The Benefits Of Multiple Mates

New research could explain why females of many species have multiple partners. Published on Friday 21 November 2008 in leading journal Science, the study was carried out by a team from the Universities of Exeter (UK), Okayama (Japan) and Liverpool (UK).



Females of most species, including many mammals, mate with multiple partners. The driving forces for this practice, known as 'polyandry', have been a mystery for evolutionary biologists for decades. This research suggests that polyandry could be the result of females adapting to avoid producing offspring carrying selfish genetic elements that reduce male fertility.



The research team based the study on the fruitfly Drosophila pseudoobscura, which they bred over ten generations. Some males of this species carry a 'selfish gene' on their X chromosome that causes sperm carrying the Y-chromosome to fail. This means that males carrying this gene can only produce daughters, all of which carry the sperm damaging gene.



In this study females evolved to mate with more partners when they were exposed to males carrying this selfish gene. There was no way for the females to tell whether or not a potential mate carried the gene, but they evolved to re-mate more quickly. After ten generations, they re-mated after an average of 2.75 days, compared with 3.25 days among the original population. By mating more frequently, females ensure sperm from different males compete. This competition favours males without the sperm-damaging selfish genes, allowing females to bias paternity against these males.



Corresponding author Dr Nina Wedell of the University of Exeter said: "Multiple mating by females has puzzled biologists for decades. It's more risky and costs precious time and energy for females. Our study suggests that these significant costs are worthwhile because the female increases her chances of producing healthy offspring of both sexes that do not carry the selfish gene."



Selfish genes occur at random as a result of mutations. They spread quickly through populations because they subvert normal patterns of inheritance, increasing their presence in the next generation.



The researchers believe the findings have relevance for a range of species with polyandrous females, including some primates. Dr Nina Wedell explains: "Selfish genetic elements exist in all living organisms and many compromise male fertility. Our study could provide a new explanation for why polyandry is so remarkably widespread."



At this stage the researchers do not know what implications these findings might have for understanding human reproduction. However, it is possible that some types of male fertility disorder are caused by the manipulation of selfish genes.







This study was funded by the Natural Environment Research Council.



Source: Sarah Hoyle


University of Exeter

Commercial Sense And Sensor Abilities From DegraSense Ltd.

A new company, DegraSense Ltd, has been established to develop a point of care dental diagnostic that could improve the treatment of periodontal disease and other inflammatory conditions.



The new Queen Mary spin out aims to commercialise novel protease biosensor technology developed from the research activities of Dr Steffi Krause from the School of Engineering and Materials Science, and Dr Mike Watkinson from the School of Biological and Chemical Sciences.



Drs Krause and Watkinson believe there are potential applications for the biosensor technology in a range of industries including environmental and food testing, but they will initially focus on developing a non-invasive sensor capable of monitoring inflammation and bacterial infection. The initial application will be the diagnosis and treatment of periodontal disease, estimated to cost the NHS ВЈ250 million per year.



There are currently no accurate clinical methods for dentists to distinguish between active and dormant sites in periodontal disease progression. DegraSense plans to develop a low cost, disposable biosensor that will enable a dentist to identify areas of active inflammation immediately prior to treatment. This will enable more efficient targeting of expensive and labour intensive surgical treatment for patients with gum disease.



Dr Krause, who has been appointed founder Director of the new company said: "This is a new and exciting prospect. It brings together a number of years of research and the involvement of industrial partners so we can push forward towards a product that can make a real difference to dental treatment everywhere. The diagnosis of periodontal disease should reduce the incidences of invasive and uncomfortable dental procedures to the patient and at the same time should bring significant savings both to the patient and the health care provider."






Queen Mary, University of London



Queen Mary is one of the leading colleges in the federal University of London, with over 13,000 undergraduate and postgraduate students, and an academic and support staff of around 2,600. Queen Mary is a research university, with over 80 per cent of research staff working in departments where research is of international or national excellence (RAE 2001). It has a strong international reputation, with around 20 per cent of students coming from over 100 countries.



The College has 21 academic departments and institutes organised into three sectors: Science and Engineering; Humanities, Social Sciences and Laws; and the School of Medicine and Dentistry. It has an annual turnover of ВЈ200 million, research income worth ВЈ43 million, and it generates employment and output worth nearly ВЈ400 million to the UK economy each year.



