Syndicate content

Archive - 2016

December 29th

New Study Sets Oxygen-Breathing Limit for Ocean’s Hardiest Organisms; Bacteria Can Survive in Marine Environments That Are Almost Completely Starved of Oxygen

Around the world, wide swaths of open ocean are nearly depleted of oxygen. Not quite dead zones, they are “oxygen minimum zones,” where a confluence of natural processes has led to extremely low concentrations of oxygen. Only the hardiest of organisms can survive in such severe conditions, and now MIT oceanographers have found that these tough little life-forms — mostly bacteria — have a surprisingly low limit to the amount of oxygen they need to breathe. In a paper published online on November 25, 2016 by the journal Limnology and Oceanography, the team reports that ocean bacteria can survive on oxygen concentrations as low as approximately 1 nanomolar per liter. To put this in perspective, that’s about 1/10,000th the minimum amount of oxygen that most small fish can tolerate and about 1/1,000th the level that scientists previously suspected for marine bacteria. The researchers have found that below this critical limit, microbes either die off or switch to less common, anaerobic forms of respiration, taking up nitrogen instead of oxygen to breathe. The open-access artice is titled “A Theoretical Basis for a Nanomolar Critical Oxygen Concentration.” With climate change, the oceans are projected to undergo a widespread loss of oxygen, potentially increasing the spread of oxygen minimum zones around the world. The MIT team says that knowing the minimum oxygen requirements for ocean bacteria can help scientists better predict how future deoxygenation will change the ocean’s balance of nutrients and the marine ecosystems that depend on them.

With $8.6 Million NIH Grant, UCLA-Led Consortium Will Map Heart’s Nervous System; Seven-University Initiative Could Lead to New Treatments for Cardiovascular Diseases

A consortium directed by UCLA’s Dr. Kalyanam Shivkumar has received a three-year, $8.6 million grant from the National Institutes of Health to map the heart’s nervous system, according to a UCLA release published on December 22, 2016. The group’s goal: To conduct research that leads to new ways to treat cardiovascular disease by targeting nerves in the heart’s nervous system. More than 800,000 people in the U.S. die each year from cardiovascular diseases such as heart failure, arrhythmia, and hypertension. These problems are often linked to the autonomic nervous system, the part of the nervous system that signals the heart to beat and controls breathing, digestion, and other body processes that typically happen without conscious effort. Researchers believe that modulating those electrical signals holds promise as a way to treat heart failure and other common cardiovascular problems. “Understanding the nervous system’s control of the heart is such a complex problem that it requires a collaborative approach, and we’re pleased that so many experts are coming together for this initiative,” said Dr. Shivkumar, the study’s lead investigator and Director of the UCLA Cardiac Arrhythmia Center and Electrophysiology Programs. “Our goal is to precisely map the heart’s anatomy and code the function of the nerves that control the heart from a very basic level all the way to clinical studies in humans.” UCLA is one of seven institutions participating in the project. Principal investigators at the other universities are Dr. Viviana Gradinaru of Caltech, Dr. Stephen Liberles of Harvard University, Dr. Charless Fowlkes of UC Irvine, Dr. Irving Zucker of the University of Nebraska Medical Center, Dr.

Anti-Aging Therapies Targeting Senescent Cells: Opinion Piece Examines Facts & Fiction

