Friday, 20 December 2013

New Europe PMC plus Watch and Claim features

Europe PMC plus provides manuscript submission and grant reporting services for authors who are funded by Europe PMC funding organisations.

The new Europe PMC plus features ‘Watch’ and ‘Claim’ allow users to monitor progress of manuscripts for which they are not a submitter and enables them to take over reviewing author duties for submissions that may have stalled during the submission process.

This may be of particular use for administrators, librarians and co-ordinators that manage Europe PMC self-submissions on behalf of their Principal Investigators and Authors.

While the features are distinct modules of Europe PMC plus they work well in conjunction with each other allowing a level of manuscript management functionality previously unavailable in Europe PMC plus.

The Watch feature
The ‘Watch’ feature allows you to monitor progress of a manuscript for which you are a not already a submitter, PI or reviewing author. Watchers can view manuscript information and submit a ‘claim request’ if the manuscript stalls.

Source: Shutterstock Copyright: Konstantinos Kokkinis

Who can ‘Watch’ a manuscript?
You can submit a ‘Watch Request’ for any manuscript that does not appear in your ‘My Manuscripts’ list. However, you must know the manuscript ID number; for manuscripts that are not yet publically available, you will be asked to verify your request by providing the manuscript and journal titles.

The Claim feature
The ‘claim’ feature allows you to take over reviewing duties if a manuscript submission stalls.

Source: Shutterstock Copyright: Tang Yan Song

Who can ‘Claim’ a manuscript?
You can only make a Claim Request for a manuscript which appears in your ‘My Manuscripts’ lists; this means that you must already be a PI, Secondary Author or Watcher (see above) for the manuscript.

Further information
Further information about the features can be found on the Europe PMC plus online User Guide.
Alternatively contact the Europe PMC Helpdesk: +44 (0)1937 546699

Post written by the Europe PMC Helpdesk Manager, Rob Rowbotham

Tuesday, 10 December 2013

Refine your search with our new advanced search functionality...

With our new advanced search functionality, you can now do more, more easily.

You can access the advanced search page here, or by clicking on the cog icon to the right of the search box.

Key features are:
  • Auto-suggest functionality on the journal, author, funder and grant ID fields
  • Article section-level searching: where you can restrict your search to specific sections of full text articles (more about this in a subsequent post)
  • Data links and citations: easily select the databases that you are interested in
  • External links: search by provider
  • Hover help (see blue question mark icons) provided for the fields.
As you use the fields to build your query, a query builder box at the top of the page (which can also be edited) displays the syntax of the search you are designing.

At ever at Europe PMC, we are very happy to hear your feedback about this new release (see the feedback button at the bottom right of the search page) and where appropriate build it into future developments to the form.

For more news about Europe PMC follow us on Twitter @EuropePMC_news.

Tuesday, 26 November 2013

Access to Understanding: The Real Prize

by Emma Pewsey
Winner, Access to Understanding 2013

This post is particularly aimed at those of you who are thinking about entering the Access to Understanding competition who have never entered a science writing competition before.

Access to Understanding is the perfect first-time competition to enter. Unlike most other science-writing competitions, you don’t need to struggle for inspiration for an interesting subject to write about – 10 fascinating papers are provided for you to interpret, so you can concentrate on the nitty-gritty of making their story sparkle.

(There’s plenty of advice online about how to get that summary sparkling. My advice? Don’t get too hung up on following it. Be original!)

Source: Shutterstock Copyright: GrandeDuc
But why should you enter? What’s in it for you?

The obvious answer is an iPad and the ability to go around for a year introducing yourself as officially the best plain English summary writer in the world. However, that’s only the start of the prizes.

For me, the greatest prize was the confidence to keep on writing. Before last year, I’d never written a plain English summary before, let alone entered any writing competitions. When I won, suddenly my vague career plan of ‘something where I get to tell people about science’ became a serious possibility. If you’re not planning on leaving research, it’s pretty satisfying to know your next funding application is going to include a knock-out plain English summary.

