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September 24th, 2014

Universal Enzyme Activated Differently in Different Species, Discovery Paves Way to Tackling Deadly Parasitic Diseases

An enzyme found in all living things could hold the key to combating certain deadly diseases, such as sleeping sickness, a new study suggests. Research into the enzyme, which helps cells convert nutrients into energy, has shown that it is activated in different ways in various species. Researchers say this discovery creates an opportunity to design drugs that block activity of the enzyme – known as pyruvate kinase (image) – in species that cause infection. Blocking the parasite’s enzyme would effectively kill the parasite, without affecting the same enzyme in the patient. Findings from the study could lead to new treatments for diseases spread by parasites – including sleeping sickness and Chagas disease – that affect millions of people in the developing world. Researchers say the finding could ultimately help physicians tackle a range of healthcare problems, including antibiotic resistance and some forms of cancer. Scientists used a range of analytical techniques to discover how pyruvate kinase functions in parasites, mammals, and bacteria. They found that the enzyme becomes active in all species in a similar way. A small sugar molecule binds to the enzyme to kick-start the process of nutrient absorption. But each species has a unique mechanism for activating the enzyme, providing opportunities to design drugs that block its activity in individual species. Professor Malcolm Walkinshaw, Chair of Structural Biology at the University of Edinburgh, who led the study, said: "With this discovery, we've found an Achilles heel for sleeping sickness and many other conditions.

September 14th

Scientists Can Now Explain One Third of the Inherited Risk of Prostate Cancer

Scientists can now explain a third of the inherited risk of prostate cancer, after a major international study identified 23 new genetic variants associated with increased risk of the disease. The study brings the total number of common genetic variants linked to prostate cancer to 100, and testing for them can identify 1% of men with a risk of the disease almost six times as high as the population average. Scientists at The Institute of Cancer Research, London, and in Cambridge, UK, and California led a huge search for new genetic variants including almost 90,000 men and for the first time combining populations with European, African, Japanese, and Latino ancestry. The research, published online on September 14, 2014 in Nature Genetics, was funded in equal amounts by Cancer Research UK, Prostate Cancer UK, the EU and the National Institutes for Health in the US. Researchers found that assessing the top 100 variants identified 10% of men with a risk almost three times as high as the population average, and said that this was high enough to investigate whether targeted genetic screening was merited. The researchers plan to lead a new clinical trial to test whether genetic screening can be effective. In European men, scientists had previously found 77 genetic variants which were known to increase the risk of prostate cancer. In the new research, scientists from The Institute of Cancer Research (ICR) (UK), the University of Cambridge (UK), and the University of Southern California in the U.S. examined the genetic information of 87,040 men from all over the world. They combined genetic population studies of 43,303 men with prostate cancer and 43,737 controls from European, African, Japanese, or Latino heritage to improve statistical power and increase their chances of identifying new variants.

Zebrafish Model of a Learning and Memory Disorder in Neurofibromatosis 1 Points to Different Treatment Needs

Using a zebrafish model of a human genetic disease called neurofibromatosis (NF1), a team from the Perelman School of Medicine at the University of Pennsylvania (Penn) has found that the learning and memory components of the disorder are distinct features that will likely need different treatment approaches. The research results were published in the September 11, 2014 issue of Cell Reports. NF1 is one of the most common inherited neurological disorders, affecting approximately one in 3,000 people. It is characterized by tumors, attention deficits, and learning problems. Most people with NF1 have symptoms before the age of 10. Therapies target Ras, a protein family that guides cell proliferation. The NF1 gene encodes neurofibromin, a very large protein with a small domain involved in Ras regulation. Unexpectedly, the Penn team showed that some of the behavioral defects in mutant fish are not related to abnormal Ras, but can be corrected by drugs that affect another signaling pathway controlled by the small molecule cAMP. They used the zebrafish model of NF1 to show that memory defects – such as the recall of a learned task -- can be corrected by drugs that target Ras, while learning deficits are corrected by modulation of the cAMP pathway. Overall, the team's results have implications for potential therapies in people with NF1. "We now know that learning and memory defects in NF1 are distinct and potentially amenable to drug therapy," says co-senior author Jon Epstein, M.D., Chair of the Department of Cell and Developmental Biology. "Our data convincingly show that memory defects in mutant fish are due to abnormal Ras activity, but learning defects are completely unaffected by modulation of these pathways.

