Labslink Research News

Researchers identify genes tied to deadliest ovarian cancers

Thu, 09 Sep 2010 03:33:37 PDT

Scientists at the Johns Hopkins Kimmel Cancer Center have identified two genes whose mutations appear to be linked to ovarian clear cell carcinoma, one of the most aggressive forms of ovarian cancer. Clear cell carcinoma is generally resistant to standard therapy. In an article published online in the September 8 issue of Science Express, the researchers report that they found an average of 20 mutated genes per each ovarian clear cell cancer studied. Two of the genes were more commonly mutated among the samples: ARID1A, a gene whose product normally suppresses tumors; and PPP2R1A, an oncogene that, when altered, helps turn normal cells into tumor cells. ARID1A mutations were identified in more than half of tumors studied, and, according to Siân Jones, Ph.D., research associate at the Johns Hopkins Kimmel Cancer Center, "this gene may play a significant role in this type of cancer." The researchers say that ARID1A and PPP2R1A had not previously been linked to ovarian cancer, and "they may provide opportunities for developing new biomarkers and therapies that target those genes," says Nickolas Papadopoulos, Ph.D., an associate professor of oncology and director of Translational Genetics at the Ludwig Center for Cancer Genetics & Therapeutics at the Johns Hopkins Kimmel Cancer Center. For the study, the scientists evaluated mutations in 18,000 protein-encoding genes in ovarian clear cell tumors from eight patients at Johns Hopkins and from institutions in Taiwan and Japan. They purified the cancer cells, and analyzed genes from those cells and from normal cells obtained from the blood or uninvolved tissues of the same patients. Researchers identified 268 mutations in 253 genes among the eight tumors, with an average of 20 mutations per tumor. Next, they determined the amino acid makeup, or sequences, of four genes with the most prevalent mutations, including ARID1A, in the tumor and normal tissues of an additional 34 ovarian clear cell cancer patients. Altogether, ARID1A mutations were identified in 57 percent of the 42 tumors. PPP2R1A mutations were found in 7.1 percent of the tumors. The landscape of cancer-related genes can be likened to a few "mountains" (highly prevalent mutations) among many "hills" (genes with less prevalence), says Papadopoulos, and "ARID1A is one of the biggest mountains found in recent years." The protein encoded by ARID1A is a component of a cellular structure called a chromatin remodeling complex. Chromatin compresses DNA to make it fit inside cells and shields it from any other chemical signals, providing a means for controlling how and when the DNA is read. When chromatin gets remodeled, the components are shuffled and certain areas of DNA become exposed, allowing genes to be switched on or off. When the ARID1A gene is mutated, the chromatin remodeling complex is altered, allowing genes to be incorrectly switched on or off. The Johns Hopkins scientists say mutated ARID1A can now be linked to so-called "epigenetic" changes – alterations to DNA occurring outside of the genome, in this case, the chromatin. "The mutations in ARID1A provide an important new link between genetic and epigenetic mechanisms in human cancer and may help identify epigenetic changes which can be targeted with therapies," says Victor Velculescu, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center. The researchers next plan to search for genes whose chromatin is specifically affected by ARID1A inactivation. Ovarian clear cell carcinoma accounts for about 10 percent of cancers that start in the cells on the surface of the ovaries. It mainly affects women ages 40 to 80 and is resistant to chemotherapy.

Investigating better endpoints for immunotherapy trials

Thu, 09 Sep 2010 03:32:35 PDT

Cancer immunotherapy calls for revised clinical endpoints that differ from those used for chemotherapy, according to an article published online September 8 in The Journal of the National Cancer Institute. Unlike chemotherapy, which acts directly on tumors, cancer immunotherapies exert their effects on the immune system, which may delay or change response patterns, perhaps owing to the dynamics of the immune system itself. For example, initial tumor burden may increase due to lymphocytic infiltration, because of T-cell proliferation, which is followed by lymphocyte-induced tumor response. These delayed reactions and other novel patterns of anti-tumor response are not part of standard criteria from the World Health Organization (WHO), or the Response Evaluation Criteria in solid Tumors (RECIST). To study and develop a new paradigm for immunotherapy clinical trials, Axel Hoos, M.D., of the Global Clinical Research division of Bristol-Myers Squibb, looked at design and outcomes of immunotherapy clinical trials, as part of several initiatives undertaken by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations between 2004 and 2009. The resulting principles for redefining immunotherapy trial endpoints were subsequently tested by Bristol-Myers Squibb (a member of the Consortium) in its immunotherapy clinical trials. In these studies, four response patterns were detected: immediate response, durable stable disease, response after tumor burden increase, and development of new lesions. The latter two are specifically recognized with immunotherapeutic agents. The results were translated into new response criteria called the immune-related response criteria, or irRC. Hoos writes, "The irRC are generally based on the WHO and RECIST criteria and do not require a substantial departure from standard oncology practice. The novelty of the irRC lies in the measurement of new lesions, which are included in the overall tumor burden, allowing for it to be described as a continuous variable." Furthermore, "Considering the time of translation of immunologic responses into clinical activity, the survival of patients may not be affected until some months after treatment started compared with chemotherapy," writes Hoos, adding that the kinetics observed for survival may require new statistical approaches for planning randomized trials. In an accompanying editorial, Donald A. Berry, M.D., of the University of Texas M.D. Anderson Center, addresses the conundrum of delayed responses often induced by immunotherapies: "Any delayed effect of therapy makes product development harder and more expensive than developing a drug that works by attacking the tumor directly." Moreover, Berry worries about another potential problem in developing immunotherapies: "To fully investigate the potential of an immunotherapy, clinicians may have to stick with it beyond a patient's progression and thereby delay switching to potentially more effective therapy," he writes.

Use of informatics, EMRs enable genetic study of vascular disease

Thu, 09 Sep 2010 03:30:41 PDT

Scientific research published in the current issue of the Journal of the American Medical Informatics Association (JAMIA) reports on a study of genetic variants that influence human susceptibility to peripheral arterial disease (PAD), made possible by leveraging electronic medical records (EMRs; also called EHRs or electronic health records). A team of authors from the Mayo Clinic Divisions of Cardiovascular Diseases and Biomedical Informatics and Statistics conducted the study and concluded that EMR-based data, used across institutions in a structured way, "offer great potential for diverse research studies, including those related to understanding the genetic bases of common diseases." The authors, Iftikhar Kullo, MD; Jin Fan, MD; Jyotishman Pathak, PhD; Guergana Savova, PhD; Zeenat Ali, MD; and Christopher G. Chute, MD, DrPH, demonstrated the feasibility of leveraging EHRs to launch a genome-wide association study of PAD, which affects approximately eight million Americans 40 years old and older, and which includes 20 percent of the elderly (70+ years old) in the United States. According to the authors, PAD is associated with "significant mortality and morbidity, underscoring the necessity of a rigorous investigation." The physicians used EHRs to confirm cases of PAD, and to identify phenocopies, i.e. mimics of atherosclerotic PAD. With patient consent, and the approval of Mayo's Institutional Review Board, the research team accessed electronic health records in a federated warehouse of patient data that Mayo Clinic has used since 1997—a database of more than eight million patients. Using the Mayo Enterprise Data Trust (EDT), the researchers extracted relevant clinical variables on study participants that could confound the association of genetic susceptibility variants with PAD. Dr. Chute observed that the EDT "provides a scalable solution for clinical research, providing comparable and consistent data that can be employed in comparative effectiveness studies, outcomes research, or translational research as illustrated by this JAMIA paper." In the study, PAD was defined as a resting/post-exercise ankle-brachial index (ABI) less than or equal to 0.9, a history of lower extremity revascularization, or having poorly compressible leg arteries. Controls were patients without evidence of PAD. Demographic data and laboratory values were extracted from EHRs. Medication use and smoking status were identified by natural language processing (NLP) of clinical notes. "Although manual abstraction of medical records can provide high-quality data," the authors write, "for large studies such as genetic association studies, manual review of medical records can be prohibitively expensive and time-consuming. Our study demonstrates . . . .several significant advantages over traditional approaches to genomic medicine research by simplifying logistics, reducing timelines, and overall costs through efficient data acquisition." In their statistical analyses, the researchers used metrics long recognized in the NLP and information-retrieval community—precision, recall, and F-measure—to evaluate EMR-based algorithms compared with manual medical record review. Most cardiovascular risk factors and co-morbidities were captured from the EMRs with an accuracy rate higher than 90 percent. The researchers analyzed age, sex, BMI, race, geographical distribution, risk factors, co-morbidities, smoking status, and medications.

Novel sensing mechanism discovered in dendritic cells to increase immune response to HIV

Thu, 09 Sep 2010 03:28:56 PDT

Dendritic cells are the grand sentinels of the immune system, standing guard 24/7 to detect foreign invaders such as viruses and bacteria, and bring news of the invasion to other immune cells to marshal an attack. These sentinels, however, nearly always fail to respond adequately to HIV, the virus causing AIDS. Now a team of scientists at NYU Langone Medical Center has discovered a sensor in dendritic cells that recognizes HIV, spurring a more potent immune response by the sentinels to the virus. They report their findings in the September 9, 2010, issue of Nature. "This is the first time that an alarm system that recognizes retroviruses like HIV has been discovered," says Dan Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Departments of Pathology and Microbiology at NYU Langone Medical Center and a Howard Hughes Medical Institute investigator, and the study's lead author. "The ability to stimulate a protective immune response against HIV is critical to the development of therapeutic or preventive vaccines for the virus," says Dr. Littman. In contrast to normal vaccines, which prevent infection, therapeutic vaccines are designed to boost the severely weakened immune systems of people infected with HIV. Dendritic cells, named for their branching, tree-like shape, have been called the maestros of the immune system because they orchestrate a dynamic range of immune responses. These cells have attracted intense interest from researchers in many fields because of their potential to fight disease and prevent rejection of organ transplants. When a dendritic cell captures a dangerous pathogen, it tears it apart and delivers a piece to the soldiers of the immune system cells, called T-cells, which in turn expand like a clonal army to coordinate immune defenses and destroy the invader. But dendritic cells fail to recognize HIV as a danger. Instead, HIV exploits the cells to get a free ride to T-cells, which become infected with the virus. "The virus actually infects the same soldiers that are supposed to protect us from it," explains co-author Derya Unutmaz, MD, associate professor in the Departments of Microbiology, Pathology and Medicine at NYU Langone Medical Center. Although HIV enters dendritic cells, an unknown mechanism blocks the virus from infecting them—going into the nucleus of the cells to make copies of itself. Recently, a technique was discovered to overcome this block by bathing the cells with a protein derived from SIV, a relative of HIV that only infects monkeys. Using these techniques, the researchers discovered that when HIV was forced to enter the nucleus of dendritic cells, the cells unexpectedly recognized the virus as an intruder and went into action to initiate a program to stimulate a stronger T-cell response against the virus. What set off the alarm, the researchers found, was a protein called capsid, which encapsulates HIV's genetic material. "It's surprisingly unexpected that the sensing mechanism of the dendritic cell recognizes the capsid of the virus, rather than the genetic material inside," says co-author Nicolas Manel, PhD, of The Kimmel Center for Biology and Medicine at the Skirball Institute at NYU Langone Medical Center and the Institut de Genetique Moleculaire de Montpellier. "Nevertheless, by adding elements of this capsid to a vaccine," says Dr. Manel, "it may be possible to improve the immune response of those who already have HIV or actually mount a potent immune response before the individual is infected." "We still don't understand why this sensor is triggered only when we force HIV to integrate into dendritic cell genome to make its own copies," adds Dr. Unutmaz. "One possibility is that this cryptic sensing mechanism has evolved to recognize the thousands of ancient retroviruses that have infected us in the past and now make up almost 10% our genome. It is conceivable that dendritic cells have evolved this internal sensor in case any of these archaic retroviruses were reawakened. Nonetheless, the finding is extremely exciting because not only it could lead to new directions in HIV vaccine research but it can also be exploited to enhance vaccines against other viruses."

Single gene regulates motor neurons in spinal cord

Thu, 09 Sep 2010 03:27:47 PDT

In a surprising and unexpected discovery, scientists at NYU Langone Medical Center have found that a single type of gene acts as a master organizer of motor neurons in the spinal cord. The finding, published in the September 9, 2010 issue of Neuron, could help scientists develop new treatments for diseases such as Lou Gehrig's disease or spinal cord injury. The "master organizer" is a member of the Hox family of genes, best known for controlling the overall pattern of body development. By orchestrating a cascade of gene expression in the early embryo, Hox genes allow for the creation of an animal's overall structure and body part orientation. Scientists first discovered the genes in fruit flies but they have since detected Hox activity in mammals. Humans harbor 39 such genes and 21 have been identified as coordinating motor neurons in the spinal cord. "We knew that there were 21 Hox genes that determine how connections are made between motor neurons in the spinal cord and muscles in the limbs," says Jeremy S. Dasen, PhD, an associate professor in the Departments of Physiology and Neuroscience at NYU Langone Medical Center and a Howard Hughes Medical Institute Early Career Scientist. "But what was surprising to us in this study was that a single Hox gene acts as a global organizer of motor neurons and their connections. The next step will be to see how Hoxc9 in motor neurons affect motor behaviors such as walking and breathing." In mammals, many hundreds of motor neurons are needed to control the variety of muscle cells used to coordinate movement. Proper function depends on each of these neurons in the embryo finding its way from the spinal cord to the group of muscles that it is equipped to control. Dr. Dasen and his colleagues have been working to discover the blueprint for this motor neuron diversity. For this study, scientists studied mice with a mutation in Hoxc9 gene. They analyzed the molecular markers that distinguished between motor neurons in the limb and thoracic area and discovered mutation of Hoxc9 transformed the thoracic motor neurons into limb motor neurons. In a series of biochemical experiments they further showed that Hoxc9 orchestrates gene expression in motor neurons by repressing the Hox genes dedicated to limb coordination. "What we are trying to understand is how the nervous system is wired to control movements such as breathing and walking and see how genetic programs can further control these circuits in terms of exploring this paradigm as a way at looking at the vital circuits of the body," adds Dr. Dasen.

Brown-led research divines structure for class of proteins

Thu, 09 Sep 2010 03:26:48 PDT

Most proteins are shapely. But about one-third of them lack a definitive form, at least that scientists can readily observe. These intrinsically disordered proteins (IDPs) perform a host of important biological functions, from muscle contraction to other neuronal actions. Yet despite their importance, "We don't know much about them," said Wolfgang Peti, associate professor of medical science and chemistry. "No one really worried about them." Now, Peti, joined by researchers at the University of Toronto and at Brookhaven National Laboratory in New York, has discovered the structure of three IDPs — spinophilin, I-2, and DARPP-32. Besides getting a handle on each protein's shape, the scientists present for the first time how these IDPs exist on their own (referred to as "free form") and what shape they assume when they latch on to protein phosphatase 1, known as "folding upon binding." The findings are reported in the journal Structure. Determining the IDPs' shape is important, Peti explained, because it gives molecular biologists insight into what happens when IDPs fold and regulate proteins, such as PP1, which must occur for biological instructions to be passed along. "What we see is some amino acids don't have to change much, and some have to change a lot," Peti, a corresponding author on the paper, said. "That may be a signature how that (binding) interaction happens." For two years, the researchers used a variety of techniques to ascertain each IDP's structure. With I-2, which instructs cells to divide, they used nuclear magnetic resonance spectroscopy to create ensemble calculations for the protein in its free and PP1-bound form. They confirmed I-2's binding interaction with PP1 (known as the PP1:I-2 complex) with the help of small-angle X-ray scattering measurements at the National Synchrotron Light Source, located at the Brookhaven lab. The researchers did the same thing to determine the structure of spinophilin and DARPP-32 in their free-form state and to gain insights into their shapes when they bind with PP1. "It's analogous to putting a sack cloth over a person," Peti explained. "You can't see the details, but you can get the overall shape. This is really a new way to create a structure model for highly dynamic complexes."

Study identifies critical 'traffic engineer' of the nervous system

Thu, 09 Sep 2010 03:25:22 PDT

A new University of Georgia study published in the journal Nature has identified a critical enzyme that keeps traffic flowing in the right direction in the nervous system, and the finding could eventually lead to new treatments for conditions such as Alzheimer's and Parkinson's disease. "There was no medical or any other applied science drive for this project; it was purely curiosity about how transport inside cells works," said study co-author Jacek Gaertig, professor in the cellular biology department in the UGA Franklin College of Arts and Sciences. "But it looks like we have identified an important enzyme that acts in the nervous system." He explained that cells contain a network of tubes known as microtubules that are made of protein and serve as tracks for the shuttling of materials from one part of the cell to another. The traffic signs on this microtubule network are chemical additions such as acetylation marks. Microtubules in parts of neurons in the brain that send signals, for example, are loaded with acetylation marks. Microtubules in parts of neurons that receive signals, on the other hand, have few. Acetylation marks were discovered in 1983, and researchers recently determined their role in regulating the binding of the motor proteins that shuttle materials along microtubules. What has been unclear for more than 25 years, however, was the cellular process by which these acetylation marks are formed. In other words, which enzyme decides where the traffic signs go? Through a series of studies using the microscopic protozoan Tetrahymena, the nematode C. elegans, zebrafish and human cancer cells, Gaertig and his colleagues revealed that an a protein known as MEC-17 is the traffic engineer in charge of microtubule acetylation. MEC-17 acts as an enzyme to catalyze the acetylation reaction on microtubules, and is involved in the sensation of touch in the nematode. Its depletion in zebrafish, which are commonly used as a model organism to study basic processes, results in neuromuscular defects. Importantly, several research groups have previously reported that the levels of acetylation marks on microtubules are altered in human neurodegenerative diseases such as Huntington's, Parkinson's and Alzheimer's. Gaertig said that with the enzyme identified and its mechanism of action known, it is now possible for drug manufacturers to search for compounds that block or enhance its activity. Graduate student Shilpa Akella and postdoctoral associate Dorota Wloga in Gaertig's lab studied the enzyme in the protozoan and in vitro, while Jihyun Kim and Natalia Starostina in the lab of Edward Kipreos, professor of cellular biology, showed how it worked in the nematode and found that the enzyme is active in human cancer cells. The lab of associate professor and Georgia Cancer Coalition Distinguished Scholar Scott Dougan deduced its role in zebrafish, and Sally Lyons-Abbott and Naomi Morrissette at the University of California-Irvine biochemically purified microtubules that are marked by MEC-17. "Working together allowed us to use all kinds of models to establish that this microtubule acetylation process using MEC-17 is an evolutionarily conserved function," Gaertig said. "Without close collaboration, that would not have been possible."

