An international team of researchers led by Professors Mark Caulfield and Patricia Munroe, from the William Harvey Research Institute at Barts and The London School of Medicine and Dentistry with Chris Cheeseman at the University of Alberta in Canada and Kelle Moley at the University of Washington in USA, have shown that the SLC2A9 gene, which encodes a glucose transporter, is also a high-capacity urate transporter, and thus possibly a new drug target for gout.  Their findings are published in this week’s PloS Medicine (7 October 2008).

Several urate transporters have already been identified but recently, using an approach called genome-wide association scanning, Caulfield and others found that some genetic variants of a human gene called SLC2A9 are more common in people with high serum urate levels than in people with normal levels.  SLC2A9 encodes a glucose transporter (a protein that helps to move the sugar glucose through cell membranes) and is highly expressed in the kidney’s main urate handling site.  Professor Caulfield and his team investigated the possibility that the protein made by the SLC2A9 gene might be a urate transporter and tested whether genetic variations in SLC2A9 might be responsible for the association between serum urate levels and high blood pressure.

The team first expressed SLC2A9 in frog eggs, a type of cell that does not have its own urate transporter.  They found that SLC2A9 transported urate about 50 times faster than glucose, and that glucose facilitated SLC2A9-mediated urate transport.  Similarly, over expression of SLC2A9 in human embryonic kidney cells more than doubled their urate uptake.  Conversely, when the researchers used a technique called RNA interference to reduce the expression of mouse SLC2A9 in mouse cells that normally makes this protein, urate transport was reduced.  Researchers then looked at two genetic variations within SLC2A9 that vary between individuals (so-called single polynucleotide polymorphisms) in nearly 900 men who had had their serum urate levels and urinary urate excretion rates measured.  They found that certain genetic variations at these two sites were associated with increased serum urate levels and decreased urinary urate excretion.  Finally, the researchers used a statistical technique called meta-analysis to look for an association between one of the SLC2A9 gene variants and blood pressure.  In two separate meta-analyses that together involved more than 20,000 participants in several studies, there was no association between this gene variant and blood pressure.

Overall, these findings indicate that SLCA9 is a high capacity urate transporter, and suggest that this protein plays an important part in controlling serum urate levels.  They provide confirmation that common genetic variants in SLC2A9 affect serum urate levels to a marked degree, although they do not show exactly which genetic variant is responsible for increasing serum urate levels.  They also provide important new insights into how the kidneys normally handle urate and suggest ways in which this essential process may sometimes go wrong.  The findings could eventually lead to new treatments for gout and possibly for other diseases that are associated with increased serum urate levels.

Professor Mark Caulfield said: “This MRC funded study shows how a team of international researchers can find a completely unsuspected mechanism for urate handling in the kidney.  Such discoveries could pave the way for new medicines.”

One of the smallest seals – the Caspian has joined a growing list of mammal species in danger of extinction.

Scientists from the University of Leeds together with international partners have documented the disastrous decline of the seal a species found only in the land-locked waters of the Caspian Sea – in a series of surveys which reveal a 90 per cent drop in numbers in the last 100 years.

The research findings have prompted the International Union for Conservation of Nature (IUCN) to move the Caspian seal from the Vulnerable category to Endangered on its official IUCN Red List of Threatened Species, announced today in Barcelona [06 October 2008].

Dr Simon Goodman of Leeds’ Faculty of Biological Sciences says: “Each female has just one pup a year, so with numbers at such a low levels, every fertile female that dies is a nail in the coffin of the species.  We’re hoping that the seal’s change in Red List status will help raise awareness about their plight, and the many important conservation issues facing the whole Caspian ecosystem.”

Commercial hunting, habitat degradation, disease, pollution and drowning in fishing nets have caused the population of the seal collapse from more than 1 million at the start of the 20th century to around 100,000 today.

Results from surveys conducted in 2005 and 2006, published recently in the scientific journal Ambio, show that in 2006 there were only 17,000 breeding females, barely enough to keep the population viable, given the low survival rate of pups.

Moreover, new results from surveys conducted by the team in 2007 and 2008, show that since 2005 the number of pups being born has plummeted by a catastrophic further 60 per cent to just 6,000-7,000, and the number of adults seen on the breeding grounds of the winter ice-field is down by a third on 2005.