Queen Mary's roots lie in four historic colleges: Queen Mary College, Westfield College, St Bartholomew's Hospital Medical College and the London Hospital Medical College.



Source: Sian Halkyard


Queen Mary, University of London

Biological Clue In Brain Tumour Development

Scientists at The University of Nottingham have uncovered a vital new biological clue that could lead to more effective treatments for a children's brain tumour that currently kills more than 60 per cent of young sufferers.



Clinician-scientists at the University's Children's Brain Tumour Research Centre, working on behalf of the Children's Cancer and Leukaemia Group (CCLG), have studied the role of the WNT biological pathway in central nervous system primitive neuroectodermal tumours (CNS PNET), a type of brain tumour that predominantly occurs in children and presently has a very poor prognosis.



In a paper published in the British Journal of Cancer, they have shown that in over one-third of cases, the pathway is 'activated', suggesting that it plays a role in tumour development. The research also highlighted a link between WNT pathway activation and patient survival - patients who had a CNS PNET tumour that was activated survived for longer than those without pathway activation.



The reason for the link between WNT pathway activation and better patient prognosis is as yet unclear. It could be that these tumours represent a less aggressive subset or that pathway activation itself actually harms the tumour. However, the pathway could represent an important new target for the treatment of more effective drugs, with fewer side effects.



Senior author Professor Richard Grundy, from the Children's Brain Tumour Research Centre, said: "The principal aim of our research is to reduce the morbidity and mortality of children with central nervous system tumours through improved understanding of tumour biology. Following on from this, we need to translate this knowledge into effective new treatments for brain tumours through the development and assessment of accurately targeted treatments that will cause fewer side effects than conventional chemotherapy or radiotherapy and be more effective. The ultimate aim is to develop 'drugs' that target just the abnormal genes in cancer cells, rather than the current norm which involves the indiscriminate destruction of dividing cells which might be healthy or malignant. Overall, this is an important finding in a poorly understood, poor prognosis disease, which we hope, in time, will lead to the development of new treatments for CNS PNETs.



"We hope our findings will lead to a more detailed understanding of CNS PNETS, which is crucial if we are to ensure each child receives the most appropriate treatment for their disease and that we reduce the number of children in which their cancer recurs."



In total, around 450 children and young adults under 18 years are diagnosed with a brain tumour each year in the UK. Overall, 60 per cent of children with the cancer in the UK can be successfully treated, but survival for CNS PNETs is less than 40 per cent.



Notes:



Funding was provided by the Connie and Albert Taylor Trust, The Samantha Dickson Brain Tumour Trust, the Brain Tumour Research Fund Birmingham Children's Hospital Special Trustees.















The paper, An Investigation of WNT Pathway Activation and Association with Survival in Central Nervous System Primitive Neuroectodermal Tumours (CNS PNET) by HA Rogers, S Miller, J Lowe, M-A Brundler, B Coyle and RG Grundy is published in the latest edition of the British Journal of Cancer.



About the Children's Cancer and Leukaemia Group



Cancer Research UK is the major funding provider of the Children's Cancer and Leukaemia Group and funds the UK clinical trials work of the group in 21 paediatric centres throughout the British Isles. The Children's Cancer and Leukaemia Group is the national professional body responsible for the organisation, treatment and management of virtually all children with cancer in the UK. The group is acknowledged as one of the world's leading childhood cancer clinical trial groups who have made a significant contribution to the international success in treating childhood cancer, resulting in improvements in survival.



British Journal of Cancer



The BJC is owned by Cancer Research UK. Its mission is to encourage communication of the very best cancer research from laboratories and clinics in all countries. Broad coverage, its editorial independence and consistent high standards have made BJC one of the world's premier general cancer journals. bjcancer.



The University of Nottingham



The University of Nottingham is ranked in the UK's Top 10 and the World's Top 100 universities by the Shanghai Jiao Tong (SJTU) and Times Higher (THE) World University Rankings.



More than 90 per cent of research at The University of Nottingham is of international quality, according to RAE 2008, with almost 60 per cent of all research defined as 'world-leading' or 'internationally excellent'. Research Fortnight analysis of RAE 2008 ranks the University 7th in the UK by research power. In 27 subject areas, the University features in the UK Top Ten, with 14 of those in the Top Five.