September 13th

African Midge’s Ability to Survive Extreme Conditions May Provide Clues to Better Long-Term Storage and More Successful Transport of Sensitive Biological Materials

New collaborative research published online on September 12, 2014 in an open-access article in the journal Nature Communications by scientists from Japan, Russia, and the United States contains the genetic analysis of a species of African midge, which can survive a wide array of extreme conditions, including large variations in temperature, extreme drought, and even airless vacuums such as space. The team successfully deciphered the genetic mechanism that makes the midge invulnerable to these harsh conditions. Professor Noriyuki Satoh and Dr. Takeshi Kawashima of Professor Satoh’s Marine Genomics Unit, as well as Professor Alexander Mikeyhev of the Ecology and Evolution Unit, and Mr. Manabu Fujie and Dr. Ryo Koyanagi of the DNA Sequencing Section at the Okinawa Institute of Science and Technology Graduate University have contributed to the collaboration. The midge, Polypedilum vanderplanki (image), is capable of anhydrobiosis, a unique state that allows an organism to survive even after losing 97% of its body water. Anhydrobiotic organisms are also able to survive other severe conditions such as extreme temperatures ranging from 90°C to -270°C, vacuums, and high doses of radiation; all of which would be lethal to most other life forms. The midge found in northern Nigeria lives in an environment where the dry season lasts for at least six months and droughts can last up to eight months. By the time eggs have hatched and larvae have developed, the pools of water they breed in have dried up. However, these dried larvae can survive in this dehydrated state for more than 17 years. “This is a very interesting kind of phenomena,” remarks Professor Satoh.

Breakthrough in Detecting Early Onset of Refractory Epilepsy in Children May Lead to Effective Treatment Using Non-Pharmacological Therapies

65 million people around the world today suffer from epilepsy, a condition of the brain that may trigger an uncontrollable seizure at any time, often for no known reason. A seizure is a disruption of the electrical communication between neurons, and someone is said to have epilepsy if they experience two or more unprovoked seizures separated by at least 24 hours. Epilepsy is the most common chronic disease in pediatric neurology, with approximately 0.5-1% of children developing epilepsy during their lifetime. A further 30-40% of epileptic children develop refractory epilepsy, a particular type of epilepsy that cannot be managed by antiepileptic drugs (AED). Regardless of etiology, children with refractory epilepsy are invariably exposed to a variety of physical, psychological, and social morbidities. Patients whose seizures are difficult to control could benefit from non-pharmacological therapies, including surgery, deep brain stimulation, and ketogenic diets. Therefore, the early identification of patients whose seizures are refractory to AED would allow them to receive alternative therapies at an appropriate time. Despite idiopathic etiology being a significant predictor of a lower risk of refractory epilepsy, a subset of patients with idiopathic epilepsy might still be refractory to medical treatment. Using a new electroencephalography (EEG) analytical method, a team of medical doctors and scientists in Taiwan has successfully developed a tool to detect certain EEG features often present in children with idiopathic epilepsy. The team developed an efficient, automated, and quantitative approach towards the early prediction of refractory idiopathic epilepsy based on EEG classification analysis. EEG analysis is widely employed to investigate brain disorders and to study brain electrical activity.

Milestone Achieved in Work to Create Artificial Kidney

Regenerative medicine researchers at Wake Forest Baptist Medical Center have addressed a major challenge in the quest to build replacement kidneys in the lab. Working with human-sized pig kidneys, the scientists developed the most successful method to date to keep blood vessels in the new organs open and flowing with blood. The work was reported online on September 3, 2014 in the journal TECHNOLOGY. "Until now, lab-built kidneys have been rodent-sized and have functioned for only one or two hours after transplantation because blood clots developed," said Anthony Atala, M.D., director and professor at the Wake Forest Institute for Regenerative Medicine and a senior author of the study. "In our proof-of-concept study, the vessels in a human-sized pig kidney remained open during a four-hour testing period. We are now conducting a longer-term study to determine how long flow can be maintained." If proven successful, the new method to more effectively coat the vessels with cells (endothelial) that keep blood flowing smoothly, could potentially be applied to other complex organs that scientists are working to engineer, including the liver and pancreas. The current research is part of a long-term project to use pig kidneys to make support structures known as "scaffolds" that could potentially be used to build replacement kidneys for human patients with end-stage renal disease. Scientists first remove all animal cells from the organ - leaving only the organ structure or "skeleton." A patient's own cells would then be placed in the scaffold, making an organ that the patient theoretically would not reject. The cell removal process leaves behind an intact network of blood vessels that can potentially supply the new organ with oxygen.

Depicting the Dynamic Structures of Sugar Chains by an NMR-Validated Simulation

We often experience difficulties in identifying the accurate shape of dynamic and fluctuating objects. This is especially the case in the nanoscale world of biomolecules. The research group lead by Professor Koichi Kato of the Institute for Molecular Science, National Institutes of Natural Sciences, has developed a methodology for quantitatively describing the dynamic behaviors of complicated sugar chains in solution at atomic resolution by combining a sophisticated NMR spectroscopic approach with an ingenious molecular dynamics simulation technique. This study was published online on September 4, 2014 in Angewandte Chemie International Edition, a scientific journal that is published on behalf of the German Chemical Society. The sugar chains are flexible accessories decorating the surface of proteins. These variable accessories actually mediate protein-protein communication and even determine the fates of the protein. In other words, the sugar chains serve as transformable "code" that governs the protein's action in our body. For example, it has been revealed that particular sugar chains modifying lipids on cell surfaces offer acceptor sites for viral infections and trigger conformational changes of proteins involved in neurodegenerative disorders including Alzheimer's disease. Hence, decoding the sugar codes is desired not only for better understanding the molecular mechanisms behind a variety of biological processes, but also for designing new drugs targeting these processes. However, conformational characterization of the sugar chains has been hampered by their dynamic properties. Many experimentalists and theorists have taken on the challenge to solve this problem.