With commercial hunters from Dagestan in the Russian Federation killing more than 8,000 pups in recent years, the team is urging the governments of the Caspian countries to instate a ban on hunting as the first step in avoiding further declines.  “Without a suite of conservation measures there is a very high risk the species will become extinct, and possibly within our lifetime,” says Dr Goodman.

The team is using its latest figures and ongoing research to develop a conservation action plan, which will prioritise a ban on hunting the seal and establish protected areas with the countries bordering the Caspian Sea.  The basic plan has been completed, but the main recommendations are yet to be fully implemented by the countries of the region.

Dr Susan Wilson, a consultant in seal conservation biology and one of the authors of the Ambio paper says: “Although there are no easy fixes to the problems facing Caspian seals, we hope to get some concrete measures in place over the next year, particularly in Kazakhstan where the government has been quick to recognise the need for urgent action.”

A potentially blinding neurological disorder, often confused with multiple sclerosis (MS), has now become a little less mysterious.  A new study by researchers at the Mayo Clinic in Rochester, Minnesota, may have uncovered the cause of Devic’s disease.  Their new study, which will appear online on October 6th in the Journal of Experimental Medicine, could result in new treatment options for this devastating disease.

Devic’s disease, also known as neuromyelitis optica (NMO), results in MS-like demyelinating lesions along the optic nerves and spine.  Affected individuals often experience rapid visual loss, paralysis, and loss of leg, bladder, and bowel sensation.  Some lose their sight permanently.  Unlike MS, Devic’s disease can be diagnosed by the presence of a specific self-attacking immune protein—an autoantibody referred to as NMO-IgG—in the blood.  Until now, however, clinicians didn’t know how that protein damaged nerves and contributed to disease symptoms.

The Mayo team, lead by Dr. Vanda Lennon, now show that NMO-IgG sets off a chain of events that leads to a toxic build-up of a neurotransmitter called glutamate.  NMO-IgG binds to a protein that normally sops up excess glutamate from the space between brain cells.  When NMO-IgG is around, this sponge-like action is blocked, allowing glutamate to accumulate.  And too much glutamate can kill the cells that produce myelin—the protein that coats and protects neurons.  The authors suggest that glutamate-induced damage to nerve cells and their insulating myelin coats might account for the neurological symptoms associated with Devic’s disease.

If the groups’ results—generated using nerve cell cultures—are confirmed in vivo, drug development could be very straightforward.  Therapeutic trials for glutamate blockers, created to treat other neurodegenerative diseases like Lou Gehrig’s disease (or ALS), are already underway.

From majestic African elephants to tiny and often unappreciated rodents, mammals on Earth are in a state of crisis.  One in four mammal species on Earth is being pushed to extinction, according to the Global Mammal Assessment, the most comprehensive assessment of the world’s mammals.

Writing in the October 10 issue of Science, (”The Status of the World’s Land and Marine Mammals: Diversity, Threat, and Knowledge”) and unveiling a “Red List” of endangered mammal species (at the International Union for Conservation of Nature World Conservation Congress in Barcelona, Spain), the researchers who worked on the exhaustive study say that from 25 percent to 36 percent of species may be in danger of extinction.

“It is frightening that after millions and millions of years of evolution that have given rise to the biodiversity of mammals we are perched on a crisis where 25 percent of species are threatened with being lost forever,” said Andrew Smith, an Arizona State University professor who played a key role in the mammalian assessment.  Smith and his research assistant, Charlotte Johnson, are two of the 103 authors of the Science paper.

The Global Mammal Assessment was conducted by more than 1,800 scientists from more than 130 countries working under the auspices of the International Union for Conservation of Nature.  It was made possible by the volunteer help of IUCN Species Survival Commission’s specialist groups and collaborations between top institutions and universities, including Arizona State University, Texas A&M University, University of Virginia, Conservation International, Sapienza Università di Roma and the Zoological Society of London.

The mammal assessment is the first comprehensive look at the health of terrestrial and marine mammals across the globe.  It is a companion assessment to similar documentation of the world’s amphibians, released four years ago by IUCN.

“Mammals are important because they play key roles in ecosystems and provide important benefits to humans,” Smith explained.  “If you lose a mammal, you often are in danger of losing many other species.”