The University provides innovative and top quality teaching, undertakes world-changing research, and attracts talented staff and students from 150 nations. Described by The Times as Britain's 'only truly global university', it has invested continuously in award-winning campuses in the United Kingdom, China and Malaysia. Twice since 2003 its research and teaching academics have won Nobel Prizes. The University has won the Queen's Award for Enterprise in both 2006 (International Trade) and 2007 (Innovation - School of Pharmacy), and was named 'Entrepreneurial University of the Year' at the Times Higher Education Awards 2008.



Nottingham was designated as a Science City in 2005 in recognition of its rich scientific heritage, industrial base and role as a leading research centre. Nottingham has since embarked on a wide range of business, property, knowledge transfer and educational initiatives (science-city) in order to build on its growing reputation as an international centre of scientific excellence. The University of Nottingham is a partner in Nottingham: the Science City.



Source: Emma Thorne


University of Nottingham

The Shapes of Life: NIGMS Project Yields More Than 1,000 Protein Structures

The Protein Structure Initiative (PSI), a national program aimed at determining the three-dimensional shapes of a wide
range of proteins, has now determined more than 1,000 different structures. These structures will shed light on how proteins
function in many life processes and could lead to targets for the development of new medicines.



The PSI is a 10-year, approximately $600 million project funded largely by the National Institute of General Medical Sciences
(NIGMS), part of the National Institutes of Health. The first half of this project-a pilot phase that started in 2000-has
centered on developing new tools and processes that enable researchers to quickly, cheaply, and reliably determine the shapes
of many proteins found in nature.



"One thousand protein structures is a significant milestone for the PSI, and it shows an impressive return on the investment
in the technology and methods for rapid structure determination," said Jeremy M. Berg, Ph.D., director of NIGMS. "These
structures are interesting in their own right and provide the basis for modeling many important proteins."



Some of the newly determined structures are of proteins found in plants, mice, yeast, and bacteria, including the pathogenic
types that cause pneumonia, anthrax, and tuberculosis.



The nine PSI pilot centers have transformed protein structure determination from a mostly manual process to a highly
automated one. Robotic instruments rapidly clone, express, purify, crystallize, and analyze many proteins simultaneously,
cutting the time it takes to determine a single protein structure from months to days. For example, a robotic arm drops
protein solution into thousands of tiny wells for crystallization trials, and an imaging system quickly scans the wells
looking for signs of crystal formation-key to capturing protein structures.



"At this large scale, it would be unthinkable to do all these steps by hand," said John Norvell, Ph.D., director of the PSI
at NIGMS and a scientist trained in protein structure determination. He noted that some robotics and automated tools have
been refined and are now marketed by companies for general structural biology applications.



As the PSI pilot centers have put automated structure determination pipelines in place, the number of protein structures they
have solved has increased significantly. In the second, third, and fourth years of the pilot phase, the centers in aggregate
reported 109, 217, and 348 structures, respectively. Now, halfway through the fifth year, they've surpassed a total of 1,000.
Many of these structures are very different from previously known structures, said Norvell.



The findings contribute to the initiative's ultimate goal of providing structural information on 4,000-6,000 unique proteins
that represent the variety found in organisms ranging from bacteria to humans. Researchers can use these structures, which
are determined experimentally, to build computer models of the structures of other proteins with related amino acid
sequences.
















Although the main focus of the second phase of the PSI will be on solving protein structures, Norvell said there will be
continued development of new technology: "As we reach for higher-hanging fruit-protein structures that are more complex and
harder to solve-we will need to develop additional tools and methods."



As part of the PSI effort, all the structures determined by the centers are collected, stored, and made publicly available by
the Protein Data Bank (PDB), rcsb/pdb, a repository of
three-dimensional biological structure data.



"The protein structures solved by the PSI are more than a scientific stamp collection," explained Norvell. "They will help
researchers better understand the function of proteins, predict the shape of unknown proteins, quickly identify targets for
drug development, and compare protein structures from normal and diseased tissues." In general, a broad range of biomedical
researchers will benefit from the PSI's technical advances, experimental data, and availability of new materials, such as
reagents.



"There are a lot of proteins that are incredibly important to understanding human biology and medicine, yet we know very
little about most of them," said Norvell. "The PSI will provide important information about these molecules so vital to
life."