Source: Shutterstock Copyright: Genialbaron
So where did that confidence lead me? Well, I entered two more science writing competitions. In one of them, my entry sunk without trace, but I was shortlisted for the Wellcome Trust Science Writing Prize (where I ran into a couple of familiar faces from Access to Understanding at the awards ceremony). Now, I’m finishing up my PhD so I can start my new job as an Assistant Features Editor in a couple of months.

So even if you’ve never written anything like this before, give it a go – those prizes are well worth winning. Have fun writing and good luck!

This post is by Emma Pewsey, winner of Access to Understanding 2013. You can read her winning entry, 'Hip, Hip, Hooray!' here.

Thursday, 21 November 2013

ORCIDs in Europe PMC

Following the development of the ORCID-based Article Claiming Tool (see this blog post), Europe PMC has now integrated ORCIDs into its website, search systems, and web services. This is proving useful for authors who want to show their publications list unambiguously on the Europe PMC website, allowing them to show for each article citation counts, linked data sets, and full text availability in Europe PMC.

Currently over 425K articles in Europe PMC have been linked to 57K ORCIDs, a count that grows significantly with each update from the ORCID foundation.

ORCIDs are now shown in two ways on articles:
  1. In the article author list, when an author has linked the article to their ORCID, there is an option to search by ORCID rather than author name.
  2. As a list of ORCIDs at the end of an abstract, with the name of the author in the mouse-over. Clicking triggers a search on that ORCID
See, for example, the article that describes the initial sequence of the human genome:

ORCID-based author searching is particularly useful for people who have frequently occurring last names, or have changed their name, but also in the case of Consortium authorship, it allows scientists to claim their contribution to these works - something that name-based author searching cannot do in many cases.

For those interested in programmatic access, we have incorporated ORCIDs into the core response of the RESTful web service, linking the ORCID to specific author names as far as possible, and including a complete ORCID list for each record.

If you use the Europe PMC Article-Claiming tool and/or make your ORCID bibliography public, your ORCID will be shown in Europe PMC as described above, when there is corresponding content available. We will soon be making the associations made using the Article-claiming tool available on a more immediate basis, and welcome any further suggestions for improvement from our users. 

Follow us on Twitter: Europe PMC news and Europe PMC articles

Tuesday, 19 November 2013

Five reasons to enter Access to Understanding

We are thrilled that you are considering entering Europe PMC’s Access to Understanding science writing competition, in partnership with The British Library. If you are an early career researcher and have not already decided this competition is for you, let me remind you of a few elements that make this competition unique.

1. You will be published!
In addition to the iPad prize (and a trophy), the winner’s entry will be published in eLife, an online, open-access journal that publishes exceptional research in life sciences and biomedicine. A collaboration between the Howard Hughes Medical Institute, Max Planck Society and Wellcome Trust, eLife is changing the way scientific articles are reviewed and published, exposing readers to the review process and providing a “Digest” version of each article to summarise the findings in non-specialist terms. Having your entry published by eLife not only gives you further international recognition, but provides you with a citable journal publication! (NB. at the discretion of the judges, second and third place will also be published).

Source: Shutterstock Copyright: Heiti Paves

2. You get to summarise cutting-edge research!
This competition challenges you to summarise one of ten pre-selected research articles published in 2013, and freely available from Europe PMC. Rather than write a journalism style report of the research, we ask for a clear presentation of the research and its key findings that will engage and inform a layperson/non-specialist as to the importance of this research. We do not expect this to be an easy task, but feel the challenge is incredibly important and will allow you, as a researcher, to develop engagement and communication skills which will be useful throughout your career. The requirement that you write on pre-selected articles hopes to raise your awareness of current research being done in a variety of biomedical topics. This way, you can focus all your efforts on the writing and need not worry about picking a winning topic. It also puts you in direct competition with other scientists. Additionally, your entry, which will be read next to entries summarising the same article, will contribute to an on-going effort by the British Library Science team and Europe PMC team to better understand the important elements of a plain English summary.

3. Your work will be approved by the senior authors themselves!
Each short-listed entry will be reviewed by the senior author of the article about which the entry was written. They will confirm whether they feel their research has been accurately represented. This additional step is an exciting way to engage senior researchers. Further, it validates the scientific content of each entry.