The assessment shows that at least 1,141 of the 5,487 mammals on Earth are known to be threatened with extinction.  At least 76 mammals have become extinct since 1500.  The real situation could be much worse as 836 mammals are listed as “data deficient.”

The culprits driving this precarious position include habitat loss and over exploitation for terrestrial mammals, and pollution, global warming and over exploitation for marine mammals, Smith said.

“Within our lifetime hundreds of species could be lost as a result of our own actions, a frightening sign of what is happening to the ecosystems where they live,” said Julia Marton-Lefevre, IUCN director general in announcing the Red List.  “We must now set clear targets for the future to reverse this trend to ensure that our enduring legacy is not to wipe out many of our closest relatives.”

In the Science article, which includes the contributions of more than 1,700 scientists, the researchers state that 188 mammals are in the highest threat category of “critically endangered,” including the Iberian Lynx (Lynx pardinus), which has a population of just 84 to 143 adults and has continued to decline due to a shortage of its primary prey, the European Rabbit (Oryctolagus cuniculus).

China’s Père David’s Deer (Elaphurus davidianus), is listed as “extinct in the wild.”  However, the captive and semi-captive populations have increased in recent years and it is possible that truly wild populations could be re-established soon.  It may be too late, however, to save the additional 29 species that have been flagged as “critically endangered, possibly extinct” including Cuba’s Little Earth Hutia (Mesocapromys sanfelipensis), which has not been seen in nearly 40 years.

Nearly 450 mammals have been listed as “endangered,” including the Tasmanian Devil (Sarcophilus harrisii), after its global population declined by more than 60 percent in the last 10 years due to a fatal infectious facial cancer.  The Fishing Cat (Prionailurus viverrinus), found in Southeast Asia, was listed as endangered due to habitat loss in wetlands.  Similarly, status of the Caspian Seal (Pusa caspica) was moved to endangered.  Its population has declined by 90 percent in the last 100 years due to unsustainable hunting and habitat degradation.

Habitat loss and degradation affect 40 percent of the world’s mammals.  It is most extreme in Central and South America, west, east and central Africa, Madagascar, and in south and Southeast Asia.  Over harvesting is wiping out larger mammals, especially in Southeast Asia, but also in parts of Africa and South America.

The Grey-faced Sengi or Elephant-shrew (Rhynchocyon udzungwensis) is only known from two forests in the Udzungwa Mountains of Tanzania, both of which are protected but vulnerable to fires.  The species was first described this year and has been placed in the vulnerable category.

In order to improve the current state of these mammals, Smith suggests a few actions that could help immediately.

“Curtail the trade of endangered species,” he said.  “It would do an amazing amount of good for stabilizing the situation in Southeast Asia, which is a biodiversity hot spot.  There also is so much needless habitat loss.  Trees from too many lush tropical forests end up as coffee tables or in high-end furniture.”

Conservation’s role

“Our results paint a bleak picture of the global status of mammals worldwide,” the authors of the Science article state.  “Yet, more than simply reporting on the depressing status of the world’s mammals, these Red List data can and should be used to inform strategies for addressing this crisis, for example, to identify priority species and areas for conservation.

“Further, these data can be used to indicate trends in conservation status over time,” they added.  “Despite the general deterioration in the status of mammals, our data also show that species recoveries are possible through targeted conservation efforts.”

For example, the Black-footed Ferret (Mustela nigripes) moved from extinct in the wild to endangered after a successful reintroduction by the U.S. Fish and Wildlife Service into eight western states and Mexico from 1991-2008.  Similarly, the Wild Horse (Equus ferus) moved from extinct in the wild in 1996 to critically endangered this year after successful reintroductions started in Mongolia in the early 1990s.

The African Elephant (Loxodonta africana) moved from vulnerable to near threatened, although its status varies considerably across its range.  The move reflects the recent and ongoing population increases in major populations in southern and eastern Africa.  These increases are big enough to outweigh any decreases that may be taking place elsewhere.

“This work sets a benchmark for us to understand what is happening with biodiversity of mammals worldwide and provides a platform from which all future conservation efforts can be measured,” said Smith, who initiated the database that was used to inventory the world’s mammals.  “This effort hopefully will spur greater attention on the conservation of mammals and the habitats they occupy, for the benefit of all biodiversity.”