House-sharing with microbes

Thu, 09 Sep 2010 03:24:12 PDT

Household dust contains up to 1000 different species of microbes, with tens of millions of individual bacterial cells in each gram. And these are just the ones that can be grown in the lab! Dr Helena Rintala, speaking at the Society for General Microbiology's autumn meeting in Nottingham describes how we share our living and working spaces with millions of microbes, not all of whom are bad news. Microbes are a part of our normal environment and can be both beneficial and detrimental to our health. "Exposure to microbes in childhood can prevent the development of allergies. On the other hand, mould growth can increase the risk of asthma," said Dr Rintala from the National Institute for Health and Welfare in Finland. In indoor environments microbes thrive on surfaces that are occasionally moist or wet, for example in the kitchen and bathroom. Prolonged damp anywhere in the house can lead to greater numbers of microbes. "These microbes, their spores and the molecules they secrete can be released into the air which can lead to health problems if they are breathed in," she said. Dr Rintala explains why it is important to study the microbes, both good and bad, that typically live in indoor environments. "When you consider that we spend more than 90% of our lifetime in indoor environments and breathe the indoor air with all its components, it is important to know that the environment is healthy and that the air is safe to breathe," she said. The Finnish group is working towards identifying microbial species that are important to our health - both good and bad - and developing rapid detection methods for them. "Culture methods are slow and selective – but with the development of new DNA-based methods we can assess the indoor air quality of homes and workplaces more rapidly, enabling people to take faster action if there is a problem," said Dr Rintala.

MIT researchers find that interneurons are not all created equally

Thu, 09 Sep 2010 03:22:41 PDT

A type of neuron that, when malfunctioning, has been tied to epilepsy, autism and schizophrenia is much more complex than previously thought, researchers at MIT's Picower Institute for Learning and Memory report in the Sept. 9 issue of Neuron. The majority of brain cells are called excitatory because they ramp up the action of target cells. In contrast, inhibitory cells called interneurons put the brakes on unbridled activity to maintain order and control. Epileptic seizures, as well as symptoms of autism and schizophrenia, have been tied to dysfunctional inhibitory cells. "Too much activity and you run the risk of uncontrolled activity, while too little leads to cognitive and behavioral deficits," said Mriganka Sur, Paul E. Newton Professor of Neuroscience, whose laboratory carried out the study. "Normal brain development and function hinges on the delicate balance between excitation and inhibition." For a long time, interneurons, which make up only one-fifth of brain cells, were thought to be a kind of generic, homogenous shutdown agent. The MIT study points to a new view: At least some interneurons have very precise responses and form specific connections and circuits. "If these cells are targeted in brain disorders, then these disorders must arise from precise dysfunction in specific circuits," said Sur, head of the MIT Department of Brain and Cognitive Sciences. "This study sheds light on precisely what is going on in these circuits that may be targeted for future treatments." Inhibitory cells are diverse: researchers are only starting to discern distinct electrophysiological profiles, shapes and molecular signatures among the 20 or more known types. But all interneurons fall into two clear subtypes: those that target the cell body, or soma, of their target cells and those that target the branchlike dendrites. The soma-targeting type expresses a protein called parvalbumin and has been linked to brain disorders and circuit development. This type of interneuron was thought to dampen activity uniformly across the cortex. "Our paper overturns this view," Sur said. "These neurons had been thought to have only broad response features that would nonspecifically dampen their target cells. Our finding indicates that they have well-defined properties and functions," he said. MIT graduate student Caroline Runyan and postdoctoral fellows James Schummers, Audra Van Wart and Nathan Wilson used cutting-edge techniques to examine the properties of parvalbumin-expressing inhibitory neurons. With the help of mice genetically engineered to have just these cells fluoresce red in their visual cortex, the researchers used a sophisticated technique called two-photon imaging to identify and record the activity of these cells in living animals. They found that parvalbumin-expressing interneurons have a range of response features. Many of these cells have precisely tuned responses. Some only respond to very specific signals and locations in space. "These cells are components of and contributors to highly specific networks that shape the selectivity of neuronal responses," Runyan said. "They need to be defined by a combination of features, including structure, connections, gene expression profiles, electrophysiological properties and response types. "This study supports the idea that individual cell classes may provide specific forms of inhibition and serve unique functions," she said.

Researchers identify potential new drug for neurodegenerative disease

Thu, 09 Sep 2010 03:21:17 PDT

Scientists have discovered a small molecule that helps human cells get rid of the misfolded, disfigured proteins implicated in Alzheimer¹s disease and other neurodegenerative ailments. This potential drug could have applications for other conditions as well. Cells create and discard proteins continuously, a process that relies on a balance between the speed with which new proteins are created and damaged ones destroyed. Protein destruction occurs through a sophisticated system that marks proteins for disposal by tagging them with a small molecule called ubiquitin. Ubiquitin latches onto these proteins, often forming long chains. The cell¹s protein waste-disposal system, the proteasome, recognizes these ubiquitinated proteins and breaks them down. If that finely tuned system malfunctions, damaged or misfolded proteins begin to accumulate in the cell and may become toxic. A number of ailments, including Parkinson¹s, CreutzfeldtJakob and Alzheimer¹s have been linked to this build up of misfolded proteins. To better understand just what causes this malfunction, a research team led by Harvard Medical School researchers Daniel Finley, professor of cell biology, and Randall King, associate professor of cell biology, zeroed in on an enzyme called Usp14. They found that, when activated, Usp14 disassembles the ubiquitin chain, slowing down the proteasome¹s ability to rid the cell of bad proteins. As a result, the cell makes new proteins faster than it rids itself of the old ones, leading to a build-up of misfolded proteins. The researchers wanted to see if they could find a molecule that inhibited Usp14, thus allowing the proteosome to work effectively. To identify such a selective inhibitor, Byung-Hoon Lee, a postdoctoral researcher, developed a special screening assay with assistance from the Institute of Chemistry and Cell Biology-Longwood Screening Facility at HMS. Lee screened 63,000 compounds, looking for molecules that inhibited only Usp14 and could easily infiltrate the cell. The strongest candidate was a small molecule they named IU1. Experimenting in both human and mouse cell cultures, Min Jae Lee, also a postdoctoral researcher, and his coworkers found that IU1 inhibited Usp14 and allowed the proteasome to dispose of proteins more quickly. In other words, adding IU1 to cells boosted proteasome activity. Though scientists are still investigating just how IU1 works, it appears that the molecule suppresses Usp14¹s ability to trim the ubiquitin chain. In addition to discovering IU1, this research has also shed light on an aspect of proteasome function that was not previously understood, King says. Scientists had thought that the proteasome was not involved in regulating the speed of protein degradation, but that other proteins work with ubiquitin to modulate the process. ³Our work suggests that there is another level of control where the rate at which the proteasome can degrade these ubiquinated proteins is also controlled,² King says. ³It looks like there are multiple control steps along the way in this pathway.² As scientists learn more about the link between misfolded proteins and human disease, interest in the proteasome has increased. While much of that focus has been on ways to inhibit proteasome function, there may be an advantage to developing a drug that boosts proteasome activity rather than hinders it, Finley speculates. ³If you take a typical cell growing in culture and kill its Usp14 activity, the cell will continue to thrive,² he says. ³If you kill its proteasome activity, it would immediately die.² This research could have far-reaching implications for the development of drugs to treat not only neurodegenerative diseases, but also other illnesses that have been linked to an accumulation of misfolded proteins, King says. For example, when a cell suffers oxidative damage‹say from a stroke or heart attack‹proteins may fold improperly and be marked for degradation by the ubiquitin system. If the proteasome becomes overwhelmed, misfolded proteins could accumulate in the cell, triggering a cascade of problems. In this latest study, researchers induced protein oxidation in cells and then treated them with IU1, which resulted in rapid elimination of the oxidized proteins. At the same time, the ability of cells to survive oxidative insult was enhanced.

Brain cells determine obesity -- not lack of willpower: Study

Thu, 09 Sep 2010 03:19:45 PDT

An international study has discovered the reason why some people who eat a high-fat diet remain slim, yet others pile on the weight. The study, led in Australia by the Monash Obesity and Diabetes Institute (MODI) at Monash University, found a high-fat diet causes brain cells to become insulated from the body preventing vital signals, which tell the body to stop eating and to burn energy, from reaching the brain efficiently. MODI director and Australian Life Scientist of the Year Professor Michael Cowley said there were two clear outcomes from the findings. 'We discovered that a high-fat diet caused brain cells to become insulated from the body, rendering the cells unable to detect signals of fullness to stop eating," Professor Cowley said. "Secondly, the insulation also created a further complication in that the body was unable to detect signals to increase energy use and burn off calories/kilojoules." The research showed that support cells in the brain developed overgrowth in a high-fat diet. This prevented the regular brain cells (the melanocortin system or POMC neurons) from connecting with other neural mechanisms, which determine appetite and energy expenditure. Professor Cowley said the study findings provide a critical link in addressing the obesity epidemic. "These neuronal circuits regulate eating behaviours and energy expenditure and are a naturally occurring process in the brain. The circuits begin to form early in life so that people may have a tendency towards obesity even before they eat their first meal," Professor Cowley said. Eating a high fat diet causes more "insulation" in the nerve cells, and makes it even harder for the brain to help a person lose weight. "Obese people are not necessarily lacking willpower. Their brains do not know how full or how much fat they have stored, so the brain does not tell the body to stop refuelling. Subsequently, their body's ability to lose weight is significantly reduced." Professor Cowley and fellow MODI researcher Dr Pablo Enriori collaborated with Research Chair and Professor of Comparative Medicine and Professor of Neurobiology Tamas Horvath and his team at the Yale School of Medicine in the United States, together with teams of scientists in Cincinnati, New Jersey, Mexico and Spain. For a period of four months, the researchers monitored the eating and body composition of groups of mice and rats and found that those with a neural predisposition to obesity gained 30 per cent more weight compared to six per cent of the group with obesity-resistant cells.

Micro-RNA determines malignancy of lung cancer

Thu, 09 Sep 2010 03:18:33 PDT

Cancer becomes life-threatening when tumor cells start leaving their primary site. They travel through the lymph and blood streams to other tissues where they grow into metastases. This transition to malignancy is associated with characteristic changes in the cancer cells. The activity of several genes is reprogrammed and, thus, the production of proteins anchoring cells to a tissue is reduced. On the other hand, the amount of surface markers which make a cancer cell mobile increases. Professor Dr. Heike Allgayer heads a Clinical Cooperation Unit of DKFZ and UMM. She is an expert for those cellular processes that lead to metastasis in cancer. In recent years, scientists have discovered that production of many proteins is regulated by what are called micro-RNAs. These RNA molecules, which consist of only about 23 building blocks, attach specifically to messenger RNAs, which contain the blueprints for proteins. In this way, they block the production of the respective protein. "We believe that micro-RNAs also play an important role in metastasis and that they program cells in a way that leads to malignant growth," medical researcher Heike Allgayer explains. In an international collaboration with researchers in Turin, Italy, Allgayer and her team used various cell lines of non-small cell lung cancer to investigate a particularly suspicious candidate called miR-200c and its role in malignant growth. The research team found out that the less miR-200c is produced by a cell line, the higher its motility and its capacity to invade surrounding tissue. When the researchers experimentally equipped the cancer cells with additional miR-200c, the amount of tissue-anchoring molecules on their surface increased and their invasive capacity became lower. In animal experiments, these cells produced less metastasis. A dreaded characteristic of non-small cell lung cancer is its resistance to chemotherapy and targeted anticancer drugs. A lack of miR-200c also seems to play a role here. Therapy-resistant lung cancer cell lines that were experimentally equipped with miR-200c could subsequently be killed by the chemotherapy drug cisplatin and responded to cetuximab, a drug that block growth signals. Allgayer's Team also discovered how the loss of miR-200c is brought about in cancer cells. In the highly aggressive cells, the miR-200c genes are turned off by chemical labeling with methyl groups. Drugs that remove these labels made the production of miR-200c rise again. Studying the tumor cells of 69 lung cancer patients, the investigators realized that miR-200c not only plays a role in the culture dish. They determined miR-200c levels and compared these with the patients' disease progression data. The lower the miR-200c level in the cancer cells, the more frequently metastasis had already begun. "Our results clearly show a connection between a loss of miR-200c and transition to aggressive, invasive growth, metastasis and chemoresistance," Heike Allgayer summarizes. "Therefore, we will now investigate whether miR-200c production in cancer cells can be used for predicting metastasis and, thus, may serve as a prognosis factor for the progression of a lung cancer. It is also possible that the miR-200c level can help to better predict the effectiveness of particular drugs."

Scientists make leap forward in early detection for Alzheimer's and cancer

Thu, 09 Sep 2010 03:17:22 PDT

Scientists at the UK's National Physical Laboratory have developed a new strategy for quicker and more precise detection of biomarkers – proteins which indicate disease. The work could pave the way for new tools to detect early stages of Alzheimer's and cancer at the molecular level. All diseases have proteins specifically linked to them called biomarkers. Identifying these in body fluid such as blood can be a powerful tool in identifying diseases in their early stages. This would help doctors increase the success rate of treatment through early intervention and help drug companies develop more effective drugs for these diseases. The search for new diagnostic and prognostic biomarkers to underpin targeted medicines is of growing priority. However the potential of biomarkers is currently hampered by technical difficulties in detecting them. They are often present at very low levels, in amongst many other different proteins. Reducing a sample down to a concentration where they could be identified is difficult and time-consuming. "This new strategy, developed by NPL, uses a probe to 'fish' for likely proteins, selecting them from a crowded blood sample," says Dr Max Ryadnov, Principle Research Scientist in the group. "A microgel on the probe works like a sponge, picking up proteins which have a charge or mass within a certain range." Whether or not the biomarker is present in this more select sample can then be determined using mass spectrometry – a technique where the molecules are charged and identified from their mass-to-charge ratio. The team tested the probe on fluids containing human growth hormone – a protein which is used therapeutically and is also banned in competitive sports. It's typically found in blood at very low frequencies, at around 100 nanograms per millilitre. However the probe was able to pick up the hormone even when only 40 nanograms per millilitre were present. Another problem with current biomarker detection is speed. This new strategy could greatly cut the time needed to search for a biomarker in a fluid. "You can do it in one day instead of a few days or even a week," says Dr Ryadnov. The Biotechnology Group want to develop biomarker detection techniques further, and are already working on a probe which can select one specific protein, rather than ranges of size or charge. They also want to see tests that can quantify levels of a protein, rather than just detecting if it is present or not. "What we want to do is something simple," says Dr Paulina Rakowska, Senior Research Scientist in the group. "These types of probe would in theory be suitable for different classes of diseases, mainly Alzheimer's and the like, but I also hope they would have applications for cancer."

Abnormal body weight related to increased mortality in colon cancer patients

Thu, 09 Sep 2010 03:16:01 PDT

Postmenopausal women diagnosed with colon cancer may be at increased risk of death if they fail to maintain a healthy body weight before cancer diagnosis, according to a study published in the September issue of Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research. The researchers found that women considered "underweight" or "obese," or who had increased abdominal obesity prior to cancer diagnosis seemed to face a greater risk of mortality. "Maintaining a healthy body weight is beneficial for postmenopausal women. This may also be beneficial for those diagnosed with colon cancer later in life. It looks like abdominal obesity may be a useful indicator of higher colon cancer mortality," said Anna E. Prizment, Ph.D., M.P.H., a postdoctoral fellow in the division of epidemiology and community health at the University of Minnesota, Masonic Cancer Center. "It is too early to say whether a decrease in weight characteristics after diagnosis will also decrease mortality risk; at that point it may be too late. Therefore, it's best to maintain a normal, healthy body weight throughout life." Prizment and colleagues extracted data from the Iowa Women's Health Study, which included 1,096 women diagnosed with colon cancer who were observed over a maximum 20-year period. During that time, 493 died, of which 289 died from colon cancer. Women classified as obese, with a BMI of at least 30 kg/m2, had a 45 percent increased overall mortality rate. The few women classified as underweight, with a BMI less than 18.5 kg/m2, had an 89 percent increased mortality rate compared to those with normal BMI. Furthermore, women with high waist-to-hip ratio had a 30 to 40 percent greater risk of colon cancer related death. Prizment said that the "exact mechanisms underlying the link between obesity and higher mortality of colon cancer patients are unknown." "Obese people may be diagnosed at later stage, have different treatment or more comorbidities," she said. However, the facts that the increased abdominal obesity was associated with colon cancer mortality and those associations persisted after correcting for age, stage at cancer diagnosis and comorbidities suggest that obesity could have a direct biological effect. Obese women, especially those with higher abdominal obesity, have higher hormone levels and may have more aggressive cancer. These women have been already known to have a higher risk of developing colon cancer. Prizment encouraged further investigation of the potential effect of obesity, in particular, abdominal obesity, on the prognosis after colon cancer diagnosis.

