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Archive - Oct 2015

October 28th

Personalized Medicine Analysis Identifies Novel Mutation That Gives PTEN Protein New Tumor-Promoting Ability, While Preserving Its Normal Tumor Suppressor Activity

In a “personalized medicine” study that presents a framework for interpreting a single patient’s genome, collaborating scientists at the Stanford University School of Medicine, UCSF, Gladstone Institutes, and Phillipps-Universitat Marburg, have identified a novel point mutation in the PTEN tumor suppressor gene that allows the altered PTEN protein product (image shows structure of normal PTEN protein) to retain its known suppressor function, while gaining new tumor-promoting activities. In addition, the scientists have demonstrated that the tumor-promoting activities of the mutated PTEN protein can be substantially mitigated by chemical inhibitors of PI3K (phosphoinositide 3-kinase). The researchers believe that their work suggests a new role for PTEN, as well as other tumor suppressors, in cancer formation, and also reveals the potential wealth of biological information currently underexploited by the lack of systematic approaches for cancer genome interpretation services. The authors believe that their results “demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.” The new PTEN mutation and the systematic analyses that led to its discovery and characterization are described in an online open-access article published on October 26, 2015 in PNAS.

October 27th

Calcium Phosphate Particles in Stomach Are Highly Porous; Capable of Trapping & Transporting Antigens to Instestinal Immune Cells; May Be Involved in Diseases Like Crohn’s & Ulcerative Colitis

There are numerous studies related to the absorption of nutrients from the stomach because understanding what happens in our digestive system is crucial, for example, in order to be able to avoid in the future some of the diseases that affect part of the population to a lesser or greater extent. In the UK, a group of researchers from the Medical Research Council, led by Professor Dr. Jonathan J. Powell, have been working along these lines for years. They have led various studies of this type, the latest of which is a study in which 16 institutions from various countries participated, including the University of Cadiz in Spain. As a result of this international study, an article entitled “An Endogenous Nanomineral Chaperones Luminal Antigen and Peptidoglycan to Intestinal Immune Cells” has been published in the April 2015 issue of Nature Nanotechnology. In this article, the formation of calcium phosphate in the stomach, its function, and its direct relationship with the immune system are analyzed from an innovative perspective. In fact, the origin of digestive diseases such as ulcerative colitis or Crohn’s disease is possibly explained, opening up a new line of research, unknown until now, and which, in the long term, could result in the development of drugs that may alleviate the dire effects of these diseases. In order to better understand the important role of Spain’s Dr. Juan Carlos Hernández-Garrido (photo) in this study, it is important to know that the University of Cadiz is an international reference point in electronic microscopy and there are very few experts in the tri-dimensional characterization of materials using electronic microscopy, an area in which Dr. Hernández-Garrido is a specialist. In addition, it should be noted that Dr.

Study Led by NICHD Section Chief Suggests Drugs That Activate the NF-α1/FGF2/Neurogenesis Pathway Can Offer New Approach to Depression Therapy

In an article published in the June 2015 issue of Molecular Psychiatry, a scientific team led by senior author Y.Peng Loh, Ph.D., Chief of the Section on Cellular Neurobiology, National Institute of Child Health and Development (NICHD), NIH, reported that neurotrophic factor-α1 [NF-α1, which is also known as carbozxypeptidase E (CPE)] can prevent stress-induced depression through enhancement of neurogenesis and that NF-α1 is activated by rosiglitazone, a drug known to have anti-depressive activity. Major depressive disorder is one of the most common psychiatric illnesses in the United States, and its development is linked to the experience of stressful conditions. Short­term stress, however, is unlikely to be harmful, but prolonged stress may contribute to depression by triggering the release of chemicals that, at sustained, high levels, can kill nerve cells. Recent research indicates that neurotrophic factors and growth factors—naturally occurring substances that promote cell growth—play a role in relieving depression. Scientists suspect they do so by stimulating the generation of new brain cells, a process called neurogenesis. To explore this possibility, Dr. Loh and her team subjected mice to short-term stress and found increased levels of NF-α1, fibroblast growth factor 2 (FGF2), and neurogenesis in the hippocampus, a brain region minvolved in depression. These mice displayed no signs of depression-like behaviors. However, after long-term restraint stress, levels of NF-α1 and FGF2 fell and the mice displayed depression-like behaviors. In a separate set of experiments, mice genetically engineered to lack NF‐α1 had reduced FGF2 and reduced neurogenesis in the hippocampus and showed depression-like behavior. Giving the mice FGF2 reversed the depression.

