What makes a human different from a chimp?  Researchers from the European Molecular Biology Laboratory’s European Bioinformatics Institute [EMBL-EBI] have come one important step closer to answering such evolutionary questions correctly.  In the current issue of Science they uncover systematic errors in existing methods that compare genetic sequences of different species to learn about their evolutionary relationships.  They present a new computational tool that avoids these errors and provides accurate insights into the evolution of DNA and protein sequences.  The results challenge our understanding of how evolution happens and suggest that sequence turnover is much more common than assumed.

“Evolution is happening so slowly that we cannot study it by simply watching it.  That’s why we learn about the relationships between species and the course and mechanism of evolution by comparing genetic sequences,” says Nick Goldman, group leader at EMBL-EBI.

The four letter code that constitutes the DNA of all living things changes over time; for example individual or several letters can be copied incorrectly [substitution], lost [deletion] or gained [insertion].  Such changes can lead to functional and structural changes in genes and proteins and ultimately to the formation of new species.  Reconstructing the history of these mutation events reveals the course of evolution.

A comparison of multiple sequences starts with their alignment.  Characters in different sequences that share common ancestry are matched and gains and losses of characters are marked as gaps.  Since this procedure is computationally heavy, multiple alignments are often built progressively from several pairwise alignments.  It is impossible, however, to judge if a length difference between two sequences is a deletion in one or an insertion in the other sequence.  For correct alignment of multiple sequences, distinguishing between these two events is crucial.  Existing methods, that fail to do that, lead to a flawed understanding of the course of evolution.

“Our new method gets around these errors by taking into account what we already know about evolutionary relationships,” says Ari Löytynoja, who developed the tool in Goldman’s lab.  “Say we are comparing the DNA of human and chimp and can’t tell if a deletion or an insertion happened.  To solve this our tool automatically invokes information about the corresponding sequences in closely related species, such as gorilla or macaque.  If they show the same gap as the chimp, this suggests an insertion in humans.”

Findings achieved with the new technique suggest that insertions are much more common than assumed, while the frequency of deletions has been overestimated by existing methods.  A likely reason for these systematic errors of other techniques is that they were originally developed for structural matching of protein sequences.  The focus of molecular biology is shifting, however, and understanding functional changes in genomes requires specifically designed methods that consider sequences’ histories.  Such approaches will likely reveal further bugs in our understanding of evolution in future and might challenge the conventional picture of sequence evolution.

A tiny but powerful engine that propels the bacterium Bacillus subtilis through liquids is disengaged from the corkscrew-like flagellum by a protein clutch, Indiana University Bloomington and Harvard University scientists have learned. Their report appears in this week’s Science.Scientists have long known what drives the flagellum to spin, but what causes the flagellum to stop spinning — temporarily or permanently — was unknown.

“We think it’s pretty cool that evolving bacteria and human engineers arrived at a similar solution to the same problem,” said IU Bloomington biologist Daniel Kearns, who led the project. “How do you temporarily stop a motor once it gets going?”

The action of the protein they discovered, EpsE, is very similar to that of a car clutch. In cars, the clutch controls whether a car’s engine is connected to the parts that spin its wheels. With the engine and gears disengaged from each other, the car may continue to move, but only because of its prior momentum; the wheels are no longer powered.

EpsE is thought to “sit down,” as Kearns describes it, on the flagellum’s rotor, a donut-shaped structure at the base of the flagellum. EpsE’s interaction with a rotor protein called FliG causes a shape change in the rotor that disengages it from the flagellum’s proton-powered engine.

The discovery of EpsE and its function was accidental. Kearns and colleagues were actually interested in learning more about the genes that cause individual cells of B. subtilis to cease wandering in solitude and take up residence in a massively communal, stationary assemblage called a biofilm. The stability of biofilms can be jeopardized by hyperactive bacterial cells whose flagella continue to spin.

“We were trying to get at how the bacterium’s ability to move and biofilm formation are balanced,” Kearns said. “We were looking for the genes that affected whether the cells are mobile or stationary. Although B. subtilis is harmless, biofilms are often associated with infections by pathogenic bacteria. Understanding biofilm formation may eventually prove useful in combating bacterial infections.”