Source: Shutterstock Copyright: ollyy

4. You are judged by experts!
Access to Understanding competition entries are targeted towards the general public. By summarising biomedical research in plain English you are making this information accessible to everybody, including those who it may directly affect. Two members of our esteemed judging panel, notably Sharon Douglas and Graham Steel, are non-scientists who represent patient advocate groups. As such, your work will be evaluated by experts with a strong understanding of what a plain English summary of research should accomplish.

5. You can familiarise yourself with the wonderful resource that is Europe PMC!
Europe PMC is a free information resource for biomedical and life science researchers. With over 2.6 million PMC full-text articles, the PubMed abstracts, as well as access to a wide range of other resources including clinical guidelines, biological patents, research grant information and data, Europe PMC will be an indispensable resource as you continue your involvement in science and research. Take the opportunity to explore the site and see how Europe PMC can work for you!
The feedback from last year’s nearly 400 entrants concluded that this competition will present a challenge, but equally, offer you an opportunity to develop or improve your writing skills. And most importantly, it will be fun! So why wouldn't you enter?

Remember, the competition closes at 16:00 GMT 10 December 2013. If you have any questions or want further information please contact We look forward to receiving your entry!

This post is by Rebecca Withers (Science Engagement Intern for Europe PMC).

To stay up-to-date with Europe PMC news you can also follow us on Twitter @EuropePMC_news

Wednesday, 13 November 2013

Science-writing competition now open!

Access to Understanding is a prestigious, international science-writing competition aimed at PhD students and early career post-doctoral researchers, developed by Europe PubMed Central and The British Library.

The winner will receive an iPad and have their entry published in eLife. Read on for more…

For more information:

Access to Understanding is supported by the Europe PubMed Central Funders Group.

Follow us on Twitter: Europe PMC news and Europe PMC articles

Monday, 11 November 2013

Hip, Hip, Hooray!

by Emma Pewsey (University of Cambridge, UK)
Winner of Access to Understanding 2013

X-rays can now be used not only to show where bones have fractured, but also to investigate why these bones break in the first place. Results suggest the possibility of preventing the trauma of thousands of broken hips using drugs already commonly used for treating osteoporosis.

Normal healthy bones can be thought of as nature’s scaffold poles. The tightly packed minerals which make up the cortical bone form a sheath around an inner core of spongy bone and provide the strength which supports our bodies. Throughout our lives, our skeletons are kept strong by the continuous creation of new, fresh bone and the destruction of old, worn out bone. Unfortunately, as we age destruction becomes faster than creation, and so the cortical layer thins, causing the bone to weaken and break more easily. In severe cases, this is known as osteoporosis. As a result, simple trips or falls which only bruise a younger patient can cause serious fractures in the elderly. However, half of elderly patients admitted to hospital with a broken hip do not suffer from osteoporosis.
Medical illustration of broken hip
Shutterstock Image ID: 158328935 Copyright: Sebastian Kaulitzki
So why do those hips break? This is a question of great importance, as hip fractures are debilitating. Repairing one requires traumatic surgery that, even if successful, may not enable a patient to regain the full mobility they had beforehand. The National Osteoporosis Society estimates that 13,800 people in the UK die every year as a direct result of hip fractures. This is over 10% of patients injured. ( Therefore, understanding how these fractures occur and acting to prevent them is vital for improving the quality and length of life of our aging population.

To better understand why hips fracture, researchers in Cambridge and Prague analysed CT scans performed on the opposite, unbroken hips of a group of elderly women admitted to Bulovka University Hospital, Prague with hip fractures. Previous studies have shown that these tend to be in a similar condition to the broken hip pre-fracture.

CT scanners are now standard pieces of equipment in most hospitals, and are used to examine organs and tissues inside the body. Essentially a rotating X-ray machine, a CT scanner takes many X-ray snapshots at different angles around a body part to produce a 3D image of its internal structure. X-rays are energetic waves of energy which are partially absorbed by the materials they pass through. The amount of absorption depends on the density of the structure encountered – denser structures, like bone, absorb more of the X-ray energy, leaving less energy to be measured by the detector on the other side. However, the resolution of the images collected by a standard hospital CT scanner is not sensitive enough to accurately determine the thickness of the cortical bone.
CT scanner
Shutterstock Image ID: 150772538 Copyright: sfam_photo
A new image processing technique has changed that. Using it, the researchers in Prague and Cambridge were able to extract information from clinical CT scans that was sensitive enough to produce coloured maps on the surface of a model hip showing the variation of cortical bone thickness in more detail than ever. Variations in thickness of only 30 microns – the size of a grain of dust – could be detected.