New research suggests that the identification and examination of key cell signaling events required for initiation and progression of cancer might be best accomplished at the single cell level.  The research, published by Cell Press in the October issue of the journal Cancer Cell, provides new insight that may lead to better diagnosis and treatment of some complex cancers.

Recent advances in flow cytometry, a technique that allows detailed examination of individual cells, have enabled simultaneous measurement of cell type and signaling pathways.  Lead study authors Dr. Garry P. Nolan from the Stanford University School of Medicine and Dr. Mignon L. Loh from the UCSF Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center were interested in determining whether examination of cellular signaling abnormalities caused by genetic mutations associated with cancer could provide a precise correlation between aberrant signaling events and disease physiology.

“We had a strong hunch that we could use ‘deranged’ cellular signaling to track how cancer cell populations behave at diagnosis through therapy, as well as during remission or return of the cancer,” explains Dr. Nolan.  “By measuring how signaling proteins respond to certain stimuli at diagnosis and which are modified by resistant cancers, we are essentially monitoring key highways that cancers use to drive their own growth.  The advantage of diagnosing a patient’s cancer at the single cell level provides us an approach for early detection of cancer and yield insights into how cancer cells are responding or adapting to therapy.  A byproduct of the single cell technique, when appropriately extended, is that we should eventually be able to predict those pathways cancer cells might be using to circumvent current therapies and more intelligently direct the patient towards alternative treatments.”

The researchers focused on juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative disorder of young children.  JMML is difficult to diagnose and has a complex molecular profile.  Although genetic lesions impacting Ras signaling and alterations downstream of the activated GM-CSF receptor (both linked with inappropriate cell growth and survival) have been linked with JMML, there are very few methods for identifying therapeutic agents and assessing efficacy in JMML patients.

The researchers used flow cytometry to profile signaling at the single cell level, including molecules associated with GM-CSF and Ras signaling, for the presence of primary JMML cells with altered signaling behavior that correlated with disease physiology.  Cells samples came from JMML patients, healthy individuals and patients with other myeloproliferative disorders, some who had initially been diagnosed with JMML.  An unexpected STAT5 signaling signature was seen in most of the JMML patients, suggesting a critical role for JAK-STAT signaling in the biological mechanism of this cancer and suggesting potential targets for future therapies.

“This work successfully used single-cell profiling to follow patients over time and show that disease status in JMML – at diagnosis, remission, relapse and transformation – was indicated by a subset of cells with an abnormal signaling profile,” says Dr. Loh.  “Revealing cell subpopulations, even rare cells, that are associated with disease opens additional avenues for measuring minimal residual disease, assessing biochemical effects of targeted therapies at the single cell level and understanding drug actions and mechanisms of diseases of heterogeneous origins and manifestations in diverse patient populations.”

Just as a credit crunch is reshaping the global economic landscape, an often-unheralded shortage of clean water is confronting business and industry with a range of profound new challenges and opportunities, according to an article scheduled for the October 6 issue of Chemical & Engineering News, ACS’ weekly news magazine.

The cover story, written by C&EN Senior Business Editor Melody Voith, points out that big industrial companies, such as Dow Chemical, General Electric, Nalco, and Ashland, must manage day-to-day operations in ways that conserve and reuse water.  Once regarded as a cheap and inexhaustible resource, clean water increasingly is in short supply around the world, Voith explains, noting that lack of clean water is “a growing risk” to industry.

“There is just no replacement for good, clean water — and it is getting harder to come by,” Voith states.  At the same time, companies that supply water purification and conservation technology are taking advantage of new opportunities.  The articles explain how companies are investing in new technologies to meet the evolving demand for water treatment chemicals, services, and equipment.

Researchers in Iran are publishing what they describe as the first study on a fungus that can remove sulfur — a major source of air pollution — from crude oil more effectively than conventional refining methods.  The finding could help reduce air pollution and acid rain caused by the release of sulfur components in gasoline and may help oil companies meet tougher emission standards for fuel, the scientists say.  Their study is scheduled for the Oct. 1 issue of ACS’ Industrial & Engineering Chemistry Research, a bi-weekly journal.

Jalal Shayegan and colleagues point out that existing processes for refining so-called “heavy,” or high-sulfur, crude oil convert sulfur to hydrogen sulfide gas at high temperatures and pressures.  However, they leave behind some kinds of sulfur-based compounds, which wind up in gasoline and other fuels.  Scientists long have known that certain microbes can remove sulfur from oil.  But nobody had tried using these microbes in so-called biodesulfurization of heavy crude oil until now, they indicate.