An important genetic cardiovascular risk factor explained

Wed, 08 Sep 2010 03:30:15 PDT

New findings reported in the September issue of Cell Metabolism, a Cell Press publication, appear to explain why people who carry specific and common versions of a single gene are more likely to have high cholesterol and to suffer a heart attack. Studies in mice show that the gene, known as sortilin (SORT1), controls the release of LDL (a.k.a. "bad") cholesterol from the liver into the bloodstream. The findings suggest that SORT1 may be a good target for new cholesterol-lowering drugs, according to the researchers. "The vast majority – some 95 percent -- of cardiovascular disease is the result of environmental factors modified by genes," said Anders Nykjaer of Aarhus University in Denmark. "Some people can eat a diet enriched in fat, be overweight, and not develop cardiovascular disease. Others can't." SORT1 appears to be one of those important genetic variables, and now the researchers have a pretty good idea why that might be. The researchers had earlier studied SORT1 in a completely different context. The gene also plays a role in the nervous system. So they were intrigued by the results of genome-wide association studies, which look for associations between common variation in the human genome and diseases or traits, showing that a particular stretch of sequence on chromosome 1 was linked to cardiovascular risk. That sequence covered three genes, including SORT1. (It was not immediately clear which of those three genes was responsible for the rise in cardiovascular risk.) To investigate SORT1's role further, the researchers created a mouse that lacked SORT1 altogether. That mouse showed 20 percent lower blood cholesterol levels when fed a high-fat Western diet than did normal mice. Importantly, this reduction in cholesterol translated into an approximately 50 to 60 percent reduction in the buildup of plaque in the animals' artery walls. Mice with higher-than-normal levels of SORT1, on the other hand, had higher cholesterol. If the mice fared better without SORT1 at all, what is it good for? "Everybody says that LDL cholesterol is a bad guy, but you can't do without cholesterol," Nykjaer explains. Cholesterol is a key ingredient in cell membranes and in steroid hormones, for instance. SORT1 facilitates the release of cholesterol into the bloodstream, making that fat available to body tissues that need a certain amount of it. The problem comes in when you start eating a diet loaded with fat and cholesterol. "Overall, it's good to have sortilin if you don't eat that much," Nykjaer said. "Now, it might be better not to have it all." Based on the findings, Nykjaer said it might be helpful for people to know what version of SORT1 they carry. Almost a quarter of all people carry the "bad" version of the gene. But he would sooner suggest that everyone live a healthier lifestyle, given that cardiovascular disease is influenced by many factors. Perhaps the most important implication of the study, he says, is that SORT1 might be a good target for drugs that could block excess cholesterol in the liver, keeping it out of the bloodstream and protecting the heart. "Lowering LDL cholesterol is considered one of the most efficient strategies to reduce the risk of coronary artery disease," the researchers wrote in conclusion. "Identification of regulators in lipoprotein metabolism such as sortilin will help to develop therapeutic strategies aimed at reducing plasma LDL cholesterol, the single most predictive cardiovascular risk factor." Notably, loss of SORT1 doesn't result in a buildup of bad cholesterol in the liver, as one might expect, Nykjaer said. That's because the blocked path to the bloodstream engages other molecular players that dump cholesterol from the liver into bile. In other words, he says, the liver appears to protect itself by ridding the body of that cholesterol.

Ghostwritten articles overstate benefits of hormone replacement therapy and downplay harms

Wed, 08 Sep 2010 03:28:14 PDT

The first academic analysis of the 1500 documents unsealed in recent litigation against the pharmaceutical giant Wyeth (now part of Pfizer) reveals unprecedented insights into how pharmaceutical companies use ghostwriters to insert marketing messages into articles published in medical journals. Dr. Adriane Fugh-Berman, associate professor in the Department of Physiology at Georgetown University Medical Center in Washington DC, analyzed dozens of ghostwritten reviews and commentaries published in medical journals and journal supplements that were used to promote unproven benefits and downplay harms of Prempro—a brand of menopausal hormone therapy (HT)—and to cast competing therapies in a negative light. These articles were widely circulated to drug reps and doctors to disseminate the company's marketing messages. The analysis appears in this week's PLoS Medicine. Wyeth used a medical education & communication company, DesignWrite, to produce ghostwritten articles in order to mitigate the perceived risks of breast cancer associated with HT, to defend the unsupported cardiovascular ''benefits'' of HT, and to promote off-label, unproven uses of HT such as the prevention of dementia, Parkinson's disease, vision problems, and wrinkles, writes Fugh-Berman. The analysis revealed that DesignWrite was paid US$25,000 to ghostwrite articles reporting clinical trials, including four manuscripts on the HOPE trials of low-dose Prempro. DesignWrite was also assigned to write 20 review articles about the drug, for which they were paid US$20,000 each. The analysis concludes that "Given the growing evidence that ghostwriting has been used to promote HT and other highly promoted drugs, the medical profession must take steps to ensure that prescribers renounce participation in ghostwriting, and to ensure that unscrupulous relationships between industry and academia are avoided rather than courted." In July 2009, PLoS Medicine, represented by the public interest law firm Public Justice, and The New York Times acted as intervenors in litigation against menopausal hormone manufacturers by 14,000 plaintiffs whose claims related to the development of breast cancer while taking the hormone therapy Prempro (conjugated equine estrogens). This resulted in a US federal court decision to release approximately 1500 documents to the public. The Wyeth Ghostwriting Archive is available at http://www.plosmedicine.org/static/ghostwriting.action or through the UCSF Drug Information Document Archive at http://dida.library.ucsf.edu/documents.jsp

Smoking damages men's sperm and also the numbers of germ and somatic cells in developing embryos

Wed, 08 Sep 2010 03:26:03 PDT

Two new studies have shed more light on how smoking may damage fertility, and give further weight to advice that mothers and fathers-to-be should stop smoking before attempting to conceive. The research is published online in Europe's leading reproductive medicine journal Human Reproduction today (Wednesday 8 September). In the first study [1], researchers found that a mother's smoking during early pregnancy dramatically reduces the numbers of germ cells (the cells that form eggs in females and sperm in males) and somatic cells (the cells that form every other part of the body) in the developing foetus. They believe that this may have an adverse effect on the fertility of the baby in later life. In the second study [2], researchers looked at specific proteins called protamines in the sperm of men who smoked and compared them with the protamines in non-smokers. Protamines play an important role in the development of sperm – they are necessary for the process that results in the formation of chromosomes during cell division – and, therefore, have an effect on subsequent male fertility. For the first study, Claus Yding Andersen, Professor of Human Reproductive Physiology at the University Hospital of Copenhagen (Denmark), and his colleagues looked at 24 embryonic testes obtained after women had undergone legal termination between 37-68 days after conception. They also took blood and urine samples and questioned the women about their lifestyle during pregnancy, including smoking and drinking habits. They found that the number of germ cells was more than halved (reduced by 55%) in the testes of embryos from mothers who smoked compared with those from the non-smoking mothers. The number of somatic cells was also reduced by more than a third (37%). The effect was dose dependent, with a greater reduction in germ and somatic cells being seen in embryos from the mothers who smoked the most. This remained the same, even after adjusting for coffee and alcohol consumption. When these results were added to their earlier work that looked at the effect of smoking on 28 female embryos, the researchers found that, overall, germ cells in the ovaries and testes of embryos exposed to smoking were reduced significantly by 41% compared with the number of germ cells in non-exposed embryos. The results also showed that germ cells were more susceptible to damage caused by smoking than somatic cells. Prof Andersen said: "As the germ cells in embryos eventually develop to form sperm in males and eggs in females, it is possible that the negative effect on the numbers of germ cells caused by maternal smoking during pregnancy may influence the future fertility of offspring. In addition, the reduction in the number of somatic cells also has the potential to affect future fertility, as somatic cells in the testes support the development of germ cells to form functional sperm. If the somatic cell number is reduced, fewer functional sperm will be produced. "These findings may provide one potential cause of the reduced fertility observed in recent years. Although the prevalence of smoking during pregnancy has declined in the last decade in developed countries, one in eight mothers continue to smoke throughout their pregnancy, and in Denmark the prevalence of smoking actually increased to 43% in 2005 among women younger than 20 at the time of delivery. This tendency is alarming, and when you take the results from this study in combination with the other known negative effects of cigarette smoke during pregnancy, it further emphasises that pregnant mothers should refrain from smoking." The first trimester is the crucial time when the sexual organs in the developing embryo are differentiating to form either testes or ovaries. "This process is very delicately regulated, with a number of hormones fluctuating. If something goes wrong at this point, just six to eight weeks after conception, it may have an impact on the function of the gonads later in life," said Prof Andersen. "Our results show that the gonads are susceptible to factors, such as cigarette smoke, just at this critical time when they start to differentiate." The authors warn that their study does not clarify whether the reduction in germ and somatic cell numbers is permanent or reflects a growth delay that might be compensated for later on. Prof Andersen said: "We would expect adverse effects to be more pronounced if the mother continues smoking throughout pregnancy, but we have only studied gonads from the first trimester and can only guess whether this effect actually will occur. So the effect on future fertility is still unknown. However, this study does indicate that smoking during pregnancy may have an adverse effect on the future reproductive ability of offspring, since both the number of germ cells and somatic cells are dramatically reduced and these are the foundations of future fertility." In the second study, researchers led by Professor Mohamed Hammadeh, head of the assisted reproductive laboratory in the Department of Obstetrics and Gynaecology at the University of the Saarland, (Homburg Saar, Germany), looked at the levels of two protamines, 1 and 2, in the sperm of 53 heavy smokers (more than 20 a day) and 63 non-smokers. P1 and P2 are necessary for proper chromatin condensation. This is the process whereby chromatin (the combination of DNA and proteins that make up chromosomes) condenses and packages up DNA into chromosomes that can fit inside cells. Poor chromatin packaging adversely affects sperm and is associated with a number of fertility problems such as lower chances of fertilisation after intercourse, poor fertilisation after IVF and ICSI (intracytoplasmic sperm injection), and a higher incidence of miscarriages. This is the first study to investigate the effect of smoking on protamines. Prof Hammadeh and his colleagues found that P2 concentrations were 14% lower in the sperm of smokers compared with non-smokers. "The concentration of P2 from smokers was 334.78 ng in every million sperm, compared with P2 concentrations of 388.8 ng per million sperm in non-smokers," said Prof Hammadeh. "This means that sperm from smokers suffer from protamine deficiency, probably caused by the cigarette smoke, and this could be a reason for incomplete or poor chromatin packaging in sperm, leading to infertility." The researchers found that the ratio of P1 to P2 was altered in smokers. "In normal, fertile men, the ratio of P1 to P2 is almost equal at 1:1. Any increase or decrease in this ratio represents some kind of infertility. In this study the ratio was significantly higher in smokers than in non-smokers, with higher levels of P1 than of P2," said Prof Hammadeh. The study also showed that levels of oxidative stress were higher in smokers than in non-smokers. Oxidative stress is an imbalance between chemically reactive molecules containing oxygen, other, unstable and highly reactive atoms called free radicals (collectively known as "reactive oxygen species"), and anti-oxidant compounds. It can cause damage to proteins, lipids and DNA. "Oxidative stress is known to cause damage to sperm DNA in a number of ways," said Prof Hammadeh. "These results suggest that induced oxidative stress by cigarette smoking may have a significant inverse effect on chromatin condensation by disrupting P2." He concluded: "Given the potential adverse effects of smoking on fertility, cancer and so on, physicians should advise infertile patients who smoke cigarettes to quit smoking. We are carrying out further research into the levels of P1 and P2 in order to find out the effect of smoking on the silencing or changing of the P2 gene in an attempt to clarify the potential mechanism behind this effect."

A missing link from obesity to infertility found

Wed, 08 Sep 2010 03:24:20 PDT

Obesity and infertility frequently go hand in hand. Now, researchers reporting on studies of mice in the September issue of Cell Metabolism, a Cell Press publication, might have figured out why that is, and the results come as something of a surprise. "There was a sense that the reproductive dysfunction was due to insulin resistance," said Andrew Wolfe of Hopkins Children's. "What we propose is a fundamentally new model showing that different tissues respond to obesity differently and that while cells in the liver and muscle become insulin resistant, cells in the pituitary remain sensitive to insulin." Infertility arises when those insulin-sensitive pituitary cells get flooded with the rising insulin levels that are so common in obesity, the new research shows. The pituitary is a gland found at the base of the brain. Special cells inside the pituitary known as gonadotrophs produce hormones (specifically gonadotropin-releasing hormone and luteinizing hormone, or LH) that control ovulation and fertility. It appears that insulin overstimulation in those cells sets off a kind of hormonal chain reaction that leads to infertility. The researchers earlier discovered that gonadotrophs harbor insulin receptors, but no one really knew what the effect of insulin on those receptors was. In the new study, the researchers investigated by creating mice lacking insulin receptors only in the gonadotroph. When healthy and lean, those mice appeared to do just fine. The researchers asked what might happen if they made the mice obese by feeding them an unhealthy, high-fat diet for three months. Normal obese mice became infertile, as expected, and showed signs of a condition that is known in humans as polycystic ovarian syndrome (PCOS). (PCOS affects as many as one in ten women and is the most common cause of infertility.) Those symptoms included high LH and testosterone levels, irregular reproductive cycles, and fewer ovulations. But obese mice lacking pituitary insulin receptors maintained normal reproductive cycles and near-normal hormone levels. To confirm the effects on fertility, the researchers allowed the mice to mate. Lean mice with or without pituitary insulin receptors had six times the number of successful pregnancies compared to otherwise normal obese mice. The obese mice with missing pituitary insulin receptors fared almost as well; they had five times more successful pregnancies than typical obese mice. "This suggests that insulin receptor signaling in the pituitary is fundamental to the dysregulation of LH secretion associated with the obese state," the researchers wrote. Wolfe said these effects had been missed before because most studies of obesity and insulin resistance have focused on metabolic tissues, including fat, liver, and muscle. In fact, insulin receptors are found all over the body. That means there may be some other surprises in store as scientists begin to unravel the effects of obesity and rising insulin levels on other body tissues. The current findings might be most relevant in humans to understanding PCOS, Wolfe said. In many cases, PCOS is related to obesity and insulin resistance. One of the most common treatments for PCOS is insulin sensitizers, which can sometimes restore fertility. Most had assumed the treatment worked by making body tissues more sensitive to insulin. The new results suggest that they could instead work by lowering insulin levels as metabolic tissues regain sensitivity to the hormone, Wolfe said. Wolfe said they would still like to work out exactly what it is that's different about the pituitary insulin receptors that allows them to remain sensitive. They also plan to explore the role of insulin receptors found in ovarian cells.

A new role for insulin in cell survival, cell metabolism and stress response

Wed, 08 Sep 2010 03:23:07 PDT

Researchers at the Buck Institute for Age Research have discovered a novel way in which insulin affects cell metabolism and cell survival. Surprisingly the insulin signaling pathway, which is involved in aging, diabetes and stress response, is active at a deeper level of cell activity than scientists expected. The study appears in the September 8th issue of Cell Metabolism. Insulin is vitally involved in many cell functions. Buck Institute faculty and lead author Gordon Lithgow, PhD, says scientists have known for years that insulin is involved at the level of cell activity called transcription, where DNA produces RNA. Lithgow said the new research, in the nematode worm C. elegans, revealed that insulin is also active at the level known as translation, where RNA specifies protein synthesis. Lithgow says the discovery of this new level of regulation opens a host of opportunities. "We are desperate to understand why aging is a risk factor for disease, we want to know why diabetes is associated with aging," said Lithgow. "Here we have a insulin signaling pathway involved in aging, diabetes and stress response. This gives us more precise avenues to explore how we might intervene in disease," he said. Using long-lived mutant worms, researchers demonstrated that increased tolerance to stress, due to lower insulin signaling, is not dependent on stress-induced responses at the level of transcription, but instead requires active protein translation. Lithgow says the research fits in with work being done in the Buck Institute laboratories of Brian Kennedy and Pankaj Kapahi, all of which point to the importance of translation. Lithgow, who directs the Institute's Geroscience program, says the research will lead to new collaborations. "This work highlights the importance of protein homeostasis – the maintenance of metabolic equilibrium," said Lithgow. "What proteins are made within the cell? When are they made? How and when are they gotten rid of? What happens when they are damaged?" Lithgow thinks control of protein homeostasis is vital for healthy aging and is intrinsically involved in diseases such as Parkinson's and Alzheimer's where protein homeostasis seems to get muddled up. "It's about connections," said Lithgow, "Now we need to connect with what is known about insulin signaling in diabetes with various disease states; we need to know how this small part of cell metabolism fits into the bigger picture of aging and disease."