October 26th

Astrocyte-Derived Exosomal miRNA Induces Loss of PTEN Gene Expression in Brain & Primes Brain Tumor Metastasis; More Evidence for Dynamic and Reciprocal Cross-Talk Between Tumor Cells and Metastatic Environment

It’s no surprise that people enjoy warm places like Hawaii, but may suffer in hostile locales such as Antarctica. A tumor suppressor gene called PTEN is similar in that it is affected by the microenvironments of certain bodily organs in which it finds itself. Scientists at The University of Texas MD Anderson Cancer Center, together with colleagues, have found that PTEN is regulated by different organs. For patients with brain metastases, this is not good, as PTEN in cells is shut off in the brain. Surprisingly, PTEN is restored once cells migrate to other organs. It’s a discovery that may be important for developing effective new anti-metastasis therapies of particular importance for advanced-stage brain cancer patients. The study findings were published in the October 19, 2015 issue of Nature. The article is titled “Microenvironment-Induced PTEN Loss by Exosomal microRNA Primes Brain Metastasis Outgrowth.” “Development of life-threatening cancer metastasis requires that tumor cells adapt to and evolve within drastically different microenvironments of metastatic sites,” said Dihua Yu (photo), M.D., Ph.D., Deputy Chair of the Department of Molecular and Cellular Oncology at MD Anderson. “Yet it is unclear when and how tumor cells acquire the essential traits in a foreign organ’s microenvironment that lead to successful metastasis. Our study showed that primary tumor cells with normal PTEN expression lose PTEN expression when they reach the brain, but not in other organs.” The study of Dr. Yu and colleagues found that metastatic brain tumor cells that have experienced PTEN loss have PTEN levels restored once they leave the brain. The researchers determined that the “reversible” PTEN loss is induced by microRNAs (miRNAs) from astrocytes located in the brain and spinal cord.

Exosomes from Stem Cell Transplants Transfer Normal Fas Protein in Mouse Model of Systemic Lupus Erythematosus (SLE); May Underly Mechanism for Mysterious Bone Preservation Induced by Such Transplants

People with lupus, an autoimmune disease, suffer from fatigue, joint pain, and swelling, and also have a markedly increased risk of developing osteoporosis. Clinical trials have shown that receiving a mesenchymal stem cell transplant (MSCT) can greatly improve the condition of lupus patients, yet it has not been clear why this treatment strategy works so well. Now, University of Pennsylvania (Penn) researchers, and colleagues, have puzzled out a mechanism by which stem cell transplants may help preserve bone in an animal model of lupus. In a paper published in the October 6, 2015 issue of Cell Metabolism, the research team shows that the transplanted cells provide a source (exosomes) of a key protein called Fas, which improves the function of bone marrow stem cells through a multi-step, epigenetic effect. The work has implications for potential therapeutic strategies for lupus, as well as other diseases for which stem cell transplants have shown promise. “When we used stem cells for these diseases and put them into the circulation, we didn’t know exactly what they were doing, but saw that they were very effective,” said Songtao Shi (photo), D.D.S., Ph.D., Chair and Professor of the Department of Anatomy and Cell Biology in Penn’s School of Dental Medicine and a co-corresponding author on the paper. “Now we’ve seen, in a model of lupus, that bone-forming mesenchymal stem cell function was rescued by a mechanism that was totally unexpected.” Dr. Shi collaborated on the work with Shiyu Liu, Dawei Liu, Chider Chen, and Ruili Yang of Penn Dental Medicine; Kazunori Hamamura, Alireza Moshaverinia, and Yao Liu of the University of Southern California; and co-corresponding author Yan Jin of China’s Fourth Military Medical University.