The nine pilot centers participating in the first phase of the PSI are:


-- The Berkeley Structural Genomics Center, strgen


-- The Center for Eukaryotic Structural Genomics, uwstructuralgenomics


-- The Joint Center for Structural Genomics, jcsg


-- The Midwest Center for Structural Genomics, mcsg.anl


-- The New York Structural Genomics Research Consortium, nysgrc


-- The Northeast Structural Genomics Consortium, nesg


-- The Southeast Collaboratory for Structural Genomics, secsg


-- The Structural Genomics of Pathogenic Protozoa Consortium, sgpp


-- The TB Structural Genomics Consortium, doe-mbi.ucla/TB


The pilot phase of the PSI will end in mid-2005. Centers for the second phase will be announced in July 2005.



In addition to NIGMS, the PSI currently receives funding from the National Institute of Allergy and Infectious Diseases, a
component of the National Institutes of Health.



For more information about the PSI, please visit nigms.nih/psi. To schedule an interview with Jeremy M. Berg, Ph.D., or John Norvell,
Ph.D., please contact the NIGMS Office of Communications and Public Liaison at 301-496-7301.



NIGMS is one of the 27 components of NIH, the premier federal agency for biomedical research. The NIGMS mission is to support
basic biomedical research that lays the foundation for advances in disease diagnosis, treatment and prevention.


Emily Carlson - carlsonenigms.nih

NIH/National Institute of General Medical Sciences

Neurons That Control Obesity In Fruit Flies Pinpointed By Caltech Researchers

A team of scientists from the California Institute of Technology (Caltech) have pinpointed two groups of neurons in fruit fly brains that have the ability to sense and manipulate the fly's fat stores in much the same way as do neurons in the mammalian brain. The existence of this sort of control over fat deposition and metabolic rates makes the flies a potentially useful model for the study of human obesity, the researchers note.



Their findings were published in the August 13 issue of the journal Neuron.



By manipulating neural activity in fruit fly brains using transgenic techniques, the researchers found that, "just as in mammals, fly fat-store levels are measured and controlled by specific neurons in the brain," says Caltech postdoctoral scholar Bader Al-Anzi, the Neuron paper's first author. "Silencing these neurons created obese flies, while overactivating them produced lean flies."



Mammalian brains are given information about the body's fat stores by hormones such as leptin and insulin, and respond to that information by inducing changes in food intake and metabolism to maintain a constant body weight. The researchers found that similar behavioral and metabolic changes occurred in the fruit flies, though which changes occurred depended on which of the two sets of newly identified neurons was silenced.



For instance, silencing one group of neurons led to an increase in food intake, a decrease in metabolism, and an increase in the synthesis of fatty acids (the building blocks of fat). Silencing the other group led to a similar decrease in metabolism and increase in fatty-acid synthesis, as well as to a defect in the flies' ability to utilize their fat stores.



Increasing activity in either of the groups of neurons, on the other hand, resulted in depletion of fat stores by increasing the flies' metabolism and decreasing their synthesis of fatty acids.



The next step is to "see exactly how neurons regulate fat storage, and how the two different groups of neurons identified in this study work," says Kai Zinn, professor of biology at Caltech, who led the research group. "They clearly regulate fat storage using different mechanisms."



The paper is the result of research originally led by Caltech biologist Seymour Benzer, a pioneer in the study of genes and behavior. Zinn continued this research after Benzer's death in late 2007.



"The goal was to establish a model system for obesity in humans," Zinn explains. "This could, at some point, eventually define new drug targets."



The search for a model system is critical, adds Al-Anzi. With obesity on the rise - statistics say that more than a third of adults in Western society are overweight - efforts to find its roots in human brains or human genes have similarly increased. Unfortunately, Al-Anzi notes, these efforts "have not been extremely successful."
















In addition, says Al-Anzi, "While mammalian models such as the mouse have provided progress in the field, they tend to be difficult and expensive research subjects."



Thus, he notes, "The obesity research field would benefit greatly if another model organism could be used, one that is accessible for easy, fast, and affordable biomedical research methods. We believe the fruit fly can be such an organism.



"There is a surprising amount of overlap between the simple fruit fly and more complex mammals in many basic biological processes," Al-Anzi adds. "This is why it's an excellent model system for exploring such medically relevant issues as Alzheimer's disease, alcoholism, and addiction. Our results thus far suggest that body-weight regulation will be no different."