The results were striking. Not only did the women with fractured hips have generally thinner cortical bone than normal, but some patients also had local patches of even thinner bone. This was the case even in women who did not suffer from osteoporosis. Most importantly, the extra-thin regions were found on the femoral neck – the part of the hip bone where fractures most commonly occur. In some patients, these patches were 30% thinner than the surrounding bone, and as big as a thumbnail. These weaker points provide the ideal conditions for a crack to form and subsequently grow into a fracture. Further studies are needed to confirm whether these localised regions do act as the starting point for a fracture, but at the very least they affect the type, and hence severity, of fracture which occurs. They could also explain the mystery of spontaneous hip fracture, which accounts for 6% of hip fractures – 4000 broken hips a year in the UK, which break for no known reason.

The research team have named these local patches of thinner bone ‘focal osteoporosis’. However, despite the name it is not yet known if these areas can be strengthened using standard osteoporosis drugs, which slow down the natural destruction of bone cells. An extensive clinical trial will be needed to investigate further, but if the focal patches do respond to treatment it raises the tantalising possibility of a future where many fractures could be treated before they even form. The improvement this would have on our quality of life in our old age would be invaluable.

This entry describes research published in the following article, selected by Arthritis Research UK:

Cortical thickness mapping to identify focal osteoporosis in patients with hip fracture
PMCID: PMC3372523
Kenneth E. S. Poole, Graham M. Treece, Paul M. Mayhew, Jan Vaculík, Pavel Dungl, Martin Horák, Jan J. Štěpán, and Andrew H. Gee
PLoS One (2012) 7(6), e38466

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2013 there were 9 articles to choose from, selected by the Europe PMC funders.

The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for announcements about the competition.

Friday, 8 November 2013

Blood Vessels from Skin: The New Frontier in Tissue Engineering

By Claire Sand (King's College London, UK)
Awarded joint 2nd prize for Access to Understanding 2013

For years scientists have attempted to harness the potential of stem cells for repairing damaged blood vessels. The tendency of stem cells to cause cancer, however, has meant that progress has been limited. Now, a team from King’s College London, led by Professor Qingbo Xu, have found a way of converting skin cells into blood vessel cells, raising hopes of new and improved treatments for cardiovascular disease.
Why is this research so important?
In an age where diets are rich in fat, cholesterol and salt, smoking is prolific and people are living to an increasingly old age, our blood vessels have never been more vulnerable. Damage to the inside of our arteries (in particular an important layer of cells called endothelial cells) can lead to coronary artery disease – the main cause of death in most industrialised countries. Consequently, scientists are striving to find ways of repairing or replacing damaged blood vessels with specially engineered tissues.