In the new study, the scientists describe isolation and testing of the first fungus capable of removing sulfur from heavy crude oil.  The fungus, called Stachybotrys, removed 65-76 percent of the sulfur present in certain heavy crude oil from two different oil fields.  The process does not need high temperatures and high-energy consumption because it occurs slightly above room temperature, they scientists note.

In what may be an unintended consequence of efforts to make furniture safer and less flammable, residents of California have blood levels of potentially toxic flame retardants called PBDEs at levels nearly twice the national average, scientists from Massachusetts and California are reporting.  Their study, the first to examine regional variations in PBDE levels in household dust and blood within the U.S., is scheduled for posting online Oct. 1 by ACS’ semi-monthly journal Environmental Science & Technology.

In the new study, Ami Zota and colleagues note that PBDEs (polybrominated diphenyl ethers) are widely used as flame retardants in upholstered furniture and electronics.  The materials are released into the environment as dust particles, where they can accumulate in homes as well as human blood and tissue.  Although their exact effects in humans are unclear, studies in animals suggest that PBDEs may cause thyroid, developmental, and reproductive problems.  Since California has among the most stringent furniture flammability standards, the researchers suspected that state residents may have higher levels of PBDE dust exposure than others in the United States.

To find out, the scientists compared data on PBDE concentrations in house dust from 49 California homes with concentrations reported from 120 Massachusetts homes and several other areas.  The researchers also compared data on blood levels of PBDEs in California residents to blood levels in residents of other regions.  They found that PBDE levels in California homes were four to 10 times higher than other U.S. areas.  They also found that blood levels of some PBDEs were significantly higher in California residents than the rest of the country.  “These findings raise concern about pending regulations and performance standards that encourage the widespread use of chemical flame retardants, which are toxic or whose safety is uncharacterized,” the article states.  — MTS and AD

With nanotechnology yielding a burgeoning menagerie of microscopic pumps, motors, and other machines for potential use in medicine and industry, here is one good question: How will humans turn those devices on and off?  In an advance toward giving humans that control, scientists in The Netherlands are reporting use of an external electrical signal to control an atomic-scale mechanical device that looks like the flippers on a pinball machine.  Their report is scheduled for the Oct. 8 issue of ACS’ monthly journal Nano Letters.

In the study, Harold J. W. Zandvliet and colleagues point out that efforts to build ever-smaller mechanical devices have made scientists recognize the difficulty of exerting control over these nanomachines, which are too tiny for any conventional on-off-switch.  They describe construction and successful testing of a device, “grown” on a wafer of germanium crystal, that responds to on-off stimuli.

Researchers say the device — so tiny that billions would fit on the head of a pin — resembles the arms or flippers on a pinball machine.  The signals for the arms to move back and forth come from the tip of a scanning tunneling microscope.  “By precisely controlling the tip current and distance, we make two atom pairs behave like the flippers on an atomic-sized pinball machine,” they state.  “Our observations prove unambiguously that it is possible to control an atomic scale mechanical device using a simple electrical signal.  A better understanding of similar devices can shed light on the future possibilities and opportunities for the application of atomic-scale devices.”

Researchers in Greece report design of a new material that almost meets the U.S. Department of Energy (DOE) 2010 goals for hydrogen storage and could help eliminate a key roadblock to practical hydrogen-powered vehicles.  Their study on a way of safely storing hydrogen, an explosive gas, is scheduled for the Oct. 8 issue of ACS’ Nano Letters, a monthly journal.

Georgios K. Dimitrakakis, Emmanuel Tylianakis, and George E. Froudakis note that researchers long have sought ways of using carbon nanotubes (CNTs) to store hydrogen in fuel cell vehicles.  CNTs are minute cylinders of carbon about 50,000 times thinner than the width of a human hair.  Scientists hope to use CNTs as miniature storage tanks for hydrogen in the coming generation of fuel cell vehicles.