Once the scientists learned EpsE was involved in repressing flagellar motion, they devised two possible explanations for how EpsE acts. The first was that EpsE acts like a brake by pushing a non-moving part against a moving part and locking up the works. The other possibility, they imagined, was that EpsE acts like a clutch, disengaging one moving part from another. In this latter scenario, the engine can no longer drive flagellar spinning because key moving parts are no longer in contact. In this case, the flagellum would still have freedom of motion, listless as it might be.

To determine which hypothesis was correct, the scientists decided it best to let the tail wag the dog. They attached the tail end of the flagellum to a glass slide and examined the movement of the entire cell in the presence and absence of EpsE. In the absence of EpsE, the entire cell rotated once every five seconds. In the presence of EpsE, the cells stopped but could rotate passively, pushed by disturbances in the environment (Brownian motion). If EpsE acted like a brake, the cells would not have rotated at all.

The researchers also learned that when the cell begins producing EpsE, it takes about 15 minutes before the flagellar machinery is disabled.

“This makes a lot of sense as far as the cell is concerned,” Kearns said. “The flagellum is a giant, very expensive structure. Often when a cell no longer needs something, it might destroy it and recycle the parts. But here, because the flagellum is so big and complex, doing that is not very cost effective. We think the clutch prevents the flagellum from rotating when constrained by the sticky matrix of the biofilm.”

The discovery may give nanotechnologists ideas about how to regulate tiny engines of their own creation. The flagellum is one of nature’s smallest and most powerful motors — ones like those produced by B. subtilis can rotate more than 200 times per second, driven by 1,400 piconewton-nanometers of torque. That’s quite a bit of (miniature) horsepower for a machine whose width stretches only a few dozen nanometers.

Switches are a part of daily life, from snoozing your alarm, turning on the coffee maker, firing up your car engine, and so on until we turn off the lights at night. Researchers have now cataloged even more templates of possible switches within a living cell than we use throughout our day.Naren Ramakrishnan, associate professor of computer science at Virginia Tech, USA, and Upinder S. Bhalla, at the National Centre for Biological Sciences (NCBS), part of the Tata Institute of Fundamental Research in India, found that cells can make use of thousands of switches to support important biological functions.

Cells use switches for determining what kind of cell to become – skin or blood, for instance, in responding to stress, and in communication with other cells. “A switch is like a memory unit,” said Bhalla. “The state of the switch — whether it is on or off, is like a computer memory that can store a bit of 0 or 1. Although real biological switches are quite complex and regulated in many ways, we have shown the simplest possible ways in which switches could work”, Bhalla said.

The researchers report their work in the June 20 issue of the Public Library of Science (PLoS) Computational Biology, in the article “Memory Switches in Chemical Reaction Space.” Their collaboration began during a sabbatical visit by Ramakrishnan to NCBS in Bangalore, India. Ramakrishnan is a computer scientist whose expertise is in numerical simulation and data mining. Bhalla is a computational neuroscientist with broad interests in biochemical network modeling and simulation. They decided to use Virginia Tech’s System X supercomputer to search for the many ways in which cells can implement switches.

“Our exploration using System X is rather like how a tinkerer or a kid puts together things to see if they do something useful. We took a lot of ’spare parts’, each spare part being one chemical reaction, connected them together every which way, and we found that a surprising number of these artificially constructed networks actually were switches,” said Ramakrishnan.

“Popular opinion used to be that there are a small number of ways in which switches can be realized by biology, but we found thousands of switches in our search,” Ramakrishnan said.

The researchers report in PLoS Computational Biology, “We find nearly 4,500 reaction topologies, or about 10 percent of our tested configurations, that demonstrate switching behavior.”

Their research also led to a comprehensive “map” of biochemical switches. The map further revealed that most of the switches form a “family” – that is, the switches are all related to one another. “This has important implications since it suggests how evolution might stumble upon a switch rather easily.” Ramakrishnan said.

“Of course, there is more to cells than switches,” Bhalla said. “But switching and memory are the most basic behaviors possible. Armed with our catalog of switches, we can now proceed to investigate more interesting behaviors like complex information processing.”

Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), have identified a promising new target for autoimmune disease treatment – a cell-surface receptor called DR3. Their research in mice, published on line in the journal Immunity, suggests that blocking this receptor could slow or stop the damaging inflammation characteristic of autoimmune diseases, potentially without leaving the body vulnerable to serious infections, as many current therapies do.