Shutterstock Image ID: 159873314 Copyright: Somkiat Famkee
How are they doing this?
Traditionally, with stem cells. These have the ability to become any cell in the human body. During foetal development, embryonic stem cells take cues from the placental environment to become specialised heart or liver cells, for example. This process is known as differentiation.
The ability of stem cells to differentiate into any other cell has long been exploited by scientists, although ethical concerns and issues of immune rejection (where the body’s immune system attacks implanted cells) have seriously limited success. In 2006, a Japanese research group found a way of avoiding these issues by reprogramming (or de-differentiating) mature skin cells back into stem cells. These so-called induced pluripotent stem cells (or iPS cells) could then be re-differentiated, using specialised conditions, into a different cell type altogether. This breakthrough raised the exciting possibility of ‘personalised therapy’. Skin cells from a patient with heart failure, for example, could theoretically be reprogrammed into heart cells that could be implanted without the risk of immune rejection.
So what’s the problem?
The main problem with iPS cells is that they can cause tumours. In order to make iPS cells, specific stem cell genes must be inserted into differentiated cells, forcing them to de-differentiate back into a stem state. Unlimited self-renewal is a key feature of stem cells, and introduction of stem cell genes into mature cells can cause them to multiply uncontrollably – just like tumour cells. Unfortunately, scientists have found that implantation of iPS cells causes cancer in a worrying number of lab mice.
What has Professor Xu’s group done differently?
De-differentiation of mature cells into iPS cells normally takes four weeks. Scientists in Professor Xu’s lab noticed that after only four days, skin cells lost their original characteristics without gaining those of a stem cell. Using specialised conditions the scientists were able to manipulate these partial iPS cells into becoming endothelial cells, which form the essential inner lining of blood vessels. Through this partial de-differentiation, they were able to eliminate the stem cell stage of reprogramming – and with it, the risk of tumour formation.
Fibroblast cells (microfilaments [blue], mitochondria [red], and nuclei [yellow])
Shutterstock Image ID: 135258320 Copyright: Heiti Paves
Are artificial endothelial cells the same as normal ones?
They have the same shape and size as endothelial cells, and contain the same unique genes. Importantly, they don’t have any of the characteristics specific to stem cells or the original skin cells, and can be used to generate artificial blood vessels in a biological simulator.
Crucially, the scientists had to test whether their endothelial cells can contribute to blood vessel repair in the body. They injected specially dyed cells into the legs of mice with artificially damaged arteries, and found that this greatly improved blood flow in the damaged legs. When the blood vessels were later dissected, the scientists found that they contained a high proportion of dyed cells. This suggests that the lab-made endothelial cells can combine with damaged tissues, and contribute to their repair. Importantly, none of the mice injected with these cells developed cancer in the time it normally takes tumours to appear.
Where will this lead?
In the relatively near future, lab-made cells and blood vessels will be a valuable resource for drug toxicity screening. Being of human origin, these cells and tissues are particularly relevant to human medicine, and could significantly reduce, if not replace, the use of lab animals for such testing. By using partially de-differentiated cells rather than stem cells, the scientists have also greatly reduced the time it takes to obtain viable endothelial cells, making the technique more practical to use in patients. ‘Personalised transplantation’ is still a long way off, and more safety assessments are needed. Nonetheless, in overcoming the problem of tumour formation, this team from King’s College London have brought blood vessel engineering one step further on the route from the lab to the clinic.

This entry describes research published in the following article, selected by the British Heart Foundation:

PMCID: PMC3427074
Andriana Margariti, Bernhard Winkler, Eirini Karamariti, Anna Zampetaki, Tsung-neng Tsai, Dilair Baban, Jiannis Ragoussis, Yi Huang, Jing-Dong J. Han, Lingfang Zeng, Yanhua Hu, and Qingbo Xu
Proc. Natl. Acad. Sci. USA (2012) 109(34), 13793-13798

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2013 there were 9 articles to choose from, selected by the Europe PMC funders.

The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for announcements about the competition.

Wednesday, 6 November 2013

Another brick in the wall

By Ian Le Guillou (University of Cambridge, UK)
Awarded joint 2nd prize for Access to Understanding 2013

A mutation that allows cells to grow out of control could also provide a new way to target and destroy cancer cells. This potential Achilles' heel comes from a mutation in a gene called PTEN, which is found in a wide range of cancers.

PTEN is one of many tumour suppressor genes that we have to prevent our cells from growing out of control. If the PTEN gene stops working because of a mutation, it can cause tumours to develop – indeed many tumours have a mutated form of PTEN. However when a door closes, a window opens: the PTEN mutation helps the tumour to grow, but it could also mark it out as a target.

3D-rendered illustration of cancer cells
Shutterstock Image ID: 159517493 Copyright: xrender

Researchers from the Institute of Cancer Research, London, found that switching off another gene known as NLK killed tumour cells that had the PTEN mutation. This makes NLK a good target for drug developers to create a new cancer treatment.

The difficult thing about cancer is that it is made of us – our own cells mutate and grow wildly out control. That means it is unlikely there will ever be a quick fix. Antibiotics work efficiently because bacteria are so different to us that we can develop drugs that target their weaknesses yet barely affect our own cells. But how do you kill something that is the same as you? Current treatments for cancer cause a lot of side-effects in patients because as they try to kill the cancer they also do damage everything else in the body. This is why finding ways to target cancer specifically is so important.