In the new study, the researchers used computer modeling to design a unique hydrogen-storage structure consisting of parallel graphene sheets — layers of carbon just one atom thick —stabilized by vertical columns of CNTs.  They also added lithium ions to the material’s design to enhance its storage capacity.  The scientists’ calculations showed that their so-called “pillared graphene” could theoretically store up to 41 grams of hydrogen per liter, almost matching the DOE’s target (45 grams of hydrogen per liter) for transportation applications.  “Experimentalists are challenged to fabricate this material and validate its storage capacity,” the researchers note.

Some bacteria may help protect against the development of a type of esophageal cancer, known as adenocarcinoma, according to a new review of the medical literature.  These bacteria, which are called Helicobacter pylori, live in the stomachs of humans.

The review, published in the October issue of Cancer Prevention Research, a journal of the American Association for Cancer Research, found that people who had H. pylori strains carrying a gene called CagA were almost half as likely to get adenocarcinoma of the esophagus, a cancer that develops in the tube that passes food from the throat to the stomach.

“CagApositive strains of H. pylori may decrease the risk of adenocarcinoma by reducing acid production in the stomach and, therefore, reducing acid reflux to the esophagus,” said study co-author Farin Kamangar, M.D., Ph.D., a research fellow at the National Cancer Institute.  “It may also work by decreasing the production of the hormone ghrelin, which is secreted from the stomach to stimulate appetite.  A reduction in the level of ghrelin may lead to lower rates of obesity, an important risk factor for adenocarcinoma.”

H. pylori, estimated to be present in about half the world’s population, is a known cause of stomach cancer and ulcers.  Advancements in sanitation and antibiotics have made H. pylori less common and have consequently lowered the incidence stomach cancer and ulcers.  However, as H. pylori, including CagA-positive H. pylori, has become less common, esophageal adenocarcinomas have increased.  The study suggests that the declining rates of H. pylori in developed populations may be partly responsible for this increase.  Once a rare cancer, esophageal adenocarcinomas now constitute approximately half of all esophageal cancers cases in Western Countries like the U.S. and United Kingdom.

Although H. pylori was first discovered in the early 1980s, Kamangar says humans already had been living with the bacteria for 60,000 years.  The bacteria were once present in the stomachs of just about everyone.  Despite its potential for causing stomach cancer and ulcers, H. pylori’s long history of co-existence with humans suggests it also may have some beneficial effects, including possible roles in reducing diarrheal diseases and asthma, Kamangar said.

For the study, Kamangar and co-author Farhad Islami of the University of Tehran in Iran analyzed results from 19 published studies examining the associations of H. pylori with esophageal adenocarcinoma and esophageal squamous cell carcinoma, another type of esophageal cancer.

Caswell et al.report in the Journal of Cell Biology how the altered behavior of integrins can prompt metastatic movement in tumor cells.

On 2D surfaces, cells may migrate randomly, or be strongly unidirectional.  Integrins, which link the cell to the extracellular matrix, are known to influence the mode of migration, but exactly how has been unclear.  Recent work has suggested that an integrin called a5b1 drives random movement, while an integrin called avb3 has been associated with unidirectional migration—the balance of activity between the two determining the type of movement.  To further explore the contribution of a5b1 to random migration, the authors thus blocked avb3.

The treated cells changed their mode of migration from unidirectional to random, and their ability to invade 3D gels increased.  The changed behavior correlated with an increase in trafficking of a5b1 from intracellular compartments to anterior membrane protrusions.  But this increase in trafficking did not significantly alter a5b1’s contribution to cell adhesion—the ease with which cells were dislodged from a spinning disk increased as the amount of avb3 was reduced, but was not correlated with any change in a5b1.  This suggested that the cells’ increased invasive ability was due to alteration in some other property.  That property turned out to be activation of a proinvasive pathway headed by a kinase called Akt.

In avb3-blocked cells, a5b1 became associated with epidermal growth factor receptor 1 (EGFR1), which increased EGFR1’s abundance at the membrane protrusions, as well as its autophosphorylation.  Because EGFR1 is an activator of the Akt pathway, hey presto, the cells took on some new moves.

Scientists report online this week in Nature that they have linked the health of specialized gut immune cells to a gene associated with Crohn’s disease, an often debilitating and increasingly prevalent inflammatory bowel disorder.

The link to immune cells intrigued researchers at Washington University School of Medicine in St. Louis because they and others believe Crohn’s disease is caused by misdirected immune responses in the intestine that damage gut tissue.  In addition, cells in the mouse model scientists used for the study had altered genetic activity that could lead to increased production of certain hormones.  Those same hormones are elevated in some Crohn’s patients.