DR3 is a protein on the surface of cells. It is a member of the tumor necrosis factor (TNF) family of receptors, which bind to molecules related to TNF, a cell-signaling protein that promotes inflammation. Many of today’s most potent treatments for inflammatory diseases, such as rheumatoid arthritis and psoriasis, interfere with the action of TNF, thereby blocking inflammation. Since current anti-TNF therapies don’t work in all autoimmune diseases, however, the researchers turned to the study of DR3, which is a close relative of TNFR1, the main receptor for TNF.

Working with mouse models of asthma and multiple sclerosis, both immune system diseases, the researchers found that mice engineered to lack DR3 were resistant to those diseases. “The implication is that blocking DR3 in mice, and possibly in humans, is a potential therapy for these diseases and perhaps others in which the immune system goes awry,” said Richard Siegel, M.D., Ph.D., a scientist in the NIAMS’ Immunoregulation Group, who led the research effort.

While closely related to TNFR1, DR3 is expressed in T cells, a different kind of immune cell (a white blood cell that identifies and fights infection) than those that express TNFR1, Dr. Siegel said. The NIAMS group collaborated with a laboratory in Cardiff, Wales, which had generated genetically engineered mice deficient in DR3, as well as with a research group at the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which has developed mouse models of disease with strong T cell components, such as asthma and multiple sclerosis. “These findings open up new avenues for therapy of these two diseases as well as to other autoimmune diseases in which T cells play a role in causing or perpetuating the disease,” said Siegel.

The researchers hope that DR3-blocking agents will be effective anti-inflammatory treatments someday. Siegel noted that if they were to be used in rheumatic diseases, they would be a complement to strategies that block TNF because they hit a different arm of the immune system. “It could be potentially synergistic or complementary,” he said.

Of critical importance, the NIAMS scientists found that removing DR3 did not appear to suppress the immune response or the ability to fight infection within the mice – a problem with many other treatments for autoimmune disease. “We could see the effect of DR3 deficiency in the diseased organ, but when we looked systemically at the immune response at other places in the mouse, it was barely affected,” said Dr. Siegel. The group’s findings suggest that DR3-blocking agents might be more effective at specifically treating autoimmune disease without breaking down the body’s defenses against infections, a long-sought goal of researchers in the field.

The immune system of vertebrate animals consists of two components: the innate immune response, a constitutive system ready to respond to a pathogen, and the adaptive immune response, a system of immunological memory that responds to previously encountered pathogens. In a study led by Dr. Anlong Xu of Sun Yat-sen University, scientists searched the amphioxus genome for genes that may be relevant to immunity in order to gain an understanding of what the immune system repertoire of the vertebrate ancestor may have looked like. “Our chordate ancestors had a remarkably elaborate innate immune system, but this system was somehow reduced in the vertebrate lineage, which is unusual to our conventional thinking of the immune system,” explains Xu. Furthermore, Xu notes that this work helps to describe a global picture of innate immunity and uncover the evolutionary footsteps underlying the evolution of human immune pathways.

To investigate the origins of vertebrates and other features of cephalochordate biology, a team of researchers led by Dr. Linda Holland of the Scripps Institution of Oceanography searched the amphioxus genome for specific genes, gene families, and DNA elements that could shed light on chordate biology and evolution. The analysis identified a number of features of amphioxus that are conserved with vertebrates, as well as some that are unique. In addition to new insights on development, cell signaling, immunity, and endocrine systems, Holland and colleagues identified several DNA regulatory elements conserved between amphioxus and humans. Three conserved elements from two human paralogs and a single amphioxus homolog were all shown to drive gene expression in both amphioxus and the mouse. “This is the widest phylogenetic distance to date over which both the sequence and function of cis-regulatory enhancers has been found to be conserved,” explains Holland. The group concluded that while amphioxus displays many characteristics of a pre-vertebrate ancestor, it also has specialized features that have developed since diverging from chordate ancestors.

Genome Research is publishing several papers related to analyses of the amphioxus (Branchiostoma floridae) genome sequence. The amphioxus, or lancelet, is a cephalochordate residing in shallow regions of tropical and temperate seas, bearing resemblance to a small fish, however lacking pairs of eyes, limbs, and ears. A member of the chordata phylum along with tunicates (sea squirts) and vertebrates, amphioxus lacks the backbone or spinal column characteristic of vertebrate animals, yet shares the same basic body plan. Amphioxus is therefore an excellent model for investigating how vertebrates evolved from an invertebrate ancestor. Now, researchers are finding that the amphioxus genome sequence is revealing new insights into vertebrate origins and the evolution of complex biological systems, such as immunity and nervous system development. Primary research reports describing these novel findings will be published online June 19, concurrent with publication of the amphioxus genome sequence report in the journal Nature.