There are several proteins in our cells which we cannot live without, and if the genes responsible for producing those proteins are mutated or switched off the cells die. Targeting these proteins and genes are rarely going to be useful for treatments, as they will kill the patient about as quickly as they kill the cancer. So Alan Ashworth and colleagues set out to find proteins that are not essential in healthy cells, but cells with the PTEN mutation cannot live without. This would pave the way for designing drugs that target the tumour and leave healthy cells alone.

The researchers took samples of tumour cells with and without the mutation, and switched off genes for important proteins that are used for regulating lots of processes in the cell. To do this they used small molecules of RNA (DNA's less famous cousin) which interfere with the processes of specific genes. This is why these molecules are known as small interfering RNA (or siRNA). They block the chain of events that allow a gene to produce a protein, effectively switching it off. By switching off 779 genes individually, they could look for ones where cells with the PTEN mutation died and cells without the mutation survived.

Dividing cancer cells
Shutterstock Image ID: 158445182 Copyright: Juan Gaertner

This is how the researchers discovered the powerful effect of switching off the NLK gene. They are not certain how this works but it appears to protect a protein called FOXO1 that can act as a backup tumour suppressor and cause the cancer cell to die. When PTEN is mutated, the FOXO1 protein becomes vulnerable to a process called phosphorylation, which means it is ejected from the cell nucleus and destroyed. NLK is one of the proteins that phosphorylates FOXO1 and so by switching off the NLK gene, FOXO1 is able to do its job.

This is just the start of a long journey from the lab to (potentially) the hospital. The researchers have shown that targeting NLK is more likely to kill mutated cells than normal cells, but that does not mean it is safe. NLK still has a role to play in healthy cells and preventing it from working is likely to have side-effects, but it could be worthwhile if this approach can kill tumours. The next stage is to develop a drug to stop the NLK protein from working, so that it can be tested further in cells and in living organisms.

Promising leads against cancer appear often, yet very few ever make it as treatments. One big hurdle is making it through clinical trials; the new drug has to be better than currently available treatments. Targeting NLK would only work against cancers with the PTEN mutation, but now we can use the mutation as a marker to find out which patients that applies to. We are now in the age of personalised medicine, where we can have 100 different treatments for 100 different people with 100 different cancers. Gradually, we are finding ways to attack cancer in whichever form it appears and build up our range of treatments. The weaknesses that we find are not going to cure all cancers but each one provides another brick in the wall.

This entry describes research published in the following article, selected by Breakthrough breast cancer:

PMCID: PMC3483146
Ana M. Mendes-Pereira, Christopher J. Lord, and Alan Ashworth PLoS One (2012) 7(10) e47249

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2013 there were 9 articles to choose from, selected by the Europe PMC funders.

The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for announcements about the competition.

Monday, 4 November 2013

A window into brain disease is only skin deep

by Nina Rzechorzek (University of Edinburgh, UK)
Short-listed for Access to Understanding 2013

How do nerve cells die?

Many human diseases involve degeneration of the nervous system – a system of interconnecting nerve cells, allowing us to sense and respond to our environment. All of these disorders are incurable and fatal. Most of them share a common feature – aggregation of abnormal protein within nerve cells. One such protein is TDP-43 which accumulates in some dementias and disorders that affect motor neurones – the nerve cells that tell our muscles to contract. In a small number of families, motor neurone disease is inherited because the gene that produces TDP-43 is faulty. This confirms that TDP-43 is important in the disease process. It does not explain how changes in this protein cause nerve cell death.
Disease models, using animals or generic cells in a dish, do not mirror the human condition and need artificially increased protein levels to show an effect. To overcome these issues, the researchers in this study used a cutting-edge technique. It is now possible to take a skin sample from a patient, place the skin cells in a dish, and “re-program” them into stem cells. Stem cells can become any cell type in the body. They can be multiplied and ‘instructed’ to make motor neurones by exposing them to a few agents. If the donor patient has a faulty TDP-43 gene, all the neurones made from that patient’s skin will have faulty TDP-43 protein – at the relevant quantity. Skin samples from one such patient and two healthy humans were collected and reprogrammed.