Johns Hopkins researchers unravel clues to infertility among obese women

Wed, 08 Sep 2010 03:22:04 PDT

Obese women have a well-known risk for infertility, but a new Johns Hopkins Children's Center study has unraveled what investigators there believe is the mechanism that accounts for the risk. The research, conducted in mice and published online on Sept. 8 in the journal Cell Metabolism, shows that the pituitary gland actively responds to chronically high insulin levels, triggering a cascade of hormonal changes that disrupt ovarian function and impair fertility. The findings challenge the widely held belief that infertility is a result of insulin resistance — a body's insensitivity to chronically elevated insulin levels and a hallmark of obesity — and suggest a new culprit: heightened sensitivity to insulin's effects on the pituitary gland. "What we propose is a fundamentally new model showing that different tissues respond to obesity differently, and that while cells in the liver and muscle do become insulin resistant, cells in the pituitary remain sensitive to insulin," says principal investigator Andrew Wolfe, Ph.D., of Hopkins Children's. Scientists traditionally have focused on treating infertility by lowering insulin levels as a way to treat insulin resistance. However, the new model suggests that decreasing the pituitary's sensitivity to insulin could be an important new target for treatment instead. Insulin resistance, marked by persistently elevated insulin, abnormal regulation of blood sugar and insensitivity to insulin in the liver and muscle cells, occurs in type 2 diabetes, metabolic syndrome and polycystic ovary syndrome (PCOS). PCOS is the most common cause of infertility, affecting up to one in 10 women. Because ovarian function and fertility are mostly regulated by the pituitary, the body's master gland, the Hopkins team set out to find out exactly how elevated insulin levels affect the pituitaries of obese women to render them infertile. The investigators focused on a class of pituitary cells called gonadotrophs, which secrete luteinizing hormone (LH), critical for ovulation and fertility. The researchers suspected that when awash with too much circulating insulin, the gonadotrophs of obese mice start pumping out large amounts of LH, thus disrupting ovulation. To test their hypothesis, the scientists engineered mice with missing insulin receptors in their pituitary glands and compared them to mice with intact insulin receptors. After three months on a high-fat diet, the obese mice with intact insulin receptors developed all the classic symptoms of PCOS: elevated LH levels, high testosterone, irregular reproductive cycles and fewer ovulations. The mice with missing insulin receptors, however, maintained near-normal LH levels, regular cycles and normal ovulation despite their obesity. To further clarify the effect of insulin on the pituitary, the researchers compared the gonadotrophs of obese mice to those of lean mice by injecting the animals with gonadotropin-releasing hormone (GnRH), which stimulates LH and is critical for ovulation and fertility. Lean mice, with and without pituitary insulin receptors, had normal elevations of LH. Obese mice with intact insulin receptors experienced increases of LH twice as high. Yet, the obese mice with missing insulin receptors in their pituitaries had near-normal LH elevations. These results, the researchers say, show that the high levels of insulin seen in obesity make the pituitary more sensitive to GnRH and help initiate a hormonal chain-reaction that disrupts fertility. To demonstrate insulin's direct effects on the pituitary, the scientists injected mice with insulin. Mice with intact insulin receptors, lean or obese, had mild LH elevations, while mice with deleted insulin receptors, lean or obese, experienced none. To determine whether these hormonal differences would carry over into actual differences in fertility, the researchers allowed the mice to mate. The pregnancy outcomes mirrored the hormonal findings. Lean mice, with or without pituitary insulin receptors, had six times the number of successful pregnancies as obese mice. However, obese mice with missing pituitary insulin receptors had near-normal pregnancy outcomes, with five times more successful pregnancies than obese mice whose pituitary insulin receptors were intact. By deleting the insulin receptors in the pituitary cells of mice, the researchers managed to restore normal LH levels, maintain ovulation and near-intact fertility even in obese mice with elevated insulin levels. Despite normal hormonal levels and ovulation, the obese mice with missing insulin receptors were not as fertile as lean mice with normal insulin levels. The finding suggests that since the ovaries share partial control of ovulation and fertility with the pituitary, they too may be affected by high insulin levels.

Virginia Tech researchers contribute to turkey genome sequencing

Wed, 08 Sep 2010 03:20:29 PDT

An international consortium of researchers has completed the majority of the genome sequence of the domesticated turkey, thanks in part to the efforts of Virginia Tech faculty members. The research team will publish "Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis" in the journal PLoS Biology (Public Library of Science) on Sept. 7, 2010. "To date, more than 90 percent of the domesticated turkey genome has been sequenced and assembled," said Rami Dalloul, assistant professor of animal and poultry sciences in Virginia Tech's College of Agriculture and Life Sciences. The majority of data are derived from the 10 largest chromosomes, called macrochromosomes, and researchers in the consortium are still searching for the best route to sequence the remaining microchromosomes. "We have already described thousands of genes previously unknown to avian scientists," Dalloul said. Also of interest are the sequences of the sex chromosomes "Z" and "W," which were poorly covered in the past. In 2008, the research consortium set out to map the genetic blueprint for the domesticated turkey, the fourth-most popular choice of meat in the United States. The following year, Virginia Tech and the University of Minnesota received a two-year, $900,000 grant from the U.S. Department of Agriculture to complete the genome sequence, which promises new data for avian researchers and, ultimately, a better quality product for turkey producers and consumers. "In the short term, the genome sequence will provide scientists with knowledge of specific genes that are important in meat yield and quality, health and disease resistance, fertility, and reproduction," Dalloul said. "For example, we don't always know the mechanism for how host-pathogen interactions work. The genome sequence will allow us to better understand this process, which will in turn give us a better understanding of disease prevention and treatment." According to Dalloul, the genome sequence will have long-term benefits for turkey producers as well. "Poultry producers may be able to use the knowledge we gain from the genome sequence to grow turkeys faster and healthier, and if they can produce the same size bird in a shorter period of time, they can also save money," he said. An improved understanding of genetic variation in this species and in breeding populations will also lead to development of new tools that producers can use to breed turkeys that have desirable texture, flavor, and leanness, which will directly impact consumer products. In addition, the genome sequence may have applications in the biomedical field. Ed Smith, professor of animal and poultry sciences at Virginia Tech, is investigating an avian condition similar to dilated cardiomyopathy in humans. Other consortium members — Roger Coulombe at Utah State University and Kent Reed at the University of Minnesota — are studying the effects that aflatoxins have on turkeys. Aflatoxins are naturally occurring carcinogenic chemicals produced by fungi that suppress the immune system. The domesticated turkey is the most aflatoxin-susceptible species known. Clive Evans, director of the Core Laboratory Facility at the Virginia Bioinformatics Institute (VBI), said, "The availability of the Roche GS-FLX™ Titanium sequencing technology at VBI allowed the turkey research consortium to quickly and efficiently establish an early draft of the turkey genome." This draft was extended in 2009 with data from the Illumina sequencing platform at the USDA-Agricultural Research Service and assembled by scientists at the University of Maryland to produce the current genome assembly. The use of these next-generation sequencing technologies provided the turkey genome sequence assembly at a fraction of the cost of producing the red junglefowl genome assembly (the same species as the domesticated chicken) in 2004. The international consortium spent the last year annotating and analyzing the draft genome sequence, which culminated in "fleshing out the intricacies of the turkey's genetic blueprint as described in detail in the PLoS Biology paper," Evans said. The research team hopes the integrated approach used to obtain the turkey genome will provide a model for creating gene- and chromosome-level assemblies for other species with agricultural, ecological, or evolutionary importance.

First Irish genome sequenced

Wed, 08 Sep 2010 03:19:05 PDT

The first entire genome of an Irish individual has been sequenced. The sequence is reported in BioMed Central's open access journal, Genome Biology and provides insight into the evolutionary history of this distinct lineage. Led by Professor Brendan Loftus, the research team from UCD Conway Institute used data from a previous genotyping study to select a suitable Irish male representative for sequencing. Then, using pair- and single-ended Illumina short read sequencing, one of the next generation sequencing approaches, the team created 9 DNA sequence libraries, which were overlaid to generate a high quality genome sequence with 11-fold coverage. Analyses were carried out in conjunction with collaborators from Trinity College Dublin, Royal College of Surgeons of Ireland (RCSI), Beaumont hospital, the MRC Human Genetics Unit and University of Edinburgh. The researchers used HapMap and previous gene association studies to identify new DNA variants such as insertions/deletions (indels) and single nucleotide polymorphisms (SNPs). Nearly 200,000 indels and over 3 million SNPs were identified in the Irish genome sequence. Of the SNPs, 13% were novel, potentially including markers specific to Irish ancestry or indicators of disease. In particular, one of the new SNPs interferes with the production of a macrophage-stimulating protein, thought to be associated with inflammatory bowel disease and chronic liver disease. The authors also describe a new way to improve SNP calling accuracy at low genome coverage by using haplotype data from the current Human Genome Diversity Panel and they identify gene duplication events that may show recent positive selection in the human lineage. "Our findings show that there remains utility in generating whole genome sequences to illustrate both general principles and reveal specific instances of human biology", says Loftus, adding, "The Irish population is of interest to biomedical researchers because of its isolated geography, ancestral impact on further populations and the high prevalence of a number of diseases". The DNA variants in this study, funded through a Science Foundation Ireland Research Professorship award, have been uploaded to the Galaxy computing platform, facilitating the continued full analysis of this interesting genome. The authors hope that this sequence will compliment the ongoing 1000 genomes project, which currently lacks an Irish representative.

Multivitamin use doesn't impact colon cancer outcomes

Wed, 08 Sep 2010 03:17:34 PDT

Patients with colon cancer who used multivitamins during and after being treated with post-surgical chemotherapy did not reduce the risk of the cancer returning or their dying from it, according to researchers at Dana-Farber Cancer Institute. In a study of patients with stage III colon cancer – characterized as cancer in the large bowel area with some cancer cells in a few nearby lymph nodes -- the researchers found that while multivitamin use had no beneficial effect on patients' outcomes, it also did not have a detrimental effect. The findings are reported online in the Journal of Clinical Oncology and later will be published in a print edition. Kimmie Ng, MD, MPH, the paper's first author and a gastrointestinal oncologist at Dana-Farber, said that despite conflicting evidence on the efficacy of multivitamins to reduce cancer risk and death, studies suggest that approximately 30 percent of Americans take multivitamins to prevent and treat chronic diseases such as cancer. Among cancer survivors, between 26 and 77 percent report using multivitamins. "With such a high proportion of cancer patients utilizing multivitamin supplements in the belief that it will help them fight their cancer, we felt it was important to really examine the data to see what impact multivitamins had on cancer recurrence and survival," said Ng. The researchers used two questionnaires to track multivitamin use during and after chemotherapy. Of the 1,038 patients who completed the first survey, nearly half (518) responded they used multivitamins while receiving chemotherapy. Of the 810 cancer-free patients who completed the second survey six months after chemotherapy, more than half (416) reported multivitamin use. Ng and her colleagues found no statistically significant differences in the rates of disease-free survival (the study's primary endpoint), recurrence-free survival, or overall survival between those who used multivitamins and those who didn't. They also determined that an array of factors, including socio-economic status, household income, multivitamin and individual vitamin dosage, and consistency of multivitamin use did not impact their findings. However, they did find a small beneficial association between age and weight and the use of multivitamins while receiving chemotherapy. Those 60 and younger experienced some survival benefit, as did obese patients. There were no benefits for either subgroup when the multivitamins were taken after chemotherapy was completed. Ng said additional studies are needed to confirm their findings and to investigate whether there were other factors that influenced the outcomes. "This study adds to a growing body of research that questions the purported benefit of multivitamin use, and it underscores the need to investigate the use of individual vitamins, such as vitamin D, which may, in fact, provide real benefit," said Charles Fuchs, MD, director of gastrointestinal oncology at Dana-Farber and the paper's senior author. He noted that the average multivitamin typically contains only a small to modest amount of vitamin D.

Researchers at UC Riverside find solution to cell death problem vexing stem cell research

Wed, 08 Sep 2010 03:15:49 PDT

Human pluripotent stem (hPS) cells can generate any given cell type in the adult human body, which is why they are of interest to stem cell scientists working on finding therapies for spinal cord injuries, Parkinson's disease, burns, heart disease, diabetes, arthritis, and other ailments. Before hPS cell technologies can be translated into clinical applications, however, some obstacles must first be overcome. One such obstacle frustrating stem cell researchers is "cell death" that the major types of hPS cells, including human embryonic stem cells and human induced pluripotent stem cells, mysteriously undergo when cultured as single cells, rendering them less suitable for research. Researchers at the University of California, Riverside now show that a molecular motor, called "nonmuscle myosin II" (NMII), which exists naturally inside each hPS cell and controls various cellular functions, triggers the death of hPS cells when they are broken down to single cells. While many details of how exactly NMII works remain unknown, a wide consensus among researchers is that NMII induces a contraction of the main internal components of the cells, eventually resulting in cell death. To stop this cell death, the researchers treated hPS cells with a chemically synthesized compound, blebbistatin, and found that it substantially enhanced the survival of the cells by chemically inhibiting NMII. (Blebbistatin is commercially available from several companies that sell biologically active chemical compounds.) "Our research shows that blebbistatin works as effectively as the most potent cell death inhibitor of hPS cells available today," said Noboru Sato, an assistant professor of biochemistry, whose lab led the research. "This discovery brings stem cell research a step closer towards finding therapies for several diseases." Study results appear online, Sept. 7, in Nature Communications. Sato explained that most of the current culture methods to grow hPS cells require animal-derived materials, such as Matrigel, for coating the culture surfaces. Without these materials, hPS cells cannot adhere to the culture plate. But the drawback of using them is that they could potentially cause contamination of hPS cells by introducing viruses and unknown pathogens. "Another advantage of using blebbistatin is that we need no human- or animal-derived materials for coating the culture surfaces," he said. "This is because blebbistatin greatly facilitates the adhesion of cells to the culture surface. By combining blebbistatin and a chemically synthesized coating material, poly-D-lysine, we have developed a fully defined and simplified culture environment that allows hPS cells to grow under completely animal-free and contamination-free conditions." Available through many companies, poly-D-lysine is a chemically synthesized animal-free coating material that is widely used for cell culture coating for other cell types. For hPS cells to adhere to the poly-D-lysine coating, blebbistatin must be added to the culture medium. "This new method shows that a novel combination of routinely available materials can create a completely distinct technological platform," Sato said.

Researchers at Children's Hospital Los Angeles find diet-induced obesity accelerates leukemia

Wed, 08 Sep 2010 03:14:28 PDT

The first study to demonstrate that obesity can directly accelerate the progression of acute lymphoblastic leukemia (ALL) has been conducted at The Saban Research Institute of Childrens Hospital Los Angeles and will be published in Cancer Prevention Research, on October 5, 2010. Obesity has been associated with an increased incidence of many cancers, including leukemia, but it has been unknown whether the increase in incidence was a direct effect of obesity or associated with genetic, lifestyle, health, or socio-economic factors. "Given the high prevalence of obesity in our society, we felt it was critical to determine if obesity actually caused the increased incidence of leukemia and not some other associated exposure," explains Steven D. Mittelman, MD, PhD, a pediatric endocrinologist who led the study. Dr. Mittelman and his colleagues used a high-fat diet to induce obesity in two mouse models of ALL. Mice were randomized to a high-fat or a control diet. The investigators found that obesity increased the risk of ALL in both models, particularly in older mice. This observation was consistent with the type of cumulative effect seen with other exposure-related cancers, such as lung cancer related to smoking and breast cancer resulting from increased estrogen exposure. Observing the difference in older animals also agreed with the other obesity-related effects from cumulative exposure such as heart disease, diabetes, and arthritis. "Our findings are consistent with epidemiological data that show a higher incidence of leukemia in obese adults and suggests that these observations are actually due to obesity, and not some associated genetic, socio-economic, or lifestyle factor," concluded Dr. Mittelman, who is also an Assistant Professor of Pediatrics and Physiology & Biophysics at the Keck School of Medicine of the University of Southern California. "These data imply that some hormone or factor in overweight individuals, perhaps produced by fat tissue itself, may signal leukemia cells to grow and divide. Since leukemia is the most common type of childhood cancer, understanding how obesity may increase its incidence could have important public health implications."