“We now have a significant new piece of the puzzle that is Crohn’s disease, but not the solution just yet,” says senior author Herbert W. “Skip” Virgin, M.D., Ph.D., the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology.  “As many as 30 different areas in human DNA have potential links to Crohn’s disease, and to develop new treatments it’s going to be essential to find out how each of them, as well as environmental factors, contribute to the disorder.”

Crohn’s disease is one of the most common inherited bowel disorders.  In 2002, epidemiologists estimated that it affected 400,000 to 600,000 patients in North America.  Symptoms include diarrhea, abdominal pain, vomiting and weight loss.  The condition can lead to partial or full intestinal blockages, which can require surgical treatment.

Research previously revealed that some Crohn’s disease patients have a mutation in a gene known as Atg16L1.  The mutation increases risk but doesn’t automatically lead to Crohn’s disease.  To learn more, Ken Cadwell, Ph.D., a postdoctoral student in Virgin’s lab, created and studied two lines of mice with a genetic alteration that reduced their ability to make the Atg16L1 protein.

Cadwell and his colleagues found decreased Atg16L1 protein had pronounced effects on Paneth cells, which are immune cells in the lining of a portion of the small intestine.  These cells make proteins and antimicrobial peptides that they package as granules and secrete into the intestine to defend the body against infection.

“When they have less Atg16L1, the Paneth cells survive, but their ability to secrete granules is significantly impaired,” Cadwell says.

Virgin consulted with co-authors Ellen Li, M.D., Ph.D., and Thaddeus Stappenbeck, M.D., Ph.D., Washington University researchers who study and treat Crohn’s disease patients at Barnes-Jewish Hospital.  When surgery becomes necessary to repair a patient’s bowel, Li collects samples removed from the intestine for research.  Selecting tissue from patients with mutated Atg16L1, researchers compared human Paneth cells to cells from their mouse model and found what Virgin calls “striking similarities.”

To learn how Atg16L1 helps the Paneth cell, scientists conducted a follow-up experiment where a related gene, Atg5, was knocked out in mice.  Like Atg16L1, Atg5 contributes to an important process called autophagy that lets cells consume and reuse their own resources and may have other functions as well.  Paneth cells in this line of mice had impairments similar to the first line, suggesting that Atg16L1’s contributions to the Paneth cell may be linked to autophagy.

“We don’t yet know why having abnormal Paneth cells would predispose a person to Crohn’s disease or to what degree other genes linked to Crohn’s may affect the Paneth cell, but those are just a few of the very interesting questions to follow up on from these results,” Virgin says.

Chemicals used in the environment to kill bacteria could be making them stronger, according to a paper published in the October issue of the journal Microbiology.  Low levels of these chemicals, called biocides, can make the potentially lethal bacterium Staphylococcus aureus remove toxic chemicals from the cell even more efficiently, potentially making it resistant to being killed by some antibiotics.

Biocides are used in disinfectants and antiseptics to kill microbes.  They are commonly used in cleaning hospitals and home environments, sterilizing medical equipment and decontaminating skin before surgery.  At the correct strength, biocides kill bacteria and other microbes.  However, if lower levels are used the bacteria can survive and become resistant to treatment.

“Bacteria like Staphylococcus aureus make proteins that pump many different toxic chemicals out of the cell to interfere with their antibacterial effects,” said Dr Glenn Kaatz from the Department of Veterans Affairs Medical Center in Detroit, USA.  “These efflux pumps can remove antibiotics from the cell and have been shown to make bacteria resistant to those drugs.  We wanted to find out if exposure to biocides could also make bacteria resistant to being killed by the action of efflux pumps.”

The researchers exposed S. aureus taken from the blood of patients to low concentrations of several biocides and dyes, which are also used frequently in hospitals.  They looked at the effect of exposure on the bacteria and found that mutants that make more efflux pumps than normal were produced.

“We found that exposure to low concentrations of a variety of biocides and dyes resulted in the appearance of resistant mutants,” said Dr Kaatz.  “The number of efflux pumps in the bacteria increased.  Because the efflux pumps can also rid the cell of some antibiotics, pathogenic bacteria with more pumps are a threat to patients as they could be more resistant to treatment.”