It's an exciting time to be an elderly mouse. Researchers believe that by removing senescent cells (cells with a persistent damage response), which naturally accumulate with age, senior rodents can regrow hair, run faster, and improve organ function. This strategy may bring us one step closer to the "fountain of youth," but it's important to be cautious, says researcher of aging Dr. Peter de Keizer (photo) of the Erasmus University Medical Center in the Netherlands. In an Opinion piece published December 29, 2016 in Trends in Molecule Medicine, he discusses the milestones the field still needs to hit before translation to humans is ready for discussion. The piece is titled “The Fountain of Youth by Targeting Senescent Cells?" The removal of senescent cells, first discovered in the 1960s, received renewed interest in the 2010s as a therapeutic option to combat some aspects of aging. Researchers noticed that these permanently arrested cells accumulate in mature tissue and that some of them secrete factors that are harmful to tissue function and impair their neighboring cells. To explain what causes this noise in the system, Dr. de Keizer proposes a "senescence-stem lock model" in which the chronic secretion of pro-inflammatory factors by these senescent cells keeps neighboring cells in a permanent stem-like state and thereby prevents proper tissue renewal. "When bringing in a defective car for repairs it is insufficient to remove the rust and broken parts; you also want to replace these," says Dr. de Keizer "A perfect anti-senescence therapy would not only clear senescent cells, but also kick-start tissue rejuvenation by stimulating differentiation of nearby stem cells.

Satb1 Regulates Super Enhancers Essential for Regulatory T-Cell (Treg Cell) Development; Possible Links Between Satb1 Deficiencies and Autoimmunity Theorized

Scientists at the Immunology Frontier Research Center (IFReC), Osaka University, Japan, report a new molecular mechanism that could explain the cause of some autoimmune diseases. While the immune system is crucial for protecting the body from infection and disease, prolonged activation can damage healthy tissue. After its activation, the immune system is shut off by specialized immune cells known as regulatory T cells (Treg cells). Understanding the development of Treg cells is thought to be critical for combating autoimmune diseases. "The development of Treg cells in the thymus depends on super-enhancer establishment," explains IFReC Professor Shimon Sakaguchi. This super-enhancer establishment permits the expression of genes specific for Treg cell development. "Super-enhancers appeared to be a pre-requisite for Treg cell development, so we sought molecules controlling super-enhancers," he added. In the most recent publication (Decembfer 19, 2016) by the Sakaguchi lab, which can be seen in Nature Immunology, Dr. Sakaguchi and his team report that Satb1 (image) regulates the super enhancers essential for Treg cell development. The article is titled “Guidance of Regulatory T Cell Development by Satb1-Dependent Super-Enhancer Establishment.” Looking at the Treg cell development pathway, the scientists found that the level of Satb1 was highest before Treg cells develop, and dropped after Treg cell development. Further study showed that Satb1 bound to the super enhancers responsible for Treg cell development, but again, only in progenitors that differentiated into Treg cells and not Treg cells themselves. Therefore, Satb1 may regulate the epigenetic changes that precede the creation of Treg cells.

Possible Treatment Targets Found for Pre-Malignant Bone Marrow Disorders

Cincinnati Children's Hospital researchers report in Nature Immunology a new mechanism that controls blood cell function and several possible molecular targets for treating myelodysplasia syndromes (MDS) - a group of pre-malignant disorders in which bone marrow does not produce enough healthy blood cells. MDS can lead to acute myeloid leukemia (AML), a fast-spreading blood cancer that can be deadly if not treated promptly. A research team led by cancer biologist Daniel Starczynowski, Ph.D., found that over-expression of a protein called TRAF6 (image) in hematopoietic cells drives the onset of MDS. TRAF6 normally functions as an immune sensor of pathogens, according to the authors, who published their data online on December 26, 2016. The Nature Immunology article is titled “Ubiquitination of hnRNPA1 by TRAF6 Links Chronic Innate Immune Signaling With Myelodysplasia.” "We found that TRAF6 over-expression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure," said Dr. Starczynowski, a member of the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center. "Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS." In testing on laboratory mouse models and human MDS/AML samples, the researchers identified a novel substrate of TRAF6 called hnRNPA1, an RNA-binding protein. They also found molecular interactions with Cdc42, a protein that helps regulate cells also implicated in cancer. All of these molecules could be potential treatment targets for cases of MDS triggered by over-expression of TRAF6, according to Dr.