Siberian Jays Can Recognize Unfamiliar, Distant Relatives

Can animals recognize distantly related, unfamiliar individuals of the same species? Evolutionary biologists from the University of Zurich have demonstrated, for the first time, that Siberian jays (image) possess this somewhat amazing ability. The new findings were published online on October 13, 2015 in Molecular Ecology. The article is titled “Fine-Scale Kin Recognition in the Absence of Social Cues in the Siberian Jay, a Monogamous Bird Species.” Siberian jays belong to the crow family and the new work shows that they are able to accurately assess the degree of kinship to unfamiliar individuals. This ability confers advantages when sharing food and other forms of cooperation. In a few mammal, bird, and fish species, it is known that individuals can recognize unfamiliar siblings. Until now, however, it remained unclear whether animals are also able to identify more distant, unfamiliar relatives. The new work has now shown that Siberian jays evolved this ability. Kinship is a critical factor favoring cooperation between and among individuals. The reason behind this is likely that helping closely related individuals aids in propagating one’s own genes. Consequently, most insects, meerkats, or birds that breed cooperatively (i.e., individuals help to raise offspring that are not their own) live in family groups. The Siberian jay, which occurs in Northern Scandinavia and the Siberian taiga lives in family groups that share a territory. Non-breeding birds are both offspring that remain with their parents for several year beyond independency and individuals that immigrate into groups early in their lives. [Note: The Siberian taiga, also known as boreal forest or snow forest, is a biome characterized by coniferous forests consisting mostly of pines, spruces, and larches.

October 25th

Human Gene for Key Sepsis Protein (Gasdermin-D) Identified; Cleavage of GSDMD Triggers Cell Daath by Pyroptosis; Discovery May Lead to More Effective Treatments of Often-Lethal Whole-Body Infection Condition, and Also of Other Inflammatory Disorders

Scientists have identified a gene that could potentially open the door for the development of new treatments of the lethal disease sepsis. Researchers from The Australian National University (ANU) and the Garvan Institute of Medical Research worked with Genentech, a leading United States biotechnology company, to identify a gene that triggers the inflammatory condition that can lead to the full-body infection sepsis. "Isolating the gene so quickly was a triumph for the team," said Professor Simon Foote, Director of The John Curtin School of Medical Research (JCSMR) at ANU. Sepsis is a severe whole-body infection that kills an estimated one million people in the United States alone each year. It occurs as a complication to an existing infection, and, if not treated quickly, can lead to septic shock and multiple organ failure, with death rates as high as 50 per cent. Professor Foote acknowledged the vital support of the Australian Government's National Collaborative Research Infrastructure Strategy in setting up the Australian Phenomics Facility at JCSMR, where the gene was identified. Researchers were aware that sepsis occurs when molecules known as lipopolysaccharides (LPS) on the surface of gram-negative bacteria infiltrate cells, triggering an immune response that causes the cells to self-destruct. But exactly how the self-destruct button was pressed had remained a mystery, until now. The team found that the protein gasdermin-D (image) plays a critical role in the pathway to sepsis. Scientists at Genentech showed that gasdermin-D usually exists in cells in an inactive form.