Parents at highest risk for depression in the first year after child's birth

Tue, 07 Sep 2010 03:32:01 PDT

More than one-third of mothers and about one-fifth of fathers in the United Kingdom appear to experience an episode of depression between their child's birth and 12th year of age, with the highest rates in the first year after birth, according to a report posted online today that will appear in the November print issue of Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals. "Depression in parents is associated with adverse behavioral, developmental and cognitive outcomes in their children," the authors write as background information in the article. "While the maternal depression and child outcome literature is well established, there are fewer studies on paternal depression. There is evidence that paternal depression is not uncommon, with rates higher than those in the general adult male population; however, a wide range of prevalence rates for paternal depression have been reported." Shreya Davé, Ph.D., M.Sc., B.Sc., of the Medical Research Council, London, England, and colleagues examined incidence, trends and correlates of parental depression in 86,957 families seen in U.K. primary care facilities between 1993 and 2007. Mothers and fathers with depression were identified using diagnostic codes and pharmacy records. Overall, between their children's birth and age 12, 19,286 mothers had a total of 25,176 episodes of depression and 8,012 fathers had a total of 9,683 episodes of depression. The depression rate was 7.53 per 100 mothers per year and 2.69 per 100 fathers per year. The highest rates were observed in the first year after the birth of a child, with 13.93 per 100 mothers and 3.56 per 100 fathers experiencing depression in that period. "These high rates of depression in the postpartum period are not surprising owing to the potential stress associated with the birth of a baby, e.g., poor parental sleep, the demands made on parents and the change in their responsibilities, and the pressure this could place on the couple's relationship," the authors write. "The high rate of parental depression in the first year after delivery may also be partly due to a resumption of antidepressant use following a break during pregnancy and breastfeeding." Parents who had a history of depression, who were younger (age 15 to 24, compared with 25 and older) when their child was born and who were more socially deprived were more likely to develop depression. "There is a well-established link between depression and social and economic deprivation both in the general population and among parents. This finding may reflect the stresses of poverty, unemployment, low employment grade and lower social support among people of lower socioeconomic status," the authors write. In addition, "younger parents may be less prepared for parenthood with more unplanned pregnancies and may be less able to deal with the stresses of parenthood compared with older parents." The findings suggest that there is a need for appropriate detection of depression among mothers and fathers, and that clinicians should be aware of the risk factors for depression in parents and assess individuals who possess those characteristics. In addition, the authors note, future research should examine other factors associated with parental depression, such as the couple's relationship quality and stressful life events, as well as the separate and cumulative effects of maternal and paternal depression on children's health and development.

Hallucinogen appears safe, may improve mood among patients with advanced-stage cancer and anxiety

Tue, 07 Sep 2010 03:30:34 PDT

A pilot study suggests the hallucinogen psilocybin may be feasible and safe to administer to patients with advanced-stage cancer and anxiety, with promising effects on mood, according to a report published online today that will appear in the January 2011 print issue of Archives of General Psychiatry, one of the JAMA/Archives journals. "In recent years, there has been a growing awareness that the psychological, spiritual and existential crises often encountered by patients with cancer and their families need to be addressed more vigorously," the authors write as background information in the article. "From the late 1950s to the early 1970s, research was carried out exploring the use of hallucinogens to treat the existential anxiety, despair and isolation often associated with advanced-stage cancer. Those studies described critically ill individuals undergoing psychospiritual epiphanies, often with powerful and sustained improvement in mood and anxiety as well as diminished need for narcotic pain medication." Despite initial promising results, no follow-up research had been conducted; however, the medical value of hallucinogens is now being re-examined in psychiatric settings, the authors note. Charles S. Grob, M.D., of Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, explored the safety and efficacy of psilocybin—a hallucinogen with some psychological effects similar to lysergic acid diethylamide (LSD)—among 12 adults with advanced-stage cancer and anxiety. Participants served as their own controls; in two six-hour treatment sessions several weeks apart, they were given clear capsules either of active psilocybin (in a dose of 0.2 milligrams per kilogram) or a placebo (niacin, 250 milligrams) in random order. Physiological responses such as blood pressure, heart rate and temperature were measured before and after, and psychological measures including assessments of depression, mood and anxiety were administered before and at the end of the session, one day and two weeks after the session and at monthly intervals for the following six months. "Safe physiological and psychological responses were documented during treatment sessions," the authors write. "We also observed no adverse psychological effects from the treatment. All subjects tolerated the treatment sessions well, with no indication of severe anxiety or a 'bad trip.'" In addition, anxiety scores improved at one and three months after treatment and a depression inventory revealed an improvement of mood that began two weeks after treatment and reached significance at six months. "This study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety," the authors conclude. "Some of the data revealed a positive trend toward improved mood and anxiety. These results support the need for more research in this long-neglected field."

Mayo Clinic study finds mild cognitive impairment is more common in men

Tue, 07 Sep 2010 03:28:42 PDT

A new Mayo Clinic study found that the prevalence of mild cognitive impairment was 1.5 times higher in men than in women. The research, part of the Mayo Clinic Study of Aging, also showed a prevalence rate of 16 percent in the population-based study of individuals aged 70-89 without dementia who live in Olmsted County, Minn. The study will be published in the September issue of Neurology. "The finding that the frequency of mild cognitive impairment is greater in men was unexpected, since the frequency of Alzheimer's disease is actually greater in women. It warrants further study," says Ronald Petersen, M.D., Ph.D., neurologist and director of the Mayo Clinic Alzheimer's Disease Research Center. "If we consider the 16 percent prevalence of mild cognitive impairment in individuals without dementia, then add the 10-11 percent of individuals who already have dementia or Alzheimer's disease, we're looking at 25 percent or more of the population aged 70 or older who have dementia or are at risk of developing dementia in the near future. With the aging of America, these numbers are staggering and the impact on the health care economy, as well as on individuals and their families, is quite impressive. The need for early diagnosis and therapeutic intervention is increasingly important."

LA BioMed research finds hallucinogen can safely ease anxiety in advanced-stage cancer patients

Tue, 07 Sep 2010 03:27:20 PDT

In the first human study of its kind to be published in more than 35 years, researchers found psilocybin, an hallucinogen which occurs naturally in "magic mushrooms," can safely improve the moods of patients with advanced-stage cancer and anxiety, according to an article published online today in the Archives of General Psychiatry. Patients enrolled in the study at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) demonstrated improvement of mood and reduction of anxiety up to six months after undergoing treatment, with significance reached at the six-month point on the "Beck Depression Inventory" and at one and three months on the "State-Trait Anxiety Inventory." A third screening tool, the "Profile of Mood States," identified mood improvement after treatment that approached but did not reach significance. "We are working with a patient population that often does not respond well to conventional treatments," said Charles S. Grob, MD, an LA BioMed principal investigator who led the research team. "Following their treatments with psilocybin, the patients and their families reported benefit from the use of this hallucinogen in reducing their anxiety. This study shows psilocybin can be administered safely, and that further investigation of hallucinogens should be pursued to determine their potential benefits." Researchers conducted extensive investigations of psychedelic drugs in the 1950s and 1960s and found promising improvements in mood and anxiety, as well as a diminished need for narcotic pain medication among advanced-stage cancer patients. The research was abandoned in the early 1970s in the wake of widespread recreational usage that led to stiff federal laws regulating hallucinogens. "Political and cultural pressures forced an end to these studies in the 1970s," said Dr. Grob. "We were able to revive this research under strict federal supervision and demonstrate that this is a field of study with great promise for alleviating anxiety and other psychiatric symptoms." The LA BioMed study is the first research publication in several decades to examine the hallucinogen treatment model with advanced-cancer anxiety. Twelve volunteers, ages 36 to 58, with advanced-stage cancer and anxiety were given a moderate dose of 0.2 mg/kg of psilocybin and, on a separate occasion, a placebo. Neither the volunteers nor the researchers monitoring them knew whether they'd been given a placebo or psilocybin. The two experimental sessions took place several weeks apart in a hospital clinical research unit at Harbor-UCLA Medical Center, where Dr. Grob is a professor of psychiatry. The research volunteers were monitored for the six hours following their dose. The volunteers were encouraged to lie in bed, wear eye shades and listen to music during the first few hours after ingesting the medication or the placebo. They were interviewed after the six-hour session and over the next six months to assess the outcome of the treatment.

Visual pattern preference may be indicator of autism in toddlers

Tue, 07 Sep 2010 03:25:39 PDT

Using eye-tracking methods, researchers at the University of California, San Diego School of Medicine have shown that toddlers with autism spend significantly more time visually examining dynamic geometric patterns than they do looking at social images – a viewing pattern not found in either typical or developmentally delayed toddlers. The results of the study suggest that a preference for geometric patterns early in life may be a signature behavior in infants who are at-risk for autism. This preference was found in infants at-risk for autism as young as 14 months of age. “In testing 110 toddlers ages 14 to 42 months, we found that all of the toddlers who spent more than 69 percent of their time fixing their gaze on geometric images could be accurately classified as having an autism spectrum disorder or ASD,” said Karen Pierce, PhD, an assistant professor in the UCSD Department of Neurosciences and assistant director of the UCSD Autism Center of Excellence. The study will be published in the September 6 issue of the Archives of General Psychiatry. During this study, babies ranging in age between 12 and 42 months sat on their mother’s lap as they watched a one-minute movie that contained shapes moving on one side of the screen (i.e., “dynamic geometric patterns) and children dancing and doing yoga on the other (i.e., “dynamic social images”). Using an infrared light beam that bounces off the eye, Pierce and colleagues were able to measure what the baby liked to look at by measuring the amount of time they examined each side of the screen. Interestingly, the dynamic geometric patterns that absorbed the attention of autistic but not normal babies, was nothing more than a common screen saver found on most computers. Out of 51 typical infants in this study, only one preferred to look at the geometric images. However, not all autistic toddlers preferred the geometric shapes. In the UCSD study, 40 percent of the ASD toddlers had this preference, compared to just two percent of the typical and nine percent of the developmentally delayed toddlers. Thus, while 40 percent of the ASD toddlers were “geometric responders,” the remaining 60 percent were similar to the typical and developmentally delayed groups in preferring dynamic social images. “What an infant prefers to look at when given a choice between two images may turn out to be a more clearly observable indicator of autism risk than how he or she looks at a single image,” Pierce said. “Among toddlers who strongly prefer geometric patterns, we found that – almost 100 percent of the time – those children developed an autism spectrum disorder.” A preference for geometric patterns alone may be an intriguing novel identifier of early autism, but the research results also illustrated a distinct pattern of saccades – rapid, directed eye movements – among the geometric responders. “We initially predicted that ASD toddlers overall would show a reduced number of saccades,” Pierce explained However, results revealed that it was only the geometric responders, not the group as a whole, who displayed a reduced number of saccades; and this pattern was only evident when they were viewing their preferred geometric patterns. “It was almost as if they got ‘stuck’ and didn’t move their eyes as much as typical toddlers when viewing geometric patterns. The geometric patterns were apparently very absorbing to them.” The researchers concluded that a preference for moving geometric patterns, combined with how long toddlers stare when looking at moving geometric images, might be an early identifier of autism. “If your baby occasionally enjoys looking at the screen saver on your computer, it is no cause for alarm,” said Pierce. “But if your baby looks at such moving geometric patterns for long periods of time, but not at fun, social images, you might want to check for other early warning signs of autism.” Such warning signs include reduced enjoyment during back-and-forth games like peek-a-boo; the presence of an unusual tone of voice; a lack of pointing at or bringing objects to show; and a failure to respond when his/her name is called. “If your baby shows multiple such ‘red-flags,’ then speak to your pediatrician about a developmental evaluation,” Pierce advised.

Pharmaceutical conservation key to slowing rise of antibiotic-resistant infections

Tue, 07 Sep 2010 03:23:42 PDT

The United States must focus on conserving the use of antibacterial drugs, or face a public health crisis from rapidly rising rates of antibiotic-resistant infections, according to an analysis out today. Evidence indicates that our nation's supply of antibiotics is being depleted by resistance, which occurs when infection-causing microbes mutate or change so that they no longer respond to widely-used treatments. Most proposals to solve this problem focus on giving pharmaceutical companies financial incentives to develop new drugs that could replace those that are no longer working. But a new report published today in the September issue of Health Affairs suggests that approach won't work for long. New drugs will face microbial foes that figure out how to evade treatment, say two medical policy experts. "This is a war we cannot win unless we adopt a two-pronged strategy: one that would boost the supply of new drugs and at the same time preserve the ones we have left," says Aaron Kesselheim, M.D., J.D., M.P.H., one of the paper's co-authors. He conducted the analysis of antibacterial drugs and their impact on public health through a grant from Public Health Law Research (PHLR), a national program of the Robert Wood Johnson Foundation (RWJF). The current pharmaceutical reimbursement system gives companies an incentive to oversell antibiotics, says Kesselheim, who is also an instructor in medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital and Harvard Medical School in Boston. Companies that have spent large sums of money on research and development for a new drug often seek to turn a profit on that product as quickly as possible—before resistance sets in, he says. But the practice of aggressively marketing antibiotics actually adds to the resistance problem, says co-author Kevin Outterson, J.D., a professor at Boston University Law School. Overselling and overuse create an environment in which microbes are awash in antibiotics, which speeds the process of resistance, he says. "Right now, pharmaceutical companies are rewarded for actions that conflict with the public health goal of reducing antibiotic resistance," Outterson says. "That has to stop." The analysis in Health Affairs crafts an innovative solution to the problem, one that gives pharmaceutical companies financial incentives to market drugs in a way that would keep resistance rates at low levels. Specifically, Kesselheim and Outterson suggest that government experts study the rates of resistance and set "effectiveness targets" for newly approved antibiotics. To meet those goals, which the authors say would be based on factors related to the disease targeted by the antibiotic, such as lower resistance rates, drug companies would need to coordinate with physicians and hospitals so that the drugs are prescribed only when clinically indicated. Such action would remove the current incentive to oversell. Companies that met the predetermined targets (achieved through responsible use of the drugs) would be rewarded. For example, the authors suggest that Medicare could pay a bonus to companies producing drugs that meet their resistance targets. Or policy-makers could grant such companies extended market exclusivity so they could continue to earn revenues—as long as the drug use remained within the target zone. Such a policy could help slow development of resistance in microbes and ensure new antibiotics have a longer shelf life, a bonus that would help not just individual patients but society as a whole, Kesselheim and Outterson predict. The authors, and other experts, say that the United States must adopt more comprehensive strategies that give drug companies and others incentives to reduce antibiotic resistance. For example, hospitals should be financially rewarded for adhering to strict infection-control practices, which can reduce the spread of antibiotic-resistant microbes, says Ramanan Laxminarayan, Ph.D., principal investigator for Extending the Cure, an RWJF-funded project on antibiotic resistance.

Carbon mapping breakthrough

Tue, 07 Sep 2010 03:22:10 PDT

By integrating satellite mapping, airborne-laser technology, and ground-based plot surveys, scientists from the Carnegie Institution's Department of Global Ecology, with colleagues from the World Wildlife Fund and in coordination with the Peruvian Ministry of the Environment (MINAM), have revealed the first high-resolution maps of carbon locked up in tropical forest vegetation and emitted by land-use practices. These new maps pave the way for accurate monitoring of carbon storage and emissions for the proposed United Nations initiative on Reduced Emissions from Deforestation and Degradation (REDD). The study is published in the September 6, 2010, early edition of the Proceedings of the National Academy of Sciences. The United Nations REDD initiative could create financial incentives to reduce carbon emissions from deforestation and degradation. However, this and similar carbon monitoring programs have been hindered by a lack of accurate, high-resolution methods to account for changes in the carbon stored in vegetation and lost through deforestation, selective logging, and other land-use disturbances. The new high-resolution mapping method will have a major impact on the implementation of REDD in tropical regions around the world. The study covered over 16,600 square miles of the Peruvian Amazon—an area about the size of Switzerland. The researchers used a four-step process: They mapped vegetation types and disturbance by satellite; developed maps of 3-D vegetation structure using a LiDAR system (light detection and ranging) from the fixed-wing Carnegie Airborne Observatory; converted the structural data into carbon density using a small network of field plots on the ground; and integrated the satellite and LiDAR data for high-resolution maps of stored and emitted carbon. The scientists combined historical deforestation and degradation data with 2009 carbon stock information to calculate emissions from 1999-2009 for the Madre de Dios region. "We found that the total regional forest carbon storage was about 395 million metric tons and emissions reached about 630,000 metric tons per year," explained lead author Greg Asner. "But what really surprised us was how carbon storage differed among forest types and the underlying geology, all in very close proximity to one another. For instance, where the local geology is up to 60 million years old, the vegetation retains about 25% less carbon than the vegetation found on geologically younger, more fertile surfaces. We also found an important interaction between geology, land use, and emissions. These are the first such patterns to emerge from the Amazon forest." The scientists also found that the paving of the Interoceanic Highway, combined with selective logging and gold mining, caused an increase of deforestation emissions of more than 61% by 2009, while degradation emissions doubled. Forest degradation increased regional carbon emissions by 47% over deforestation alone. However, the researchers were able to detect an 18% offset to these regional emissions in forests regrowing on previously cleared and now abandoned lands. Members of the Peruvian government participated throughout the research process to familiarize themselves with the new method. In doing so, they aimed to assess the method's advantages, evaluate deforestation and forest disturbance, and determine carbon stocks in an environmentally critical area of Madre de Dios, Peru. "A valuable opportunity has opened for MINAM to count on Carnegie's scientific and technical support. This will strengthen our ability to monitor the Amazon forest, build experience in improving the interpretation of the country's environmental and land management conditions, and contribute to the establishment of the REDD mechanism," says Doris Rueda, director of Land Management at MINAM. To support REDD, the Intergovernmental Panel on Climate Change (IPCC) issued baseline carbon density estimates for different biomes of the world, while also encouraging higher resolution approaches. When used for the Peruvian study area, the IPCC baseline estimate for carbon storage is 587 million metric tons. Based on the new Carnegie approach, the estimated total is 395 million metric tons. Under REDD-type programs, however, the high-resolution accuracy of the new approach would yield more credit per ton of carbon, thereby providing financial incentives for slowing deforestation and degradation. Carnegie scientists are expanding their demonstration and training efforts in the high-resolution mapping technique with the governments of Ecuador and Colombia.

