. At first glance, your papers seem to conflict. Can you briefly explain the differences between your studies? Could you offer some possible explanations for the different conclusions?

Grimsley: Our results don’t conflict with those of Kikusui and co-workers, because the experiments were different. In fact, both papers suggest that some elements of mouse songs are innate. However, we believe that the design of their experiments did not allow them to conclusively test whether mice are capable of vocal learning. Kakusui et al state that mice would have ample opportunity to hear adult male mating song during the period of exposure to adults (the first 21 days after birth). Since hearing onset occurs when pups are 10 days old, they believe that this allows for approximately 11 days exposure to adult song. In fact, high frequency hearing above 50 kHz (the frequencies in male mating song) does not develop in mice until they are older than 14 days. So the pups may not hear adult male songs until near the end of the 21 day exposure period. In other species, e.g., songbirds, vocal learning takes place during a more extensive period of exposure to adult songs. For example, in white crowned sparrows, where vocal learning is well understood, there is a much longer critical period for juveniles to learn adult song, between 10 and 50 days old. This 40 day period occurs during a time when the birds are able to fly and are considered to be juvenile rather than chicks. A comparable time period in mice may be between weaning (age 21 days) and the onset of sexual maturity (about 40 days). No exposure to adult song was provided during this period.

Okanoya: Showing developmental changes or behavioral complexity alone cannot determine whether or not a behavior is learned. As Grimsley et al also suggested, some types of

Authors (from left to right) Nakagawa and Okanoya

sensory manipulations such as deafening or cross-fostering should be necessary. We utilized the cross-fostering procedure to indicate that mice songs do not involve imitative learning.  We think it may be necessary to define vocal learning in two types: vocal learning in the weak sense (VLW) and vocal learning in the strong sense (VLS). VLS refers to the involvement of the imitative learning, while VLW only refers to the involvement of the auditory feedback. VLS requires two steps: establishment of the auditory template for the tutor’s vocalizations and the feedback modifications of own vocalizations to match the template. VLW involves only one step: the feedback modifications of own vocalizations to match the “innate” template. While the Grimsley paper may be implying VLW but they never imply VLS. Experimental procedures used by Grimsley, while they are adequate to describe developmental changes, they do not address whether the behavior is learned or not. When we refer to vocal learning, we mean VLS, but not VLW, because human speech learning is obviously of the nature of VLS.

These two sets of experiments are a nice illustration of the complex process of scientific discovery. What have you learned from reading the other paper? Has this influenced the direction you plan to take in your own work?

Grimsley: The paper by Kakusui et al has shown some interesting strain-dependent differences in mouse song. They have also demonstrated that if there is a critical period for mice to learn song it is likely not to be before weaning at 21 days. The strong strain-dependent differences they show mean that it would be interesting to see if, behaviorally, mice are more attracted to the song from mice of their own strain.

Okanoya: As mentioned in the previous question, we feel the necessity to define vocal learning in two types. The complexity in developmental process and behavioral phenotypes as described in Grimsley paper, together with the fact that this behavior does not involve imitative learning, makes the mice vocalization an interesting preparation to study the process of unfolding of the genetically determined complex behavior.

What experiments would really answer this question of whether mouse vocalizations are innate or learned for you?

Grimsley: It would be interesting to test whether the song from a mouse with no auditory experience is different than song from a mouse with song experience. Practically, this could be

Second author of Grimsley et al. Jessica Monaghan

tested by deafening young mice prior to hearing onset and raising them with deafened parents. Raising mice with deafened parents would control for any possible factors such as behavioral feedback from the parents that might help shape their song.

Okanoya: We believe, based on our results, mice songs do not involve imitative vocal learning. In this sense, mice songs are innately determined, meaning that the under a normal developmental environment, behavioral phenotype of songs are highly stereotyped depending on the strain. In addition to our study, feedback alternation with an electric device might show the degree of auditory dependence.

What is your next big research project? Or where do you want to go from here?

Grimsley: We are using the ‘virtual mouse vocal organ’ from this study to generate bouts of mouse song to test the responses of the amygdala to social vocalizations. I am also really interested in investigating the effects of social context on the responses to these stimuli, both behaviorally and neurophysiologically.