If bacteria that live in protected environments are exposed to biocides repeatedly, for example during cleaning, they can build up resistance to disinfectants and antibiotics.  Such bacteria have been shown to contribute to hospital-acquired infections.

“Scientists are trying to develop inhibitors of efflux pumps.  Effective inhibitors would reduce the likelihood of additional resistance mechanisms emerging in bacteria,” said Dr Kaatz.  “Unfortunately, inhibitors evaluated to date do not work on a wide range of pathogens so they are not ideal to prevent resistance.”

“Careful use of antibiotics and the use of biocides that are not known to be recognised by efflux pumps may reduce the frequency at which resistant strains are found,” said Dr Kaatz.  “Alternatively, the combination of a pump inhibitor with an antimicrobial agent or biocide will reduce the emergence of such strains and their clinical impact.”

If the current financial climate has taught us anything, it’s that a system where over-borrowing goes unchecked eventually ends in disaster.  It turns out this rule applies as much to our bodies as it does to economics.  Instead of cash, our body deals in energy borrowed from muscle and given to the brain.

Unlike freewheeling financial markets, the lending process in the body is under strict regulation to ensure that more isn’t lent than can be afforded.  New research by scientists at the Salk Institute for Biological Studies reveals just how this process is implemented.

“We have all seen the sub-prime mortgage crisis,” says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study.  “If you take out a loan, sooner or later you’ve got to pay your debt, and the same is true in fasting metabolism.”

The Salk researchers’ findings, which are published ahead of print in the Oct. 5 edition of the journal Nature, may pave the way for novel therapies for sufferers of metabolic diseases in whom such regulation can spiral out of control.

Most tissues in our bodies respond to fasting by switching from their usual high-octane energy source—glucose—to burning a low-octane, cheaper alternative-fat.  For our brains, however, only the high-performance fuel will do.  If no food-derived glucose is available, the body must manufacture its own supply to maintain the brain in the manner to which it is accustomed.  It does so by taking energy from muscle in the form of protein and converting it to glucose in the liver, a process known as gluconeogenesis.  The sugar is then shipped via the bloodstream to the brain to keep it running smoothly.

Gluconeogenesis needs to be turned on rapidly in response to fasting, but shutting it off again is just as crucial.  “You don’t want gluconeogenesis to be prolonged,” says postdoctoral researcher and co-first author Yi Liu, Ph.D. “Because it uses muscle as a protein source, it will eventually lead to muscle wastage.”  Adds Montminy, “The question has always been how is the production of glucose turned on, and how is shut off again?”

Previous work by the Montminy lab and others has shown that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting.  CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating.  FOXO1, on the other hand, is activated when levels of the food-stimulated hormone insulin drop below a certain threshold.  CRTC2’s and FOXO1’s activity needs to be tightly regulated, since producing too much glucose would result in over-borrowing of energy from muscle tissue.

To uncover the mechanism that ensures that this doesn’t happen, the Salk researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies, engineered in such a way that it was only turned on when CRTC2 was active.  Using imaging equipment, they could then detect CRTC2 activity in the livers of live mice simply by measuring how much they glowed.

When the mice were fasted, CRTC2 was rapidly activated, and the livers lit up, but to the scientists’ surprise, after six hours the light went out.  Experimentally decreasing the levels of CRTC2 or FOXO1 confirmed there was a two-stage fasting-response.  Lowering CRTC2 reduced gluconeogenesis only early on, while less FOXO1 only affected late glucose production.  As in a relay race, during fasting the baton for glucose production appeared to be passed from CRTC2 in stage one to FOXO1 in stage two.

The crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage.  Yi discovered that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter, and thus the baton is safely transferred from CRTC2 to the FOXO1.

Why does the body want to change between these two regulators of glucose production?  Again, it comes down to body economics.  CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagon.  Switching to FOXO1 later on slows down this production to more sustainable levels, while at the same time helping to produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle.  “It is just like paying your loan back,” says Montminy.  “Later on you produce blood sugar at a different rate than you did at the beginning.”

Knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients.  In, particular, chemical activators of the SIRT1 switch may be key.  “This way we could provide control for patients with insulin resistance,” says Montminy, “as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active.”  Perhaps, then, a pharmacological rescue package for patients whose lending systems have been left unregulated may be on the horizon.