Diffusible molecules of the Slit family inhibit midline crossing by axons and neurons that express Robo receptors. For example, migrating inferior olive (IO) neurons extend a leading process across the midline, but the somata stop upon reaching the floor plate, which expresses Slits; the leading process forms the axon. Robo3 knock-out prevents midline crossing by the leading process, suggesting that Robo3 may interfere with repulsive signaling by other Slit–Robo pairs. To test this hypothesis, Di Meglio et al. knocked out Slits and Robos individually and in combination. As expected, IO somata crossed the midline in Slit1/2 and Robo1/2 knock-outs, confirming that these proteins normally repel neurons. Unexpectedly, however, axons failed to cross the midline in Robo1/2/3 triple knock-outs, indicating that Robo3 actively promotes crossing, rather than simply interfering with Robo1/2 signaling. In addition, the patterning of IO subnuclei was disrupted in knock-outs, suggesting an additional role for Slits and Robos.

Huge numbers of fish, seabirds, and other marine animals are routinely killed and discarded after being inadvertently caught during fishing operations. Known as marine bycatch, this problem is an ongoing challenge to the fishing industry, regulatory agencies, and conservationists. One recent proposal would compensate for bycatch by reducing other impacts on affected species, but a new analysis suggests that this strategy could end up doing more harm than good.A paper published last year in Frontiers in Ecology and the Environment made the case for “compensatory mitigation” of fisheries bycatch, using seabird deaths caused by a longline fishery as an example. The authors suggested that eradicating rats from an island with seabird nesting colonies could have more benefits for a population of shearwaters than efforts to reduce bycatch in the longline fishery.

A number of seabird experts, however, were skeptical of the paper’s findings. Given its potential influence on fishery policies, they decided the proposal warranted a careful evaluation.

“There are so many complexities involved in fisheries bycatch, we felt compelled to thoroughly examine the strengths and weaknesses of this approach and establish the criteria that would have to be met for it to work,” said Myra Finkelstein, a postdoctoral fellow in ecology and evolutionary biology at the University of California, Santa Cruz.

Finkelstein is the lead author of a paper published June 18 in the journal PLoS ONE that evaluates the potential effectiveness of compensatory mitigation for marine bycatch. She worked with a dozen coauthors whose areas of expertise include seabird conservation and ecology, marine bycatch, and mathematical modeling of wildlife populations. The researchers concluded that compensatory mitigation could only rarely succeed in reducing or offsetting the effects of marine bycatch.

“It’s very difficult to make this work,” Finkelstein said. “Most of the species threatened by bycatch evolved to live long and reproduce slowly. When bycatch kills adults, these populations just aren’t capable of making up for it through increased reproduction. It really is about the bycatch.”

Another major stumbling block is that bycatch typically involves a large variety of nontarget species, whereas compensatory mitigation actions are likely to affect only one or a few of those species.

“Marine bycatch is not a single-species problem,” Finkelstein said. “So many nontarget species are caught in a given fishery that mitigating the effects on one species could lead to a bigger impact on other species.”

The researchers also found flaws in the case study of flesh-footed shearwaters used to support the compensatory mitigation strategy in the original paper. But the bulk of the new paper is devoted to a set of five criteria for evaluating any proposals to implement such strategies. The researchers found that compensatory mitigation for marine bycatch is likely to be successful only in a limited number of situations. In many cases, they said, it has the potential to accelerate declines of marine species currently threatened by fisheries bycatch.

“These are complicated situations. We have to be very cautious, especially with critically endangered species, before we adopt a policy that allows continued mortality from bycatch,” Finkelstein said.

Nodari et al. have discovered a major new class of molecules that activate the accessory olfactory (vomeronasal) system: sulfated steroids. Vomeronasal sensory neurons (VSNs) detect cues that are important for social communication. Mouse urine strongly activates VSNs, but few of its active compounds had been identified. Using fractionation, mass spectrometry, and multielectrode physiological recordings, Nodari et al. found that sulfated steroids account for 80% of the vomeronasal-stimulating activity in female urine. Testing synthetic steroids revealed that individual neurons responded selectively and with different sensitivity to one to four closely related compounds, but, as a population, VSNs detected all classes of steroid hormones known to control mammalian physiology. Sulfation is thought to help clear steroids from the body, and the levels of sulfated corticosterone increased following restraint stress, suggesting that urine levels of sulfated hormones reflect the recent physiological state. Interestingly, sulfated steroids were not detected in males, suggesting another major class ofVSNstimuli remains undiscovered.