Having now established that fruit flies are indeed similar to mammals in the way they control fat deposition via the brain, researchers can begin to test antiobesity dietary or drug treatments on flies whose fat-regulating neurons have been silenced. "Treatments that cause these flies to return to normal body weight could then be retested for their effectiveness in a mammalian obesity model," Al-Anzi notes.



Knowing the neurons involved in the regulation of fat storage could also lead to identifying the genes that allow for the critical communications between the brain and the fat stores. "This can be done by identifying the genes that are selectively expressed only in those neurons," he explains.



In addition, this research should help researchers determine if the mechanisms behind appetite and body-weight regulation in fruit flies have been conserved over evolutionary time and throughout the animal kingdom. "This has been shown to be the case for genes that regulate behavioral phenomena like learning and circadian rhythms," notes Al-Anzi, "and we hope that body-weight and appetite regulation will be no different."



In addition to Al-Anzi, Zinn, and Benzer, other authors on the Neuron paper, "Obesity-blocking neurons in Drosophila," include Caltech research technician Viveca Sapin; Christopher Waters, formerly of Caltech; and biologist Robert Wyman from Yale University.



Their research was supported by a Life Sciences Research Foundation grant provided by Bristol-Myers Squibb to Al-Anzi, and by a National Institutes of Health RO1 grant to Benzer.



Source:
Lori Oliwenstein


California Institute of Technology

Rice, Iowa state biologists search for 'half-fusion'

Every living cell is surrounded by a membrane, a thin barrier that separates the genetic machinery of life from the
non-living world outside. Though barriers, membranes are not impervious. Cells use a complex hierarchy of proteins that work
in concert to allow cell membranes to fuse - with other cells or with membrane-encased packages of proteins and other
chemicals that the cell needs to take in or release.


Though well-studied, the molecular details of membrane fusion remain mysterious. In particular, scientists don't understand
how holes form between two membranes, but a new study by biochemists at Rice University and Iowa State University offers
intriguing new clues about the nature of this process. The study is published in this month's issue of Nature Structural and
Molecular Biology.


"Membrane fusion is one of the most basic processes of life," said James McNew, assistant professor of biochemistry and cell
biology at Rice University. "It begins at fertilization and occurs billions of times a second in our bodies, and if it ever
stops, we die."


For example, inside the cells in our brains, spines and nerves, membranes are used to seal up and transport tiny packets of
signaling chemicals from the center of the cell to the outer cell membrane. These packets, or vesicles, wait just inside the
cell membrane for the appropriate signal, and once they receive it, they fuse with the membrane and eject their contents into
the surrounding tissue, causing an immediate chain reaction that keeps our hearts beating and allows us to move our muscles.
Membrane fusion is also used to initiate disease.


"Some invading organisms like enveloped viruses use the fusion process to infect the cell," McNew said.


To understand membrane fusion, it helps to envision the basic structure of membranes. Just five billionths of meter across,
membranes are bilayers, meaning they contain two separate layers, or sheets of fatty acids. Each of these sheets has a one
side that is strongly attracted to water and one side that strongly repels it. The water-hating sides of the sheets stick
tightly to one another, sealing out water on either side of the bilayer.


Additionally, all biological membranes are dotted with proteins, and some of these are called transmembrane proteins, meaning
parts of them penetrate through the membrane like a needle through cloth. A large body of evidence suggests that a class of
transmembrane proteins called SNAREs are responsible for driving membrane fusion during normal cellular activity. Exactly how
they do this is unknown, but previous studies have suggested two possibilities.


One model proposes that the portion of the SNARE protein that crosses the membrane forms a pore-like connection that mixes
both layers of the membrane in one step. The other theory suggests that the SNARE proteins mix the two separate layers of a
membrane one at a time, generating an intermediate stated called "hemifusion" or half-fusion. During hemifusion, the outer,
water-loving sides of two membranes become connected, and the inner water-loving layers do not. In this state, the combining
cells or vesicles could transfer proteins and other material stuck to their outside layers, but they do not exchange any
material that's locked inside. Hemifusion has been observed in non-biological membranes containing no proteins, but has been
difficult to detect with SNARE proteins.