These cells will self-destruct in 5...4...

Tue, 07 Sep 2010 03:20:32 PDT

Cancer is a difficult disease to treat because it's a personal disease. Each case is unique and based on a combination of environmental and genetic factors. Conventional chemotherapy employs treatment with one or more drugs, assuming that these medicines are able to both "diagnose" and "treat" the affected cells. Many of the side effects experienced by chemotherapy patients are due to the fact that the drugs they are taking aren't selective enough. For instance, taking a drug that targets fast-growing tumor cells frequently results in hair loss, because cells in the hair follicle are among some of the fastest growing in the body. When it comes down to it, these drugs get the diagnosis wrong. But what if we had cancer treatments that worked more like a computer program, which can perform actions based on conditional statements? Then, a treatment would kill a cell if --and only if-- the cell had been diagnosed with a mutation. Only the defective cells would be destroyed, virtually eliminating unwanted side effects. With support from the National Science Foundation (NSF), researchers at the California Institute of Technology have created conditional small RNA molecules to perform this task. Their strategy uses characteristics that are built into our DNA and RNA to separate the diagnosis and treatment steps. "The molecules are able to detect a mutation within a cancer cell, and then change conformation to activate a therapeutic response in the cancer cell, while remaining inactive in cells that lack the cancer mutation," claims Niles Pierce, co-author of a recent study which appears in the September 6 issue of Proceedings of the National Academy of Sciences (PNAS). This work is part of the Molecular Programming Project, funded by NSF's Directorate for Computer & Information Science & Engineering. One of the goals of the project is to increase understanding of how information can be stored and processed by molecules, and how we might create practical applications that utilize that information. At the heart of this approach is ribonucleic acid or RNA, and all of the normal tasks it performs each and every day to keep our cells alive and healthy. RNA is the relatively short-lived counterpart of DNA, the coding system that stores full copies of our entire genome within almost every cell of our body. If we think of DNA as information stored on the hard drive of a computer, then RNA is like information stored on a more volatile kind of memory like RAM -- which is erased when you switch off your computer. RNAs perform all kinds of functions in a cell, acting as messengers and switches to communicate and monitor which genes are expressed in a cell at any given time. A particular class of RNAs, called small RNAs, is less than 30 base pairs in length (an average gene is thousands of base pairs long). These small bits of RNA are involved in many of the processes that maintain life. The treatment developed by Pierce and his colleagues relies on two separate small RNAs that structurally mimic those that occur naturally within our own cells. Because these molecules resemble small RNAs that are normally present, the researchers hope there will be few, if any side effects. "By de-coupling diagnosis and treatment, we can create molecules that are both highly selective and highly effective in killing cancer cells," said Pierce. "Conceptually, small conditional RNAs have the potential to transform cancer treatment because they change what we can expect from a molecule. Many years of work remain to establish whether this conceptual promise can be realized in human patients." Here's how it works: Treatment involves two different small RNAS. The first small RNA will open up if --and only if-- it finds the cancer mutation. A positive "diagnosis" exposes a signal that was previously hidden within the small RNA. Once this small RNA is open, a second small RNA binds to it, setting off a chain reaction in which these RNA molecules continue to combine to form a longer chain. The length of the chain is an important part of the "treatment". Longer chains trick the cell into thinking it has been invaded by a virus, tripping a self-destruct response. In the PNAS study, researchers demonstrated that this approach effectively eliminates lab-grown human brain, prostate and bone cancer cells in a mutation-specific manner. Future experiments will determine whether the treatment is effective on a larger scale.

Interrupting death messages to treat bone disease

Tue, 07 Sep 2010 03:19:12 PDT

A surface molecule on bacteria that instructs bone cells to die could be the target for new treatments for bone disease, says a scientist speaking at the Society for General Microbiology's autumn meeting today. Blocking the death signal from bacteria could be a way of treating painful bone infections that are resistant to antibiotics, such as those caused by Meticillin-resistant Staphylococcus aureus (MRSA). Bone disease, or osteomyelitis, affects 1 in 5,000 people around the world. It can occur at any stage in life and attack any bone in the body, where it leads to progressive bone destruction. Osteomyelitis is usually caused by the bacterium Staphylococcus aureus that lives commonly on human skin and in the nose. It can reach the bones through open wounds or during surgery and most often causes infections in people with compromised immune systems. Research led by Dr. Steve Kerrigan from the Royal College of Surgeons in Ireland in collaboration with Trinity College Dublin has revealed that the ability of S. aureus to latch onto bone cells depends on a specific protein called Spa, which is presented on the bacterium's surface. Once attached to the bone cell, the bacteria transmit signals prompting the bone cell to commit suicide. This causes a gradual loss of bone cells leading to progressive bone destruction and weakening of the skeletal system. Ms Tania Claro who is presenting the group's work explained how the group's findings could lead to new therapies for osteomyelitis. "Bacteria that do not have the Spa protein on their surface are unable to bind to bone cells, which prevents them from sending suicide messages," she said. "Blocking bacterial attachment to cells via Spa could therefore be a way of treating osteomyelitis, or even preventing it in the first place." Therapies that could effectively prevent and/or treat osteomyelitis could greatly improve the quality of life of sufferers. "This disease is very painful for patients and frustrating for both them and their doctors." explained Ms Claro. Current treatment involves prolonged aggressive antibiotic therapy, however this approach is often less than successful and surgical debridement is required. New treatments for the disease that do not rely on existing antibiotics would be advantageous. "The danger of invasive bacterial disease is compounded by the rapid emergence of multi-drug resistant bacteria worldwide," explained Ms Claro. "The findings of this study will help develop better diagnostic tools and treatments for osteomyelitis that will not over-rely on antibiotics."

Blood signatures to diagnose infection

Tue, 07 Sep 2010 03:17:55 PDT

Coughing and wheezing patients could someday benefit from quicker, more accurate diagnosis and treatment for respiratory infections such as flu, through a simple blood test, according to scientists. Dr. Aimee Zaas, presenting her work at the Society for General Microbiology's autumn meeting in Nottingham describes how simply looking at an individuals blood 'signature' can be used to quickly diagnose and treat ill patients and could even predict the onset of a pandemic. The team, from the Duke Institute for Genome Sciences & Policy and Duke University Medical Center in the US, looked at the blood of otherwise healthy individuals who had been exposed to rhinovirus, respiratory syncytial virus or influenza. The team found each viral infection stimulated the body to produce a very specific set of immune molecules that could be detected in the blood. Recording the distinct blood signatures for each virus in a database and matching them against blood samples from other ill patients pinpointed the cause of disease with more than 95% accuracy. Respiratory infections, including colds and flu are a common reason for seeking medical help. As Dr. Zaas highlighted, "Current methods for accurate diagnosis are time and labour intensive and are not always accurate. This means GPs are sometimes overcautious and may prescribe antibiotics unnecessarily, for viral infections. During a pandemic, this has real consequences as there is an increased risk of spreading infection." Dr. Zaas explained how her test works completely differently to current diagnostic tests as it analyses each individual's immune response to infection, rather than the actual micro-organism responsible. "We effectively look at the imprint in the blood that the virus makes, which is as individual as a signature," she said. "Not only is this much more accurate than traditional testing, it also works much faster as it can be done through a simple blood test." This work was sponsored by the US Defense Department Advanced Research Projects Agency and is part of a large team effort. If developed further, the findings could be used in emergency departments and primary care clinics to diagnose respiratory viral illness. "This could allow patients quicker access to antiviral drugs, but could also give an accurate warning of an upcoming pandemic," explained Dr. Zaas.

With HMGB1's help, cells dine in

Tue, 07 Sep 2010 03:16:30 PDT

Like some people, cells eat when they are under pressure—but they consume parts of themselves. A multi-function protein helps control this form of cannibalism, according to a study in the September 6 issue of the Journal of Cell Biology (www.jcb.org). Cells often respond to hunger or stress by digesting some of their contents. The process, known as autophagy, helps free nutrients and clean up cytoplasmic trash such as worn-out organelles and misshapen proteins. A team led by researchers at the University of Pittsburgh Cancer Institute discovered a link between this form of cellular recycling and the protein HMGB1. The team showed HMGB1 to be a critical pro-autophagic protein that enhances cell survival and limits programmed cell death. The findings suggests that blocking HMGB1 could benefit cancer patients, since tumor cells often rev up autophagy to withstand chemotherapy, immunotherapy, and radiation treatment.

The brain speaks

Tue, 07 Sep 2010 03:15:30 PDT

In an early step toward letting severely paralyzed people speak with their thoughts, University of Utah researchers translated brain signals into words using two grids of 16 microelectrodes implanted beneath the skull but atop the brain. "We have been able to decode spoken words using only signals from the brain with a device that has promise for long-term use in paralyzed patients who cannot now speak," says Bradley Greger, an assistant professor of bioengineering. Because the method needs much more improvement and involves placing electrodes on the brain, he expects it will be a few years before clinical trials on paralyzed people who cannot speak due to so-called "locked-in syndrome." The Journal of Neural Engineering's September issue is publishing Greger's study showing the feasibility of translating brain signals into computer-spoken words. The University of Utah research team placed grids of tiny microelectrodes over speech centers in the brain of a volunteer with severe epileptic seizures. The man already had a craniotomy – temporary partial skull removal – so doctors could place larger, conventional electrodes to locate the source of his seizures and surgically stop them. Using the experimental microelectrodes, the scientists recorded brain signals as the patient repeatedly read each of 10 words that might be useful to a paralyzed person: yes, no, hot, cold, hungry, thirsty, hello, goodbye, more and less. Later, they tried figuring out which brain signals represented each of the 10 words. When they compared any two brain signals – such as those generated when the man said the words "yes" and "no" – they were able to distinguish brain signals for each word 76 percent to 90 percent of the time. When they examined all 10 brain signal patterns at once, they were able to pick out the correct word any one signal represented only 28 percent to 48 percent of the time – better than chance (which would have been 10 percent) but not good enough for a device to translate a paralyzed person's thoughts into words spoken by a computer. "This is proof of concept," Greger says, "We've proven these signals can tell you what the person is saying well above chance. But we need to be able to do more words with more accuracy before it is something a patient really might find useful." People who eventually could benefit from a wireless device that converts thoughts into computer-spoken spoken words include those paralyzed by stroke, Lou Gehrig's disease and trauma, Greger says. People who are now "locked in" often communicate with any movement they can make – blinking an eye or moving a hand slightly – to arduously pick letters or words from a list. University of Utah colleagues who conducted the study with Greger included electrical engineers Spencer Kellis, a doctoral student, and Richard Brown, dean of the College of Engineering; and Paul House, an assistant professor of neurosurgery. Another coauthor was Kai Miller, a neuroscientist at the University of Washington in Seattle. The research was funded by the National Institutes of Health, the Defense Advanced Research Projects Agency, the University of Utah Research Foundation and the National Science Foundation. Nonpenetrating Microelectrodes Read Brain's Speech Signals The study used a new kind of nonpenetrating microelectrode that sits on the brain without poking into it. These electrodes are known as microECoGs because they are a small version of the much larger electrodes used for electrocorticography, or ECoG, developed a half century ago. For patients with severe epileptic seizures uncontrolled by medication, surgeons remove part of the skull and place a silicone mat containing ECoG electrodes over the brain for days to weeks while the cranium is held in place but not reattached. The button-sized ECoG electrodes don't penetrate the brain but detect abnormal electrical activity and allow surgeons to locate and remove a small portion of the brain causing the seizures. Last year, Greger and colleagues published a study showing the much smaller microECoG electrodes could "read" brain signals controlling arm movements. One of the epileptic patients involved in that study also volunteered for the new study. Because the microelectrodes do not penetrate brain matter, they are considered safe to place on speech areas of the brain – something that cannot be done with penetrating electrodes that have been used in experimental devices to help paralyzed people control a computer cursor or an artificial arm. EEG electrodes used on the skull to record brain waves are too big and record too many brain signals to be used easily for decoding speech signals from paralyzed people. Translating Nerve Signals into Words In the new study, the microelectrodes were used to detect weak electrical signals from the brain generated by a few thousand neurons or nerve cells. Each of two grids with 16 microECoGs spaced 1 millimeter (about one-25th of an inch) apart, was placed over one of two speech areas of the brain: First, the facial motor cortex, which controls movements of the mouth, lips, tongue and face – basically the muscles involved in speaking. Second, Wernicke's area, a little understood part of the human brain tied to language comprehension and understanding. The study was conducted during one-hour sessions on four consecutive days. Researchers told the epilepsy patient to repeat one of the 10 words each time they pointed at the patient. Brain signals were recorded via the two grids of microelectrodes. Each of the 10 words was repeated from 31 to 96 times, depending on how tired the patient was. Then the researchers "looked for patterns in the brain signals that correspond to the different words" by analyzing changes in strength of different frequencies within each nerve signal, says Greger. The researchers found that each spoken word produced varying brain signals, and thus the pattern of electrodes that most accurately identified each word varied from word to word. They say that supports the theory that closely spaced microelectrodes can capture signals from single, column-shaped processing units of neurons in the brain. One unexpected finding: When the patient repeated words, the facial motor cortex was most active and Wernicke's area was less active. Yet Wernicke's area "lit up" when the patient was thanked by researchers after repeating words. It shows Wernicke's area is more involved in high-level understanding of language, while the facial motor cortex controls facial muscles that help produce sounds, Greger says. The researchers were most accurate – 85 percent – in distinguishing brain signals for one word from those for another when they used signals recorded from the facial motor cortex. They were less accurate – 76 percent – when using signals from Wernicke's area. Combining data from both areas didn't improve accuracy, showing that brain signals from Wernicke's area don't add much to those from the facial motor cortex. When the scientists selected the five microelectrodes on each 16-electrode grid that were most accurate in decoding brain signals from the facial motor cortex, their accuracy in distinguishing one of two words from the other rose to almost 90 percent. In the more difficult test of distinguishing brain signals for one word from signals for the other nine words, the researchers initially were accurate 28 percent of the time – not good, but better than the 10 percent random chance of accuracy. However, when they focused on signals from the five most accurate electrodes, they identified the correct word almost half (48 percent) of the time. "It doesn't mean the problem is completely solved and we can all go home," Greger says. "It means it works, and we now need to refine it so that people with locked-in syndrome could really communicate." "The obvious next step – and this is what we are doing right now – is to do it with bigger microelectrode grids" with 121 micro electrodes in an 11-by-11 grid, he says. "We can make the grid bigger, have more electrodes and get a tremendous amount of data out of the brain, which probably means more words and better accuracy."

DNA fingerprinting pioneer discovers role of key genetic catalyst for human diversity

Mon, 06 Sep 2010 03:20:39 PDT

One of the key drivers of human evolution and diversity, accounting for changes that occur between different generations of people, is explained by new research published today (Sept 5) by world-renowned scientist Professor Sir Alec Jeffreys, who discovered DNA fingerprinting at the University of Leicester. Professor Jeffreys has spent over two decades since his landmark discovery in 1984 investigating what he describes as "pretty bizarre bits of DNA" - highly variable repeated parts of DNA called 'minisatellites' - found in the human genome. Sir Alec observed that these seemed to be changing and "picking up mutations at an extraordinary rate" when compared to other DNA. Now, in a paper published online in Nature Genetics (Sept 5), Sir Alec and his team in the Department of Genetics at the University of Leicester have demonstrated the remarkable influence of a particular gene on the development of diversity in humans. The work was funded by the Medical Research Council, the Wellcome Trust, the Boehringer Ingelheim Fonds, the Royal Society and the Louis-Jeantet Foundation. Professor Jeffreys is Royal Society Wolfson Research Professor of Genetics at Leicester. Sir Alec said: "In each generation our genetic make-up gets 'reshuffled', like a genetic pack of cards, by a process called recombination - a fundamental engine driving diversity. The work we have done over the past 10 years at Leicester has been key to understanding recombination in humans, and has allowed the molecular definition of recombination 'hotspots' - small regions in which the reshuffling process is focused. "Our new study has focused on a gene called PRDM9 that makes a protein which binds to DNA and triggers hotspot activity. The exciting finding is that people with different versions of PRDM9 show profoundly different recombination behaviours, not only in hotspots but also in chromosomal rearrangements that cause some genetic disorders." Ironically, the variation in PRDM9 is due to a minisatellite within the gene itself. Sir Alec said: 'I've come full circle – starting out with minisatellites to develop DNA fingerprinting, and arriving at a gene containing a minisatellite that plays a key role in driving all kinds of human DNA diversity, including variation at minisatellites. An intriguing possibility is that it is even driving its own evolution!' Sir Alec believes the research, along with that of others working in the field, will inevitably further scientists' ability to understand the basic processes that make us all genetically unique, as well as defining an entirely new class of genetic risk factor for numerous disease-causing DNA rearrangements that can arise when recombination goes wrong. These findings also provide a neat solution to one great puzzle of recombination hotspots – namely that they appear and disappear rapidly during evolution. Sir Alec said 'We've shown that hotspots have a strange propensity for self-destruction, so how can they possibly exist? The PRDM9 minisatellite gives the answer – it evolves rapidly, like any other unstable minisatellite, and keeps churning out variants that can trigger new hotspots, replenishing those that have committed suicide. A totally crazy mechanism to ensure that recombination keeps going, but typical of the weird solutions that evolution can throw up'.