A great deal of attention has been paid to the use of growth hormone (hGH) by elite athletes and a few vocal entertainers. But underlying this tip of the iceberg is a $2 billion dollar a year business, likely involving hundreds of thousands of regular people, and promoted by anti-aging and age-management clinics and compounding pharmacies who aggressively market and sell growth hormone with the claim that it has anti-aging or athletic enhancing properties. Since their previous article in the Journal of the American Medical Association (JAMA) in 2005 on the clinical and legal aspects of growth hormone for anti-aging, in which researchers from Boston University School of Medicine, Boston Medical Center and the University of Illinois at Chicago alerted the medical community and lay public to the deceptive mass marketing and illegal distribution of growth hormone for anti-aging and athletic enhancement, the authors provide new evidence demonstrating that these deceptive and dangerous activities have grown worse.Remarks Dr. Thomas Perls, Director of the New England Centenarian Study and an associate professor of Medicine at Boston University School of Medicine, who has monitored the anti-aging industry for over the past ten years, “despite the overwhelming evidence that the risks and dangers of growth hormone far outweigh the clinically demonstrated insignificant benefit in normally aging individuals, the prescribing, distribution and sale of hGH for alleged anti-aging aesthetic and athletic enhancement has dramatically grown over the past few years. Clearly, the coordinated and aggressive marketing campaigns of the anti-aging and age-management industries are highly and most unfortunately effective.”

Clinical evidence does support the therapeutic use of hGH for children and adults with appropriate clinical indications. However, these cases are disease specific and rare. Furthermore, any effectiveness that is demonstrated in the rare medical conditions approved for hGH distribution cannot be translated into effectiveness among healthy aging adults, a deceptive assertion often made by proponents of hGH use for a wide range of panacea-like benefits.

In January, 2007, the FDA issued an alert emphasizing that prescribing and distributing hGH for anti-aging and body building is illegal. A number of high-profile government investigations such as Operations Raw Deal, Phony Pharm and Which Doctor have attempted to make a dent in the illegal distribution of hGH and anabolic steroids for unapproved uses such as anti-aging or aesthetic reasons. As stated on the Albany County District Attorney’s website, in the case of Operation Which Doctor, numerous governmental agencies are “working together to take down a nationwide distribution ring of anabolic steroids, Human Growth Hormones and other controlled substances, by targeting the ring’s dirty doctors, its distributors that pose as clinics, and ultimately the ring’s supplier Signature Pharmacy.”

Contrary to published claims, neither long-term safety nor health benefits have been demonstrated in normally aging individuals taking hGH. A review of clinical studies among healthy, normally aging individuals found that hGH supplementation does not significantly increase muscle strength or aerobic exercise capacity. However, documented adverse effects include soft tissue edema, arthralgias (joint pains), carpal tunnel-like syndrome, gynecomastia (enlarged breasts) and insulin resistance with an elevated risk of developing diabetes. Increasingly more and more animal and laboratory studies suggest an increased cancer risk.

The authors suggest that several measures need to be taken to address the inappropriate distribution and use of hGH. Among their recommendations:

• The public must be accurately informed by physicians and scientists who do not have a vested interest in hGH, about health risks, fraudulent marketing and illegal distribution of this drug.
• Organizations that promote or indirectly profit from the medically inappropriate and illegal distribution of hGH that have been accredited by the Accreditation Council for Continuing Medical Education (ACCME) to offer American Medical Association Physician Recognition Award (PRA) category 1 CME credits or other categories of CME credit should, at a minimum, have their accreditation revoked.
• U.S. manufacturers of hGH must be more effective in, and held accountable for, controlling the distribution of the drug to companies providing the drug for illegal uses.
• Congressional hearings and media attention surrounding hGH should focus less on athletes and prominent entertainers who are also victims of deceptive marketing and pushing of hGH, and much more on the distributors who are violating federal and state laws by making the drug available for non-approved uses.
• Senators Schumer and Grassley and Representative Steven Lynch deserve the public’s support of their intention to strengthen and enhance the law regarding the illegal distribution of hGH. ‘Strengthening the law’ should entail stiffer financial and imprisonment penalties for illegally prescribing and/or distributing growth hormone for purported anti-aging, age management, aesthetic enhancement, and body building uses. Enhancing the law should include the addition of sermorlin (growth hormone releasing hormone [GHRH]) and mecasermin (insulin-like growth factor I [IGF-1]) and their analogues. GHRH (which stimulates the release of endogenous hGH) and IGF-I (which mediates many of the effects of hGH) result in hGH-like effects, and, therefore, the potential for their inappropriate use as purported anti-aging and performance enhancement therapies clearly exists.