September 12th

Small Protein Appears to Protect Against Bone Loss in Arthritis

A small protein named GILZ appears to protect against the bone loss that often accompanies arthritis and its treatment, researchers report. Arthritis, as well as aging, prompt the body to make more fat than bone, and the researchers have previously shown GILZ can restore a more youthful, healthy mix. It also tamps down inflammation, a major factor in arthritis. Now they have early evidence that GILZ might one day be a better treatment option for arthritis patients than widely used synthetic glucocorticoids, which actually increase bone loss, said Dr. Xingming Shi, a bone biologist at the Medical College of Georgia (MCG) at Georgia Regents University. The research is being presented at The American Society for Bone and Mineral Research 2014 Annual Meeting September 12-15 in Houston. In addition to bone loss, glucocorticoids, such as prednisone, produce other side effects, including diabetes. While GILZ is induced by glucocorticoids, directly overexpressing the protein appears to better target sources of bone loss and inflammation and avoid these serious side effects. For this study, the focus was tumor necrosis factor alpha, a proinflammatory cytokine that helps regulate immune cells and is a major player in arthritis. Tumor necrosis factor alpha primarily works though promoting inflammation, which is great if the target is cancer. However, when tumor necrosis factor alpha becomes dysregulated, it can also cause diseases like arthritis and inflammatory bowel disease. To look specifically at the impact on bone loss, the researchers crossed mice bred to overexpress tumor necrosis factor alpha throughout the body with mice that overexpressed GILZ in just their mesenchymal stem cells. These stem cells produce the osteoblasts, which make bone. They also make fat, and when the cells stop making as much bone, they tend to make more of the fat. Dr.

Cause Found for Elevated Pressure in Glaucoma

Glaucoma, a leading cause of irreversible blindness, is associated with elevated pressure in the eye. This elevated pressure is essentially due to a plumbing problem. Fluid builds up in the eye, increasing pressure and eventually damaging the optic nerve. For nearly 150 years, researchers have been trying to understand what causes the blockage that prevents the eye from draining properly. In a unique study of human ocular cells, a multi-institution research team led by a biomedical engineer at Northwestern University has found a new culprit. Glaucoma appears to be a consequence of mechanical dysfunction of endothelial cells -- a thin layer of cells that is the final barrier to fluid entering Schlemm’s canal (image), from which fluid then drains from the eye. The researchers found that these endothelial cells from eyes with glaucoma are stiffer than cells from healthy eyes. This stiffness limits the cells’ ability to deform and allow a fluid called aqueous humor to cross the endothelium and drain into Schlemm’s canal. This increased flow resistance is responsible for the elevated pressure associated with glaucoma. The findings were published online on September 8, 2014 in PNAS. “There is (presently) no cure for glaucoma, which affects more than two million Americans,” said Dr. Mark Johnson, the senior author of the study. “Our work shows that cells of this endothelial layer act as mechanical gates. Therapeutic strategies that alter the stiffness of these cells potentially could lead to a cure for this debilitating disease.” Dr. Johnson is a professor of biomedical engineering and mechanical engineering at Northwestern’s McCormick School of Engineering and Applied Science and a professor of ophthalmology at Northwestern University Feinberg School of Medicine.

Worldwide Study Demonstrates Accuracy of Genomic Sequencing

Physicians envision a future in which genomic data from patients is heavily used to manage care — but experts have questioned the accuracy and reliability of these analyses. Now, a study by 150 researchers in 12 countries finds real strength and agreement across RNA genomic sequencing techniques and laboratories — as well as ways to improve what little variability exists to set a new high standard. The results of the study were published in Nature Biotechnology in three separate research articles. These results should provide assurance to patients, clinicians and the research community that genomic sequencing is accurate, says E. Aubrey Thompson, Ph.D., a professor of cancer biology at the Mayo Clinic in Florida, one of three institutions that led the study. Dr. Thompson is a study co-author and member of the project leadership. "It seems very likely that decisions about patient care are going to be influenced by genomic data, derived from sequencing both RNA and DNA from patient samples, and we now know the extent to which these sequence-based analyses can be relied upon within a given laboratory or from laboratory to laboratory," he says. "That means that results of a patient's sample, from which clinical management decisions will likely be made, will be accurate worldwide," says Dr. Thompson. RNA sequencing is being used with increasing frequency to characterize a growing array of conditions — everything from prenatal birth defects to disorders of the elderly. The other institutions involved in the study are the Beijing Genomic Institute and Weill Cornell Medical School. All three institutions have extensive experience in sequencing RNA and have helped develop novel analytical tools for interpreting the data. The U.S.