'Jailbreak' bacteria can trigger heart disease

Mon, 06 Sep 2010 03:19:34 PDT

Plaque-causing bacteria can jailbreak from the mouth into the bloodstream and increase your risk of heart attack says a scientist at the Society for General Microbiology's autumn meeting in Nottingham. Professor Howard Jenkinson, from the University of Bristol explains how oral bacteria can wreak havoc if they are not kept in check by regular brushing and flossing. "Poor dental hygiene can lead to bleeding gums, providing bacteria with an escape route into the bloodstream, where they can initiate blood clots leading to heart disease," he said. Streptococcus bacteria commonly live in the mouth, confined within communities termed biofilms and are responsible for causing tooth plaque and gum disease. The University of Bristol researchers, in collaboration with scientists at the Royal College of Surgeons in Ireland (RCSI), have shown that once let loose in the bloodstream, Streptococcus bacteria can use a protein on their surface, called PadA, as a weapon to force platelets in the blood to bind together and form clots. Inducing blood clots is a selfish trick used by bacteria, as Professor Jenkinson points out. "When the platelets clump together they completely encase the bacteria. This provides a protective cover not only from the immune system, but also from antibiotics that might be used to treat infection," he said. "Unfortunately, as well as helping out the bacteria, platelet clumping can cause small blood clots, growths on the heart valves (endocarditis), or inflammation of blood vessels that can block the blood supply to the heart and brain." Professor Jenkinson said the research highlights a very important public health message. "People need to be aware that as well keeping a check on their diet, blood pressure, cholesterol and fitness levels, they also need to maintain good dental hygiene to minimise their risk of heart problems." The team is using a brand-new blood flow model, developed by Dr Steve Kerrigan at the RCSI, School of Pharmacy, Dublin, that mimics conditions in the human circulatory system. "We are currently investigating how the platelet-activating function of PadA can be blocked. This could eventually lead to new treatments for cardiovascular disease which is the biggest killer in the developed world," said Professor Jenkinson.

Talented bacteria make food poisoning unpredictable

Mon, 06 Sep 2010 03:18:11 PDT

While we are often exposed to bacteria in our food which could cause food poisoning, we don't always become ill - why should this be so? Professor Colin Hill who is presenting his work at the Society for General Microbiology's autumn meeting in Nottingham today describes how bacteria use different tricks to aid their survival inside the body, helping to explain why food poisoning can be so unpredictable. One of the biggest challenges faced by food-borne bacteria is acid. Acidic conditions, particularly in the stomach and in the gut will kill most microbes found in contaminated food. Professor Hill's group at University College Cork has revealed that Listeria bacteria, which may be found in soft cheeses and chilled ready-to-eat products, can overcome harsh acidic conditions by exploiting key food ingredients. Listeria that survive are able to cause serious and sometimes fatal infections, particularly in the elderly and pregnant women. Certain food constituents such as the amino acid, glutamate, can help the bacteria neutralise acid, allowing the bacteria to pass through the stomach unscathed. Professor Hill explains the significance of this. "People who consume foods that are contaminated with Listeria and are also high in glutamate, such as soft cheese or meat products, have a higher chance of developing serious infection than someone eating the same quantity of bacteria in a low-glutamate food," he said. "Of course this is further complicated by the fact that a contaminated, low-glutamate food could be eaten in combination with a high-glutamate food such as tomato juice, which could also increase the risk of infection." Listeria can also take advantage of food processing and storage conditions to help them survive. "Bacteria that are exposed to low pH before entering the body may adapt to become more acid-tolerant and therefore better equipped to deal with acidic conditions in the body. For example, Listeria contaminating naturally acidic foods such as cheese may be more likely to cause infection than Listeria carried at a more neutral pH in water. Professor Hill explains how his group's work could help reduce the incidence of Listeria infections. "The number of cases of listeriosis has nearly doubled in the last decade in Europe. This is because the bacterium is so good at overcoming the challenges it faces in food and in the body," he said. "Our studies show that consuming Listeria in one food may be quite safe, while eating the same amount in another food might be lethal. By understanding the role of the food matrix we may be able to identify and eliminate high-risk foods from the diet of susceptible people."

Biologists find way to reduce stem cell loss during cancer treatment

Mon, 06 Sep 2010 03:16:51 PDT

Biologists at the University of California, San Diego have discovered that a gene critical for programmed cell death is also important in the loss of adult stem cells, a finding that could help to improve the health and well-being of patients undergoing cancer treatment. “During chemotherapy or radiation therapy that kills cancer cells by inducing significant DNA damage in their genomes, one of the main side effects for human cancer patients is the depletion of their own adult stem cells, particularly the ones responsible for making new blood and intestine cells. So these patients become anemic, lose appetite and a lot of weight,” said Yang Xu, a professor of biology at UC San Diego who headed the team that published its findings in this week’s advance online issue of the journal Nature Cell Biology. “If we can prevent the loss of stem cells during cancer therapy, that would be very beneficial for these patients.” Scientists have long known that when normal cells accumulate significant amount of DNA damage, such as during cancer therapy, the tumor suppressor p53 is activated, which leads cells to stop dividing, go into hibernation and undergo a programmed cell death called apoptosis. They’ve also known that a gene called Puma, an acronym for “p53-unregulated modulator of apoptosis,” is critical for p53 to initiate the cell death of DNA-damaged cells. Using genetically modified mice with persistently activated p53, Xu and his colleagues discovered that, once activated, p53 depletes various adult stem cells, including the ones that are responsible for generating new blood and intestine cells. In addition, Puma is critical for this p53-dependent depletion of various adult stem cells. “Since p53 is a critical tumor suppressor, you cannot suppress p53 to prevent the depletion of adult stem cells since it will induce cancer,” said Xu. “But you can target Puma to prevent p53-mediated depletion of adult stem cells, because a Puma deficiency does not promote the development of cancer. This gives us a nice target for preventing the p53-dependent depletion of adult stem cells in response to DNA damage. If you can suppress Puma function, you can rescue a lot of the adult stem cells that would otherwise be lost after the accumulation of DNA damage such as during cancer therapy.” Other co-authors of this paper are Dongping Liu, Linda Ou, Connie Chao and Marshall Lutske of UCSD; Gregory Clemenson and Fred Gage of the Salk Institute for Biological Studies and Gerard Zambetti of St. Jude Children’s Research Hospital in Memphis, Tenn. Funding for the study was provided by the National Institutes of Health.

Rochester leads international effort to improve muscular dystrophy treatment

Sat, 04 Sep 2010 04:23:41 PDT

A large international study aimed at improving the care of muscular dystrophy patients worldwide is being launched by physicians, physical therapists, and researchers at the University of Rochester Medical Center. Neurologist Robert "Berch" Griggs, M.D., is heading the study of treatments for Duchenne muscular dystrophy, the most common form of the disease that affects children. The condition, which affects boys almost exclusively, progresses rapidly. Boys' symptoms start when they are toddlers; untreated, they end up in a wheelchair before they become teenagers. With today's best treatments, the disease, which affects about 28,000 boys and young men in the United States, is often fatal by the time a patient reaches his 20s or early 30s. Despite decades of research, Griggs calls the current treatment landscape for the disease "chaotic." Recently he has identified 29 different treatment regimens in use by doctors around the world. The new study is designed to eliminate the chaos. With at least $11 million in funding from the National Institute of Neurological Disorders and Stroke, Griggs and co-leader Kate Bushby, M.D., and investigators at 41 other institutions around the world will study the three treatments most commonly used today. The study will include 300 boys ages 4 through 7 throughout North America and Europe. Recruiting for the study will begin in the summer of 2011. Study funding is slated to reach close to $15 million. The central feature of Duchenne muscular dystrophy is muscle weakness. The first symptoms, often seen around age 2 or 3, usually come when a boy has difficulty running, jumping, or climbing stairs. From there, even with treatment, the disease progresses very quickly. Boys are often confined to a wheelchair by age 9 or 10 because of weakness in their legs; their breathing muscles begin to fail and their heart muscle weakens dramatically in their teen years. Most patients begin receiving assisted breathing with a ventilator while they are teenagers. About two-thirds of cases occur in families with a history of the disease – the genetic flaw responsible is passed from mother to son – but about one-third of cases occur spontaneously. That's because the disease's roots lie in a genetic flaw in the massive gene responsible for making a protein known as dystrophin, which helps make and keep muscles strong and stable. Weighing in at 2 million chemical bases, the gene is the biggest in the human body, and mutations are relatively frequent. In patients with a mutation, the body does not make enough dystrophin, and muscle fibers are gradually replaced with fat and other tissue. In a study more than 20 years ago, in studies supported by the Muscular Dystrophy Association, Griggs and colleagues found that a daily dose of prednisone improves patients' lives dramatically. Yet Griggs has found that the treatment for Duchenne muscular dystrophy is chaotic because of concern about side effects. In a recent survey of more than 100 centers worldwide that specialize in treatment of the disease, only three were consistently using the recommended treatment – a daily dose of prednisone. Others were using prednisone intermittently or were using deflazacort; 10 weren't using steroids at all. In the new study, patients will be randomly assigned to receive one of three steroid treatments: a) prednisone every day; b) prednisone every day for 10 days, alternating with 10-day periods without the drug; c) daily use of a steroid known as deflazacort, which is approved for use in Europe but not the United States. Neither the patients nor the researchers will be aware of the patients' treatment assignments until the conclusion of the trial. Doctors have found that daily prednisone boosts muscle strength dramatically and that the effects are felt by patients and witnessed by parents within just 10 days. The drug boosts muscle mass by 20 percent and slows the degeneration of the muscles in patients with the disease. But concerns over side effects leave many doctors leery of prescribing the medication on a daily basis. Side effects can include weight gain, behavioral effects such as hyperactivity or irritability, and eventually loss of bone and even possibly fractures. "People have worried about side effects of daily prednisone, and many people have felt there must be a better alternative," said Griggs, who is professor of Neurology, Medicine, Pediatrics, Pathology and Laboratory Medicine, and a member of the Center for Human Experimental Therapeutics. "Our study is designed to address exactly this question: What is the best balance between effective treatment and side effects?" Children will be evaluated every six months for three to five years. Researchers will measure the breathing capacity of the patients, which is often an indicator of how long a patient will live; they will ask patients and parents how satisfied they are with the treatment; and they will measure how long it takes patients to stand up after lying down, which is an indicator of how long a patient will be able to walk. "With a healthy child, if you clap your hands and tell him to stand up as quickly as he can, he's up on his feet in less than a second. With a child with Duchenne muscular dystrophy, it might take 30 times longer," said Griggs. "The child will roll onto his stomach, laboriously lift his bottom into the air, and slowly move his arms to one knee, then the other, bracing himself until he finally straightens up." The study brings together two worldwide groups of physicians who specialize in the study of muscle disorders. The Muscle Study Group, with nearly three dozen sites in the United States, Canada, and Europe, is based in Rochester and headed by Griggs. The TREAT-NMD study group is a consortium of dozens of institutions across Europe and elsewhere that work together to study neuromuscular disorders. TREAT-NMD is headed by Bushby, who is Action Research Professor of Neuromuscular Genetics at Newcastle University in the United Kingdom. Bushby and Griggs are leading the clinical aspects of the new study. Michael McDermott, Ph.D., professor of Biostatistics and Neurology, and Rabi Tawil, M.D., professor of Neurology, are co-leaders of biostatistical analysis and data management. The team from Rochester also includes Barbara Herr, assistant professor of Neurology, manager of the U.S. portion of the project; associate project manager Christine Annis; Shree Pandya, lead U.S. physical therapist; Mary Brown, Heart Research Program manager; William Martens, data manager; and Emma Ciafaloni, M.D., associate professor of Neurology, who will lead the study of patients in Rochester. Griggs is central to the international effort to find an effective treatment for the disease. Last week, for readers of the journal Lancet Neurology, Griggs was asked to put into perspective new findings from a study of the drug cyclosporine, which recently proved safe but not effective for patients. Griggs also served as the head of the data and safety monitoring board for a study of an investigational drug called ataluren conducted by PTC Therapeutics; earlier this year the company announced that the drug, though safe, failed to help patients in the ways doctors had hoped. Analysis of those data continues.

First clinical trials successfully completed on potent new hepatitis C drug

Sat, 04 Sep 2010 04:22:25 PDT

The first clinical trials on a new investigational drug being developed to treat infections caused by Hepatitis C virus have been successfully completed. Completion of the initial phase (phase 1a) of trials of INX-189, discovered and first prepared by researchers at Cardiff University's Welsh School of Pharmacy in 2008, means the chances of it becoming an approved medicine have significantly improved. Approximately 170 million people worldwide are affected with Hepatitis C, which can lead to liver cancer, cirrhosis and death. It is the leading cause of liver transplantation in western countries. The current treatment involves two drugs – ribavirin and interferon, which has to be given as an injection. Side effects are often severe and lead to patients failing to complete the treatment. Professor Chris McGuigan of the Welsh School of Pharmacy, academic lead on the project, said: "This is still a very early stage of the trials process but none the less a significant development. Successfully completing phase 1a demonstrates that the drug is safe, with no drug-related side effects at all in a single dose of 100mg. "The efficiency of drug release in this study has also confirmed that one single dose a day is most likely enough in treating the virus. "We believe that INX-189 offers the possibility of more potency against Hepatitis, more rapid action in the liver, and fewer side effects than existing treatments." In 2008, laboratory tests showed INX-189 killed 90 per cent of the virus at very low (nanomolar) concentration, making it the most potent compound of its kind developed to date. US pharmaceutical company Inhibitex, which owns the licence to INX-189 and has been working with the Cardiff team, has announced it is looking forward to a second trial (phase 1b), which would evaluate the compound's effectiveness in Hepatitis C patients. Cardiff University and Inhibitex filed a patent on INX-189 earlier this year. It has been cleared for human clinical trials by the Food and Drug Administration in the US.

Study exposes cognitive impairment in people with Parkinson's disease

Sat, 04 Sep 2010 04:20:57 PDT

Queen’s researchers have found that people with Parkinson’s disease can perform automated tasks better than people without the disease, but have significant difficulty switching from easy to hard tasks. The findings are a step towards understanding the aspects of the illness that affect the brain’s ability to function on a cognitive level. “We often think of Parkinson’s disease as being a disorder of motor function,” says Douglas Munoz, director of the Queen's Centre for Neuroscience Studies and a Canada Research Chair in Neuroscience. “But the issue is that the same circuit can affect more cognitive functions like planning and decision-making.” The researchers conducted an experiment using a sample of Parkinson’s patients and a control group. When asked to look at a light when it came on, people with Parkinson’s responded with greater accuracy than people without the disease. But when asked to change that behavior – to look away from the light, for instance – Parkinson’s patients struggled. Even when asked to simply prepare to change their behaviour, people with the disease found it incredibly difficult to adjust their plans. PhD student Ian Cameron, lead author of the study, says the findings are significant because they highlight how biased Parkinson’s patients are towards performing an automated response. It also suggests that medications currently prescribed to treat the symptoms of the disease that affect motor functioning could further upset a patient’s cognitive balance. Mr. Cameron is now conducting functional brain imaging in Parkinson’s patients to determine which parts of the brain are affected by medications currently used to treat the symptoms of the disease. The findings were recently published in Neuropsychologia, an international interdisciplinary journal of cognitive and behavioural neuroscience.

MIT moves toward greener chemistry

Sat, 04 Sep 2010 04:19:23 PDT

Phosphorus, a mineral element found in rocks and bone, is a critical ingredient in fertilizers, pesticides, detergents and other industrial and household chemicals. Once phosphorus is mined from rocks, getting it into these products is hazardous and expensive, and chemists have been trying to streamline the process for decades. MIT chemistry professor Christopher Cummins and one of his graduate students, Daniel Tofan, have developed a new way to attach phosphorus to organic compounds by first splitting the phosphorus with ultraviolet light. Their method, described in the Aug. 26 online edition of Angewandte Chemie, eliminates the need for chlorine, which is usually required for such reactions and poses health risks to workers handling the chemicals. While the new reaction cannot produce the quantities needed for large-scale production of phosphorus compounds, it opens the door to a new field of research that could lead to such industrial applications, says Bertrand, who was not involved in the research. Extracting phosphorus Most natural phosphorus deposits come from fossilized animal skeletons, which are especially abundant in dried-up seabeds. Those phosphorus deposits exist as phosphate rock, which usually includes impurities such as calcium and other metals that must be removed. Purifying the rock produces white phosphorus, a molecule containing four phosphorus atoms. White phosphorous is tetrahedral, meaning it resembles a four-cornered pyramid in which each corner atom is bound to the other three. Known as P4, white phosphorus is the most stable form of molecular phosphorus. (There are also several polymeric forms, the most common of which are black and red phosphorus, which consist of long chains of broken phosphorus tetrahedrons.) For most industrial uses, phosphorus has to be attached one atom at a time, so single atoms must be detached from the P4 molecule. This is usually done in two steps. First, three of the atoms in P4 are replaced with chlorine, resulting in PCl3 — a phosphorus atom bound to three chlorine atoms. Those chlorine atoms are then displaced by organic (carbon-containing) molecules, creating a wide variety of organophosphorus compounds such as those found in pesticides. However, this procedure is both wasteful and dangerous — chlorine gas was used as a chemical weapon during World War I — so chemists have been trying to find new ways to bind phosphorus to organic compounds without using chlorine. A new reaction Cummins has long been fascinated with phosphorus, in part because of its unusual tetrahedral P4 formation. Phosphorus is in the same column of the periodic table as nitrogen, whose most stable form is N2, so chemists expected that phosphorus might form a stable P2 structure. However, that is not the case. For the past few years, Cummins' research group has been looking for ways to break P4 into P2 in hopes of attaching the smaller phosphorus molecule to organic compounds. In the new study, Cummins drew inspiration from a long overlooked paper, published in 1937, which demonstrated that P4 could be broken into two molecules of P2 with ultraviolet light. In that older study, P2 then polymerized into red posphorus. Cummins decided to see what would happen if he broke apart P4 with UV light in the presence of organic molecules that have an unsaturated carbon-carbon bond (meaning those carbon atoms are able to grab onto other atoms and form new bonds). After 12 hours of UV exposure, he found that a compound called a tetra-organo diphosphane had formed, which includes two atoms of phosphorus attached to two molecules of the organic compound. This suggests, but does not conclusively prove, that P2 forms and then immediately bonds to the organic molecule. In future studies, Cummins hopes to directly observe the P2 molecule, if it is indeed present. Cummins also plans to investigate what other organophosphorus compounds can be synthesized with ultraviolet light, including metallic compounds. He has already created a nickel-containing organophosphorus molecule, which could have applications in electronics.