Perl adds: “In my capacity as a reviewer of medical records seized from anti-aging clinics by the DEA, I almost never see hGH provided in isolation. It is usually a part of a complex cocktail of one or more anabolic steroids, human chorionic gonadotropin (specifically for men to decrease the obvious signs of steroid abuse such as small testicles and enlarged breasts), thyroid hormone, DHEA and other drugs. Additional drugs such as blood pressure medicines, diuretics and insulin may be given to treat the side effects of the basic cocktail.”

Against currently held dogma, scientists at the Universities of Cambridge and Bristol have revealed that the interactions within membrane complexes can be maintained intact in the vacuum of a mass spectrometer. Their research is published in this week’s edition of Science Express.

The researchers were surprised to discover that membrane complexes could remain associated as it has always been assumed that they would not survive once transferred to the alien conditions inside the mass spectrometer.

“Even if interactions between proteins within the membrane could be maintained we would not have expected them to remain associated with proteins in the cell’s interior,” says Carol Robinson, Principal Investigator and Royal Society Research Professor at the University of Cambridge’s Department of Chemistry.

Cellular membranes surround cells and provide the ultimate in cellular security; nothing can get into a cell without the say so of membrane proteins – the worker molecules that reside in the membrane wall and provide tightly regulated entry points. This natural home of membrane proteins excludes water, yet methods available to study proteins at high resolution revolve round aqueous environments. The ability to “fly” intact membrane proteins in a mass spectrometer paves the way for weighing the proteins and identifying the molecular partners they work with in nature.

The new research, funded by the Biotechnology and Biological Sciences Research Council, will enable scientists to investigate membrane complexes with from a variety of sources and with a range of small molecules. Since about 60% of all drug targets are membrane proteins this is a significant discovery.

Ever since Professor Robinson first flew soluble protein complexes in a mass spectrometer in 1996, she has wanted to do the same with membrane complexes. Collaborating with a membrane biochemistry group in Bristol, led by Professor Paula Booth, she began to think of ways of studying these most challenging assemblies.

Dr Nelson Barrera a post-doctoral researcher in Chile, though experienced in membrane biochemistry, was a new recruit to mass spectrometry. He was largely unaware of the difficulties that had previously been encountered and approached the problem in a new way. Rather than trying to remove the detergent (used to keep the protein intact in solution once outside the natural membrane) he maintained the detergent in unusually high amounts. He then deliberately destroyed this protective detergent layer once in the gas phase. This allowed him to liberate the intact assembly. He was also able to remove units from the modular assembly in the gas phase, just as in solution.

Professor Robinson adds: “I am very excited by this finding given the importance of membrane complexes in guarding the entrance and exit to cells. The type of proteins we have been studying, for example, are involved in drug resistance in cancer cells and antibiotic resistance of bacteria.

“I look forward to exploiting this discovery to the full; not only in characterising the many membrane complexes for which controversy exists but also in discovering new assemblies and in investigating the potential of this approach in drug discovery.”

Professor Paula Booth, at the University of Bristol added: “This is a major advance that helps us understand how nature constructs cellular life. The membrane wall of cells is a precision-made, complex and highly regulated structure. We are now much better equipped to understand this incredible, natural self-assembly feat.”

Fluoride toothpaste is prohibitively expensive for the world’s poorest people, according to a study published in BioMed Central’s open access journal Globalization and Health. Researchers revealed that the poorest populations of developing countries have the least access to affordable toothpaste.

The team, which includes Ann Goldman of the School of Public Health and Health Services at the George Washington University in Washington D.C., Robert Yee and Christopher Holmgren of the World Health Organization Collaborating Centre at Radboud University Medical Centre in Nijmegen, The Netherlands, and Habib Benzian of the FDI World Dental Federation compared the relative affordability of fluoride toothpaste in 48 countries.