McNew and his Iowa State colleagues, Yeon-Kyun Shin, Zengliu Su, Fan Zhang and Yibin Xu, developed an ingenious method of
tagging both inner and outer portions of the synthetic membranes with fluorescent dyes so they could use fluorescence
spectroscopy to assay mixing of the inner and outer layers.


McNew and colleagues sought to find out if hemifusion was an intermediate fusion state in biological systems, so they created
a test system that contained a lipid bilayer studed with SNARE proteins taken from bakers yeast. Using both normal SNAREs and
a mutant variety, they were able to show that membrane fusion catalyzed by the SNARE machinery mixes the outer layer of the
membrane separately from the inner layer -- a hallmark of hemifusion -- suggesting that a hemifusion intermediate can exist
in biological systems and may well be the mechanism that all living cells utilize.


Preliminary data from follow-up studies indicate that these results are also generalizable to SNARE proteins from animals.



The research was funded by the National Science Foundation, the Welch Foundation and the National Institutes of Health.



CONTACTS: Jade Boyd

jadeboydrice

713-348-6778

Rice University

Mike Krapfl

mkrapfliastate

515-294-4917

Iowa State University

iastate

Molecular Memories Mark Males From Females

Medical Research Council scientists have found that males and females have different ways of remembering things.



In a test, male mice learned to avoid a dangerous situation better than females. In other tasks, there was no difference in learning performance, but there were different molecules in the brain being used to form the memories.



The work will help scientists to understand memory-related diseases, which affect the sexes to different extents.



"There's clear evidence now from our studies that at the molecular level there is a sex difference," said Professor Peter Giese, who led the study. "Our science would suggest that males and females simply use different memory processes."



Professor Giese describes his research in an MRC podcast. This work at the Institute of Psychiatry, King's College London, was supported by the MRC.



In the task, the team placed mice in a chamber and attempted to train them to avoid a potentially dangerous situation. They subjected the animals to a mild electric shock to their feet while playing them an audio signal.



Compared with females, a higher proportion of males learned to physically freeze when they were returned to the chamber and then exposed to the sound signal, associating this environment and the tone with danger. This ability to learn was absent in genetically-engineered male mice - but not female mice - which lacked a certain brain protein involved in the regulation of memory genes.



"We think that we have a window into understanding the molecular basis of sex differences in memory formation," said Professor Giese.



The protein, called CaMKK, may function abnormally in some brain diseases and cognitive disorders. This finding could help to understand why some brain diseases affect different proportions of women and men, such as Alzheimer's disease, schizophrenia and learning disabilities.



The protein CaMKK has a role in the process believed to underlie what happens in the brain when a memory is laid down and stored. This model of learning, established in 1973 by MRC-funded researcher Dr Tim Bliss at the National Institute for Medical Research (NIMR), is called long-term potentiation.



Dr Bliss said: "If long-term potentiation is the basis of memory, then one might predict that in animal models of Alzheimer's disease there should be an impairment of long-term potentiation. In many cases there is."



MRC scientists have found that mice with Down's syndrome - a symptom of which in humans is impaired learning ability - have deficits in long-term potentiation and memory. In 2005, a team at NIMR created a model of a Down's syndrome by engineering a mouse which contains an extra chromosome, the cause of the syndrome in humans, press release.



Dr Bliss said: "In most mouse models of Alzheimer's disease, there is an impairment in long-term potentiation. This is also true in models of neurodegenerative and other sorts of diseases in which memory is affected, including Down's syndrome as we recently showed."


Background


Professor Giese published his findings in the following papers:


Calcium/calmodulin kinase kinases ОІ has a male-specific role in memory formation.
Mizuno et al. (2007).
Neuroscience, 145, 393.



Sex-dependent up-regulation of two splicing factors, Psf and Srp20, during hippocampal memory formation.
Antunes-Martins et al. (2007).
Learn. Mem. 14, 693.



Ca2+/calmodulin kinase kinase О± is dispensable for brain development but is required for distinct memories in male, though not in female, mice.
Mol. Cell. Biol. 26, 9094.



The Medical Research Council funds excellent science with the aim of improving human health. Its work ranges from science at the molecular level to public health research carried out in universities, hospitals and a network of units and institutes. The MRC works closely with the Health Departments, the National Health Service and industry to take account of the public's needs. The results have led to some of the most significant discoveries in medical science and benefited millions of people in the UK and around the world.

Medical Research Council