Satellite data reveal why migrating birds have a small window to spread bird flu

Sat, 04 Sep 2010 04:17:58 PDT

In 2005 an outbreak of the H5N1 'bird flu' virus in South East Asia led to widespread fear with predictions that the intercontinental migration of wild birds could lead to global pandemic. Such fears were never realised, and now research published in the British Ecological Society's Journal of Applied Ecology reveals why the global spread of bird flu by direct migration of wildfowl is unlikely but also provides a new framework for quantifying the risk of avian-borne diseases. The highly pathogenic H5N1 bird flu virus is primarily a disease of poultry, often resulting in mass mortality for infected flocks. However, the virus can also infect other species, including wild birds and humans. Experimental infection has also revealed that some wild ducks, geese and swans can carry the virus asymptomatically, that is before the symptoms of the virus become apparent, meaning that they have the potential to spread the virus as they migrate. "The potential risks to humans led to extensive media coverage often focusing on migratory birds, which fuelled public concern and led to calls for the mass culling of wild birds," said lead author Dr Nicolas Gaidet. "However, the actual risk of H5N1 spread through migratory birds depended on whether infected individuals were capable of migratory movements while shedding virus, and the distance over which such individuals could travel. Our research has answered these questions using analysis of infection and migratory routes and timings for many bird species." Dr Gaidet's team analysed 228 birds from 19 species using satellite telemetry from 2006 to 2009 over the bird flu affected areas of Asia, Europe and Africa. The results indicated that migrating wildfowl do have the potential to disperse H5N1 over extensive distances as mass migration can result in infected birds covering as much as 2900km before symptoms become apparent. However, while this is theoretically possible the team found that direct virus dispersal by migrating birds would require asymptomatic infection to coincide precisely with the migration season. The results revealed a very small 'window' of between 5 to 15 days when dispersal of the virus over 500 km could occur. It is crucial to the spread of disease over such a distance that an infected bird must not be showing the symptoms of infection. If the symptoms are evident then it is highly likely that the individual may not migrate, or at least they will be unable to cover the distance as well as a healthy bird. Along with the precise timing required to spread the virus across the maximum distance, the migrating birds would also have to fly the shortest route possible, as quickly as possible. However, the team found that most migrating wildfowl stop at various staging posts throughout the trip for periods longer than the asymptomatic duration period. Virus transfer between staging birds or infection from the environment would allow a greater potential for spread, and while neither of these routes of transmission are well documented, the latter is most likely. "Our results indicate that individual migratory wildfowl do have the potential to disperse H5N1 over extensive distances, however the likelihood of such intercontinental virus dispersal by individual wildfowl is very low," concluded Gaidet. "Our results provide a detailed quantitative framework for the dispersive potential of avian borne viruses, which will help to better understand the risk posed by other avian-borne diseases such as the West Nile Virus".

AgriLife research hibiscus breeder comes up with the blue

Sat, 04 Sep 2010 04:16:36 PDT

Dr. Dariusz Malinowski is seeing blue, and he is very excited. For four years, Malinowski, an AgriLife Research plant physiologist and forage agronomist in Vernon, has been working with collaborators Steve Brown of the Texas Foundation Seed and Dr. William Pinchak and Shane Martin with AgriLife Research on a winter-hardy hibiscus breeding project. The project was first a private hobby of the inventors and became a part of the strategic plan of the Texas AgriLife Research and Extension Center at Vernon in 2009. The flower commercialization is a part of the research on non-traditional or under-utilized crops that have value because of drought tolerance. Malinowski's breeding goal has been to create a blue-flowering winter-hardy hibiscus. "A blue pigment does not exist in this species, thus hybridizers have not been successful so far in creating a plant with blue flowers," he said. "There are a couple of recently introduced cultivars with plum and lavender flower color." But now Malinowski has managed to breed a flower with the illusive color. He and his collaborators have created a number of lines with unique flower and foliage shape and color. The new hibiscus hybrids range in color from white through different shades of pink, lavender, bluish, red and magenta tones, and some of them have combinations of two or even three colors. One line has dark maroon foliage with moderately big, white flowers that blend into a pink center with darker veins, Malinowski said. Flower size of these hybrids varies from miniature blooms 2 inches in diameter to the size of dinner plates, about 12 inches in diameter. Malinowski has been using these cultivars in his breeding project for several generations. This year, they finally had one plant bloom with almost blue flowers, a significant breakthrough in efforts to create a blue hibiscus cultivar. "It took four years of work and more than 1,000 crosses among three winter-hardy hibiscus species to achieve this goal of creating an almost-blue flowering hibiscus hybrid," he said. The new hybrid is not perfect yet, Malinowski said. "The flowers get a fantastic blue hue in shade, but in full sunlight they are still plum-lavender-bluish," he said. Brown said it is important to note that in the world of ornamentals, "blue" is interpreted to have a wide range of hues. Most ornamental blues have a more purple or lavender cast. "There are very few true blue flowers in any ornamental cultivar," he said. "Although I would call this flower 'almost blue' as Dariusz has, there is no question that this development is unique in known hardy hibiscus color ranges. "My expectation is that we will see more vibrant colors in next year's F1s (cultivars) using this line as a parent," Brown said. Malinowski said he will use this plant as a parent in his breeding project this summer, with the goal to stabilize the blue color in full sunlight and increase flower size from the current 7 inches to the "magic" 12-inch diameter. Breeding of ornamental plants is not the major research area of Malinowski, but he said he enjoys new challenges and the benefits of combining his private hobby with business. "I never thought I would be an expert in breeding winter-hardy hibiscus," he said. "The knowledge I have gained during the past few years of intensive work on hardy hibiscus helps me reach most of the breeding objectives in a relatively short time." What is next? Malinowski and his collaborators have a new challenge - to create an orange flowering hardy hibiscus. This goal seems to be even more difficult, but not impossible, Malinowski said. It will require hybridization with a distantly related hibiscus species, which has shades of orange flowers. The researchers hope that with the help of molecular genetic tools they will be able to meet this objective.

Transition metal catalysts could be key to origin of life, scientists report

Sat, 04 Sep 2010 04:14:40 PDT

One of the big, unsolved problems in explaining how life arose on Earth is a chicken-and-egg paradox: How could the basic biochemicals—such as amino acids and nucleotides—have arisen before the biological catalysts (proteins or ribozymes) existed to carry out their formation? In a paper appearing in the current issue of The Biological Bulletin, scientists propose that a third type of catalyst could have jumpstarted metabolism and life itself, deep in hydrothermal ocean vents. According to the scientists' model, which is experimentally testable, molecular structures involving transition metal elements (iron, copper, nickel, etc.) and ligands (small organic molecules) could have catalyzed the synthesis of basic biochemicals (monomers) that acted as building blocks for more complex molecules, leading ultimately to the origin of life. The model has been put forth by Harold Morowitz of George Mason University (GMU), Vijayasarathy Srinivasan of GMU, and Eric Smith of the Santa Fe Institute. "There has been a big problem in the origin of life (theory) for the last 50 years in that you need large protein molecules to be catalysts to make monomers, but you need monomers to make the catalysts," Morowitz says. However, he suggests, "You can start out with these small metal-ligand catalysts, and they'll build up the monomers that can be used to make the (large protein catalysts)." A transition metal atom can act as the core of a metal-ligand complex, in which it is bound to and surrounded by other ligands. Morowitz and his colleagues propose that simple transition metal-ligand complexes in hydrothermal ocean vents catalyzed reactions that gave rise to more complex molecules. These increasingly complex molecules then acted as ligands in increasingly efficient transition metal-ligand complex catalysts. Gradually, the basic molecular ingredients of metabolism accumulated and were able to self-organize into networks of chemical reactions that laid the foundation for life. "We used to think if we could understand what carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur were doing, we would immediately be able to understand biology," Morowitz says, listing elements that constitute a large proportion of Earth's biomass. "But now we're finding that these other fairly rare elements, transition metals, are necessary in biology, so we ask, 'What was their role in the origin of life?'" The proposal suggests that the rise of life forms is a natural consequence of the unique properties of transition metals and ligand field theory, which describes the characteristics of ligand complexes. "The idea has emerged from a study of the periodic table. We strongly feel that unless you're able to see how life comes about in some formal chemical way, you're never really going to solve the problem," Morowitz says. Morowitz and his colleagues are preparing experiments to test the catalytic properties of transition metal-ligand complexes built with different types of ligands. Ligands known to bind tightly to transition metals include molecules produced during the course of the reductive citric acid cycle, a series of biochemical reactions essential for many microorganisms. "We think life probably began with the reductive citric acid cycle, and there is evidence that under hydrothermal vent conditions some of the cycle's intermediates form," Morowitz says. "We are going to start with these molecules and mix them with various transition metals, cook them at different temperatures for a while, and see what kinds of catalysts we've made." Such experiments could reveal what kinds of catalytic reactions took place to lay the foundations for life. The hypothesis also allows for the possibility that life could have arisen more than once. "Life could have originated multiples times, and, if we find life elsewhere in the universe, it could be very similar to the life we know here because it will be based on the same transition metals and ligands," Morowitz says. "It's a conjecture at the moment, but it could become a formal scientific core for the emergence of life."

NIH-sponsored research yields promising malaria drug candidate

Fri, 03 Sep 2010 04:19:21 PDT

A chemical that rid mice of malaria-causing parasites after a single oral dose may eventually become a new malaria drug if further tests in animals and people uphold the promise of early findings. The compound, NITD609, was developed by an international team of researchers including Elizabeth A. Winzeler, Ph.D., a grantee of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. "Although significant progress has been made in controlling malaria, the disease still kills nearly 1 million people every year, mostly infants and young children," says NIAID Director Anthony S. Fauci, M.D. "It has been more than a decade since the last new class of antimalarials—artemisinins—began to be widely used throughout the world. The rise of drug-resistant malaria parasites further underscores the need for novel malaria therapies." Dr. Fauci adds, "The compound developed and tested by Dr. Winzeler and her colleagues appears to target a parasite protein not attacked by any existing malaria drug, and has several other desirable features. This research is also a notable example of successful collaboration between government-supported scientists and private sector researchers." The study, in the Sept. 3 issue of Science, was led by Thierry T. Diagana, Ph.D., of the Novartis Institute for Tropical Diseases (NITD), and Dr. Winzeler. Dr. Winzeler is affiliated with The Scripps Research Institute and the Genomic Institute of the Novartis Research Foundation, La Jolla, Calif. Work on what eventually became NITD609 began in Dr. Winzeler's lab in 2007. Scientists screened 12,000 chemicals using an ultra-high throughput robotic screening technique customized to detect compounds active against Plasmodium falciparum, the most deadly malaria parasite. The screen identified a chemical with good parasite-killing abilities and the potential to be modified into a drug. Medicinal chemists at the NITD then synthesized and evaluated about 200 versions of the original compound to arrive at NITD609, which could be formulated as a tablet and manufactured in large quantities. NITD609 is one of a new class of chemicals, the spiroindolones, which have been described in recently published research by Dr. Winzeler and colleagues as having potent effects against two kinds of malaria parasites. "From the beginning, NITD609 stood out because it looked different, in terms of its structure and chemistry, from all other currently used antimalarials," says Dr. Winzeler. "The ideal new malaria drug would not just be a modification of existing drugs, but would have entirely novel features and mechanism of action. NITD609 does." In the current study, the scientists detail attributes of NITD609 that suggest it could be a good malaria drug. For example

In test-tube experiments, NITD609 killed two species of parasites in their blood-stage form and also was effective against drug-resistant strains. In humans, malaria parasites spend part of their life cycle in the blood and part in the liver.
The compound worked faster than some older malaria drugs, although not as quickly as the best current malaria drug, artemisinin.
Other laboratory tests showed that NITD609 is not toxic to a variety of human cells.

When given orally to rodents, the compound stayed in circulation long enough to reach levels predicted to be effective against malaria parasites. According to Dr. Winzeler, if NITD609 behaves similarly in people, it might be possible to develop the compound into a drug that could be taken just once. Such a dosage regimen, she says, would be substantially better than the current standard treatment in much of the world in which uncomplicated malaria infections are treated for three to seven days with drugs that are taken between one and four times daily. "We were excited by the potential NITD609 showed in the first series of test-tube experiments," says Dr. Winzeler. "We became even more enthusiastic when our co-investigators at the Swiss Tropical Institute in Basel tested NITD609 in a mouse model of malaria." Typically, she says, rodents infected with the mouse malaria parasite, Plasmodium berghei, die within a week. But a single large dose of NITD609 cured all five infected mice that received it, while half of six mice receiving a single smaller dose were cured of infection. Three doses of the smaller amount of NITD609 upped the cure rate to 90 percent. The researchers also compared NITD609 with other malaria drugs in P. berghei-infected mice. "No other currently used malaria drug was as potent," says Dr. Winzeler. NITD609's effectiveness in relatively few doses is a key point in its favor, she adds. A novel malaria drug that works in as few doses as possible leaves less opportunity for parasites to develop drug resistance. Additional tests in animals are under way and NITD609 could enter early-stage safety testing in humans later this year, says Dr. Winzeler. But, she adds, many drug candidates fail in clinical trials and thus it will be important for the community to continue to work on developing other potential antimalarial compounds. To learn how parasites might develop resistance to this potential drug, the researchers also exposed parasites to sublethal levels of NITD609 continuously for several months until drug-resistant strains emerged. Then they analyzed those strains and determined that resistance results from a single change in one of the parasite's genes. The gene contains the code to make a protein called PfATP4, which allows substances to cross cell membranes. No other anti-malaria drugs act on the PfATP4 protein, notes Dr. Winzeler. Having information in hand about the genetic basis for NITD609 resistance at this early stage of the compound's development is advantageous, she adds, because it will allow scientists to rapidly detect drug-resistant strains in clinical settings if the compound is eventually approved as a drug for human use.

New warning signs may predict kidney transplant failure

Fri, 03 Sep 2010 04:18:17 PDT

Kidney transplants that show a combination of fibrosis (scarring) and inflammation after one year are at higher risk of long-term transplant failure, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). To identify these abnormalities, doctors would need to perform routine biopsies on apparently normal kidney transplants—rather than waiting for problems to occur. "Even for some transplants that would be expected to have a very long graft survival, protocol biopsies performed in the first year may indicate the kidney is undergoing damaging inflammation, which is associated with increased risk for reduced function and graft survival," comments Mark D. Stegall, MD (Mayo Clinic, Rochester, MN). As part of a project to explore the reasons for long-term kidney transplant failure, the Mayo Clinic transplant program has been performing routine biopsies at regular intervals after transplantation. The Mayo Clinic program was among the first to incorporate such "protocol" biopsies into the routine care of clinically stable transplants. The researchers analyzed factors related to transplant survival in 151 patients who had no apparent problems after living-donor kidney transplantation. One-year biopsies showed no abnormalities in 57 percent of kidneys; another 30 percent had fibrosis (scarring) but no inflammation. In these two groups, the transplanted kidney continued to function normally from one to five years' follow-up. However, in the remaining 13 percent of transplants, the biopsies showed fibrosis plus inflammation. These transplants had declining kidney function and a reduced long-term survival rate. Kidneys showing fibrosis plus inflammation also had increased numbers of immune cells as well as a "rejection-like" gene expression signature. Thus, in apparently normal kidney transplants, biopsies showing fibrosis and inflammation signal kidney damage and an increased risk of long-term failure. "It is likely that the intragraft environment of patients with fibrosis and inflammation is damaging to the allograft," says Stegall. Without routine "protocol" biopsies, these warning signs would go undetected until clinical abnormalities developed, according to Stegall. "The use of protocol biopsies allows for more detailed investigations of the intragraft environment," he says. "Such routine biopsies could provide a unique way to predict which kidney transplant recipients may be at increased risk for loss of kidney function, or to identify potential targets for early preventative treatment." The study was limited to patients who received kidneys from living donors and who had no apparent complications during the first year. As a result, the findings may not apply to other groups of transplant recipients, including those who have complications such as delayed transplant function or acute rejection.