Globalization has led to a worldwide tendency to eat a more westernized diet, which is higher in carbohydrates and refined sugars. This has resulted in an increasing prevalence of tooth decay in developing countries, which can lead to malnutrition and a reduced quality of life. The cost and relative unavailability of dental care in poorer countries means that tooth decay usually remains untreated.

Fluoride toothpaste is the most widely used method of preventing dental decay, but currently only 12.5% of the world benefits from it. The researchers believe that the low-use of fluoride toothpaste is due to its cost, which is too high in some parts of the world. This study is the first to attempt to quantify the affordability of toothpaste across the globe.

Questionnaires regarding the cost of fluoride toothpaste were completed by dental associations, non-government oral health organisations and individuals around the world. The cost of a year’s worth of toothpaste for one person was calculated as both a proportion of household expenditure and in terms of the number of days of work needed to cover the cost.

The results showed that in different income groups in various countries, as the per capita income decreased, the proportion of income needed to purchase a year’s supply of toothpaste increased; the poorest in each country being the hardest hit.

“Because of the importance of fluoride toothpaste in preventing tooth decay, it must be made more available to the world’s poorest populations,” commented Goldman, “steps should be taken to make fluoride toothpaste more affordable and more accessible.” The authors suggest that this can be done by exempting fluoride toothpaste from taxation, encouraging the local manufacture of fluoride toothpaste and persuading multinational manufacturers to implement different pricing policies for poorer countries.

Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have discovered how evolution may have lumbered humans with allergy problems. The team from the Randall Division of Cell & Molecular Biophysics, King’s College London are working on a molecule vital to a chicken’s immune system which represents the evolutionary ancestor of the human antibodies that cause allergic reactions. Crucially, they have discovered that the chicken molecule behaves quite differently from its human counterpart, which throws light on the origin and cause of allergic reactions in humans and gives hope for new strategies for treatment. The work is published today (13 June) in The Journal of Biological Chemistry.

Researcher, Dr Alex Taylor said: “This molecule is like a living fossil – finding out that it has an ancient past is like turning up a coelacanth in your garden pond. By studying this molecule, we can track the evolution of allergic reactions back to at least 160 million years ago and by looking at the differences between the ancient and the modern antibodies we can begin to understand how to design better drugs to stop allergic reactions in their tracks.”

The chicken molecule, an antibody called IgY, looks remarkably similar to the human antibody IgE. IgE is known to be involved in allergic reactions and humans also have a counterpart antibody called IgG that helps to destroy invading viruses and bacteria. Scientists know that both IgE and IgG were present in mammals around 160 million years ago because the corresponding genes are found in the recently published platypus genome. However, in chickens there is no equivalent to IgG and so IgY performs both functions.

Lead researcher, Dr. Rosy Calvert said: “Although these antibodies all started from a common ancestor, for some reason humans have ended up with two rather specialised antibodies, whereas chickens only have one that has a much more general function.

“We know that part of the problem with IgE in humans is that it binds extremely tightly to white blood cells causing an over-reaction of the immune system and so we wanted to find out whether IgY does the same thing.”

By examining how tightly IgY binds to white blood cells the researchers have found that it behaves in a much more similar way to the human IgG, which is not involved in allergic reactions and binds much less tightly.

Professor Brian Sutton, head of the laboratory where the work was done said: “It might be that there was a nasty bug or parasite around at the time that meant that humans needed a really dramatic immune response and so there was pressure to evolve a tight binding antibody like IgE. The problem is that now we’ve ended up with an antibody that can tend to be a little over enthusiastic and causes us problems with apparently innocuous substances like pollen and peanuts, which can cause life-threatening allergic conditions.”

The next stage of the work is to examine in very fine detail the interaction between the antibodies and the surface of the white blood cell. This is with a view to designing drugs that could alter this interaction and therefore ‘loosen’ the binding of IgE, making it more like its chicken counterpart.

Oral ingestion of pomegranate extract reduces the production of chemicals that cause inflammation suggests a study published in BioMed Central’s open access Journal of Inflammation. The findings indicate that pomegranate extract may provide humans with relief of chronic inflammatory conditions.

The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.

Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.

Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.

Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.

The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi “the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients”. He adds that, “Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood.”