3D stylised neurone image
Shutterstock Image ID: 85545598 Copyright: Andrii Muzyka

Testing the kit
First, the researchers checked the reprogramming had worked, and that the faulty gene was present in the stem cells made from the patient. They confirmed that motor neurones could be generated from all samples by showing they contained a specific combination of proteins. Mature nerve cells carry electrical messages, which they transform into chemical messages to communicate with other cells. Electrical messages are created when ‘gates’ in the membrane surrounding the cell are opened and closed. The gates control the movement of charged particles into and out of the cell. Different gates permit passage of different particles, thus producing different messages. The messages can be recorded whilst blocking each type of gate in turn. In this way, the investigators demonstrated that all of the nerve cells were equipped with motor neurone gates. The gates were operating correctly.

So the faulty gene did not affect the maturation and basic function of the neurones in this study. It did however cause an increase in the level of TDP-43 protein within the cells, and some of this protein was abnormal. All proteins have natural ‘shelf-life’; old proteins must be degraded and replaced with new ones. The workers showed that the healthy and diseased neurones were producing the same amount of TDP-43. This suggested a problem of waste-disposal; either the cell recycling machinery was impaired, or it could not break down abnormal TDP-43. The faulty neurones were also nearly four times more likely to die than the healthy neurones. When a survival system within the neurones was inhibited, the healthy neurones coped better than the diseased ones. Together these findings indicated that the patient neurones were more fragile, because they contained abnormal and increased amounts of TDP-43.

An answer in the palm of your hand
Like baking bread, just four ingredients are needed to turn skin cells into stem cells. This stem cell ‘dough’ can be moulded into any cell type of choice, for any body system (e.g. the nervous system). A few more ingredients give these cells a regional identity within that body system (e.g. motor neurone). In the right environment, cells will develop a ‘native language’ so they can interact with their neighbours and perform the roles expected of them, within their cellular community. The motor neurones here had all the tools to carry out their function, but they lacked material to work on (i.e. muscle). The techniques above could be used to make muscle cells and grow them with motor neurones – the dough can always be remoulded.

Although samples came from only one patient, this paper proves that some aspects of this patient’s disease can be modelled in a dish. This concept could be extended to any other disease resulting from a faulty gene. By comparing patient samples with those from people with a normal version of the gene we can understand better how the disease develops. There are many ways in which one abnormal protein might lead to cell death – consider the endless routes that could get you from one station to another on the underground. But every route offers a further opportunity to intercept, delay, or reverse the disease process. If we discover how to treat the disease in a dish, we can make headway in treating the patient.

This entry describes research published in the following article, selected by the Motor Neurone Disease Association:

Mutant induced pluripotent stemcell lines recapitulate aspects of TDP-43 proteinopathies and revealcell-specific vulnerability
Bilada Bilican, Andrea Serio, Sami J. Barmada, Agnes Lumi Nishimura, Gareth J. Sullivan, Monica Carrasco, Hemali P. Phatnani, Clare A. Puddifoot, David Story, Judy Fletcher, In-Hyun Park, Brad A. Friedman, George Q. Daley, David J. A. Wyllie, Giles E. Hardingham, Ian Wilmut, Steven Finkbeiner, Tom Maniatis, Christopher E. Shaw, and Siddharthan Chandran
Proc. Natl. Acad. Sci. USA (2012)109(15), 5803–5808

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2013 there were 9 articles to choose from, selected by the Europe PMC funders.

The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for announcements about the competition.

Sunday, 3 November 2013

Pregnancy complications expose future disease risk

by Gráinne Long (MRC Epidemiology Unit, Cambridge, UK)
Short-listed for Access to Understanding 2013

Cardiovascular disease (CVD) describes any disease that affects the heart or blood vessels, and is currently the leading cause of death in women world-wide. Now complications during pregnancy can be used as an early indicator to identify women at high risk of future cardiovascular disease. Pregnancy provides a window into early adult female health, which can flag women at high risk of future ill health and may allow treatments to be targeted early to those who need it most. In this way CVD could be delayed or even prevented, suggest researchers who have looked at the relationship between pregnancy complications and future disease.