Okanoya: We would like to know the neural mechanisms by which mice songs gain sequential variability. We suspect the involvement of the basal ganglia and the anterior cingulated cortex for this variability. Also, we would like to know how females respond to the strain differences of the songs. We are in the process of examining these questions.

Both of the manuscripts are freely available to read, comment on and rate.

Grimsley JMS, Monaghan JJM, Wenstrup JJ (2011) Development of Social Vocalizations in Mice. PLoS ONE 6(3): e17460. doi:10.1371/journal.pone.0017460

Kikusui T, Nakanishi K, Nakagawa R, Nagasawa M, Mogi K, et al. (2011) Cross Fostering Experiments Suggest That Mice Songs Are Innate. PLoS ONE 6(3): e17721. doi:10.1371/journal.pone.0017721

In this author spotlight, Georgina Ellison, a Reader at Liverpool John Moores University, answers a few questions about her team’s recently published article on how cardiac stem cells (CSCs) not only have the increased ability to replace lost heart muscle but also have a ‘paracrine’ effect on the survival of heart muscle cells.

First a bit of background – how did you become interested in Cardiac Stem Cell Biology?

During my PhD studies I discovered some small newly formed cardiomyocytes in the injured cardiac samples I was working on. Considering the accepted paradigm of the heart at that time was as a non-proliferative organ I did not think what I found was possible, therefore I contacted Professor Bernardo Nadal-Ginard, a world-leading expert in this field, and asked for his opinion on my findings.  Prof. Nadal-Ginard was very interested in what I had discovered and offered me the opportunity to come and study further in his lab in New York, using state of the art techniques and technologies and work with his team of first class experienced researchers.

In the paper you mention that there have been many types of stem cells suggested as suitable candidates for heart cell regeneration. Bone marrow derived cells (BMDCs) are one of these suggested candidates however, you suggest using cardiac stem cells instead.  Can you explain why CSCs seem to be more promising?

So far clinical trials have used bone marrow derived cells (BMDCs) for heart repair after a heart attack. However, the improvements in heart function are modest and this could be because the bone marrow cells are not the best type of cell to be used to regenerate the lost contractile heart muscle or cardiomyocytes. We show that the endogenous CSCs have potent cardiomyocyte regenerative potential and also play a paracrine role by improving cardiomyocyte survival. In the new era of regenerative medicine it is essential to ascertain the ‘optimal’ type of cell to be used for regenerative myocardial therapies and a cell that has regenerative and renewal capacity, as well as exerting pro-survival and paracrine effects would be the ideal cell of choice.

Of the videos in your manuscript, you highlighted the one above as particularly interesting. The cells in the video express high levels of GATA-4, which is an important early maker gene in cardiomyocyte development. Can you explain why this video is notable?

This video shows that even when the GATA-4 highly expressing CSCs do not have direct cell-to-cell contact with the cardiomyocytes, the cardiomyocytes’ contractility is maintained for up to 3 weeks in vitro. This has never been shown before and was not apparent when other types of cells were used, i.e. fibroblasts or GATA-4 low expressing CSCs.

What is your next big research project? Or where do you want to go from here?

Our next big research project is to establish and manufacture the optimal cardiac regenerative treatment and this regenerative therapy must be an off-the-shelf, safe, effective, simple, available to all and affordable treatment.

Why did you decide to publish in PLoS ONE?

Because it is open access and freely available online, which is how it should be nowadays. Also, it has added features such as being able to comment on papers and metrics information on papers. Altogether, these contribute greatly to the overall impact of your research, and assessing impact is now very important in biomedical research.

The paper by Ellison, Nanako Kawaguchi, Andrew J. Smith, Cheryl D. Waring, Md Kamrul Hasan, Shinka Miyamoto and Rumiko Matsuoka paper is entitled, c-kit^pos GATA-4 High Rat Cardiac Stem Cells Foster Adult Cardiomyocyte Survival through IGF-1 Paracrine Signalling. This paper is freely available to comment on, read and rate.  If you are interested in reading more about stem cell therapy research you can try searching here.