DNA from Bronze Age Human Teeth Suggests Pneumonic Plague Was Spread from Human-to-Human without Flea Vector Almost 6,000 Years Ago; Evolved 3,000 Years Later to Permit Flea-Borne Pandemic Transmission of Deadlier Bubonic Plague

New research analyzing ancient DNA has revealed that plague has been endemic in human populations for more than twice as long as previously thought, and that the ancestral plague would have been predominantly spread by human-to-human contact -- until genetic mutations allowed Yersinia pestis (Y. pestis), the bacteria that causes plague, to survive in the guts of fleas. These mutations, which may have occurred near the turn of the 1st millennium BC, gave rise to the bubonic form of plague that spreads at terrifying speed through flea – and, consequently, rat -- carriers. The bubonic plague caused the pandemics that decimated global populations, including the Black Death, which wiped out half the population of Europe in the 14th century. Before its flea-borne evolution, however, researchers say that plague was in fact endemic in the human populations of Eurasia at least 3,000 years before the first plague pandemic in historical records (the Plague of Justinian in 541 AD). The scientists say the new evidence that Y. pestis bacterial infection in humans actually emerged around the beginning of the Bronze Age (~4,000 BC) suggests that plague may have been responsible for major population declines believed to have occurred in the late 4th and early 3rd millennium BC. The new findings were published as the open-access cover article of the October 22, 2015 issue of Cell.

October 23rd

New Method May Revolutionize Drug Design; Allows Real-Time Detection of Small Molecule-Membrane Protein Binding Kinetics on Single Intact Cells with No Molecular Labeling; Faster, More Precise, Cheaper Kinetics Measurements

Most pharmaceutical drugs consist of small molecules that target a class of proteins found on the surfaces of cell membranes. Studying these subtle interactions is essential for the design of effective drugs, but the task is extremely challenging. Now, Nongjian Tao, Ph.D., and his colleagues at Arizona State University's (ASU’s) Biodesign Institute describe a new method for examining small molecules and their communication with membrane proteins. The research will allow scientists and clinicians to study these interactions at an astonishingly minute scale with unprecedented precision. The new work has broad implications for basic research into biological function at the cellular level, as well as providing an efficient platform for new drug design, which can be carried out more rapidly and precisely, at lower cost. The method permits the first direct, real-time measurement of the binding kinetics of small molecules with membrane proteins on intact cells, without the use of molecular labeling. The study was published in an open-access article in the October 23, 2015 issue of Science Advances. The article is titled “Kinetics of Small Molecule Interactions with Membrane Proteins in Single Cells Measured with Mechanical Amplification.” "Most drugs are small molecules and most drug targets are membrane proteins," says Dr. Tao, who directs ASU’s Biodesign Center for Bioelectronics and Biosensors, which focuses on developing new detection technologies.

New Histone Function Identified: Histone H1 Couples Initiation and Amplification of Ubiquitin Signaling after DNA Damage; Finding May Improve Understanding of DNA Protection & Repair and Spawn New Disease Treatments

Researchers at the University of Copenhagen in Denmark, together with colleagues at the Netherlands Cancer Institute, have identified a previously unknown function of histone H1, one of the five known histones, which allows for an improved understanding of how cells protect and repair DNA damages. This knowledge may eventually result in better treatments for diseases such as cancer. "I believe that there's a lot of work ahead. It's like opening a door onto a previously undiscovered territory filled with lots of exciting knowledge. The histones are incredibly important to many of the cells' processes, as well as their overall well-being," says Dr. Niels Mailand from the Novo Nordisk Foundation Centre for Protein Research at the Faculty of Health and Medical Science. The findings were published online on October 21, 2015 in Nature. The article is titled “Histone H1 Couples Initiation and Amplification of Ubiquitin Signaling after DNA Damage.” Specifically, the researchers concluded that their results “identify histone H1 as a key target of [the E3 ubiquitin ligase RNF8 and the E2 ubiquitin-conjugating enzyme UBC13] RNF8–UBC13 in double-strand break (DSB) signalling and expand the concept of the histone code by showing that post-translational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond.” Histones enable the tight packaging of DNA strands within cells. The strands are approximately two meters in length and the cells are usually approximately 100,000 times smaller. Generally speaking, there are five types of histones. Four of these types are so-called “core” histones, and they are placed like beads on the DNA strands, which are curled up like a ball of yarn within the cells.