Shutterstock Image ID: 158482958 Copyright: Coffeemill

Earlier studies support a link between common complications during pregnancy and increased risk of CVD in later life. Women with a history of pregnancy related diabetes or pregnancy hypertension, pre-term delivery (i.e. before 37 weeks), or those bearing a low or high birth weight child, are more likely to develop future CVD. But whether these four complications independently predict risk of future disease, or whether one or a combination of pregnancy complications are better predictors of future health is unclear. For example, are a mother’s chances of developing future heart disease best predicted by a history of a specific complication, say pregnancy diabetes, or by a combination of complications, such as pregnancy diabetes and hypertension? This is important to figure out in order to establish whether similar pathways to CVD exist, which may provide opportunities to treat and stop disease.

Paths to disease
Debbie Lawlor and colleagues at the University of Bristol and University of Glasgow got around these pitfalls by studying the effects of all four pregnancy complications together on a range of CVD risk factors. CVD risk factors are known indicators of future increased CVD risk and include high blood glucose, insulin and fatty materials. Lawlor’s team looked at the pregnancy history of a large population of 3,416 mothers who also had key CVD risk factors measured an average of 18 years after pregnancy. Using statistical tools, a range of factors, or confounders, that could be alternative explanations for the link between pregnancy complications and CVD risk were also taken into account by Lawlor’s team; namely smoking, a mother’s education level and body mass. For example, smoking during pregnancy can increase CVD risk and also lead to a low birth weight child. So, taking smoking and other important confounders into account, allows true associations to be separated from those that are false.

Of the four pregnancy complications examined, pregnancy diabetes and hypertension were the best independent predictors of future CVD risk. Mothers with a history of pregnancy diabetes, were more likely to have raised blood glucose and insulin compared to healthy mothers some 18 years after pregnancy. Women with a history of pregnancy hypertension had a higher chance of having increased insulin and unhealthy fat (cholesterol and triglycerides) later in life, compared to their healthy counterparts. These associations did not change when statistical tools took account of all pregnancy complications and important confounders together, suggesting both pregnancy diabetes and hypertension are independent risk factors for CVD. The fact that different CVD risk factors associated with pregnancy diabetes as against hypertension, also suggests that there are different disease pathways linking these two pregnancy complications to CVD.

Human heart inside human x-ray body isolated on white background
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What about the effect of pregnancy complications on future CVD, rather than simply CVD risk factor levels? As the actual rate of CVD in this population was low, reflecting the relatively young age of the women, a well known ‘scoring system’ was used to estimate future CVD risk based on all the measured CVD risk factors combined. Using this approach Lawlor’s team found that, compared to healthy women, those suffering from pregnancy diabetes or pregnancy hypertension are 23% and 27% more likely to have a CVD event in the next 10 years, respectively. These findings held even when all pregnancy complications and confounders were taken into account together, further supporting a role for both complications as important predictors of future CVD risk.

Pregnant promises
“The stress test of pregnancy provides a glimpse into the otherwise silent early adult years in which chronic disease trajectories are set”, says Ellen Seely1 who specialises in cardiovascular diseases in women at Harvard. She says further investigation into the contribution of pregnancy complications to CVD is needed to fully understand, and benefit from, the early warning system pregnancy provides for predicting future health. Opportunities to screen during pregnancy and intervene in high risk women early to slow or stop disease progression could be on the horizon.

1Rich-Edwards, J. W., McElrath, T., McElrath, T., Karumanchi, A. and Seely, E. W. Breathing life into the lifecourse approach:Pregnancy history and cardiovascular disease in women. Hypertension (2010) 56(3), 331–334

This entry describes research published in the following article, selected by the Medical Research Council:

Associations of pregnancy complications with calculated CVD risk and cardiovascular risk factors in middle age: The Avon Longitudinal Study of Parents and Children
Abigail Fraser, Scott M. Nelson, Corrie Macdonald-Wallis, Lynne Cherry, Elaine Butler, Naveed Sattar, and Debbie A. Lawlor
Circulation (2012) 125(11), 1367–1380

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