Novel Drug (Cimaglermin) May Help Repair Failing Hearts

Cimaglermin, a new experimental drug, may help restore cardiac function after heart failure, according to a first-in-man study published in the December 1, 2016 issue of JACC: Basic to Translational Science. The open-access article is titled “A Phase I, Single Ascending Dose Study of Cimaglermin Alfa (Neuregulin 1β3) in Patients with Systolic Dysfunction and Heart Failure.” Heart failure, characterized by a loss of cardiac function, is among the leading causes of death worldwide. A significant portion of heart failure patients, particularly those with severe left ventricular systolic dysfunction, do not sufficiently respond to current medical therapy. Researchers examined the safety and efficacy of a single infusion of cimaglermin, which acts as a growth factor for the heart, helping the structural, metabolic, and contractile elements of the heart to repair itself following injury. The study enrolled 40 heart failure patients who were taking optimal medical therapy for at least three months prior to the trial. Compared to patients who received a placebo, patients who received a high dose of cimaglermin had a sustained increase in left ventricular ejection fraction, or pumping capacity, through 90 days after dosing, with the maximum increase reached at day 28. "These findings support continued clinical development of the investigational drug cimaglermin, including further safety evaluations and detailing the potential improvement on clinical heart failure outcome measures," said Daniel J. Lenihan M.D., from the Division of Cardiovascular Medicine at Vanderbilt University and the lead author of the study.

Study of Evolution of Thousands of Bacterial Proteins Allows Deciphering of Many Interactions Between Human Proteins

Cells operate like an incredibly well-synchronized orchestra of molecular interactions among proteins. Understanding this molecular network is essential not only to understand how an organism works but also to determine the molecular mechanisms responsible for a multitude of diseases. In fact, it has been observed that protein interacting regions are preferentially mutated in tumors. The investigation of many of these protein interactions is challenging. However, a study coordinated by Dr. Simone Marsili and Dr. David Juan, from Dr. Alfonso Valencia's team at the CNIO (Spain’s National Center for Oncological Investigations), should advance our knowledge on thousands of them. The work, published online on December 13, 2016 in PNAS, demonstrates that it is possible to understand a significant number of interactions among human proteins from the evolution of their counterparts in simpler cells, such as bacteria cells. The open-access PNAS article is titled “Conservation of Coevolving Protein Interfaces Bridges Prokaryote–Eukaryote Homologies in the Twilight Zone.” According to Dr. Rodríguez, from the Structural Computational Biology Group at the CNIO and first author of the paper, "the complexity of human beings does not only result from the number of proteins that we have, but primarily from how they interact with each other. However, out of 200,000 protein-protein interactions estimated, only a few thousand have been characterized at the molecular level". It is very difficult to study the molecular properties of many important interactions without reliable structural information. It is this "twilight zone" that, for the first time, CNIO researchers have managed to explore.

December 28th

Triglyceride-Lowering Drug Fenofibrate May Reduce Long-Term Cardiovascular Risk in Type 2 Diabetics Treated with Statins

A new study shows that the drug fenofibrate might reduce the risk of cardiovascular events in patients with type 2 diabetes who have high levels of triglycerides and low levels of "good" cholesterol, despite being treated with statins. The results of the study, funded by the National Heart, Lung, and Blood Institute (NHLBI), were published on December 28, 2016 in JAMA Cardiology. The article is titled “ Association of Fenofibrate Therapy with Long-term Cardiovascular Risk in Statin-Treated Patients with Type 2 Diabetes. Fenofibrate is primarily used to help reduce elevated levels of triglycerides, or fat, in the blood. But the researchers wanted to know if the drug, when combined with statin treatment, could also reduce the risk of heart disease in people with type 2 diabetes. People with type 2 diabetes are at high risk of cardiovascular-related events, such as heart attacks, stroke, and even death, often because their levels of triglycerides are so high, and their high-density lipoprotein (HDL) cholesterol levels are low. To answer their question, the researchers followed 4,640 participants from the NHLBI-funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study for five years after the conclusion of the trial in 2009. The findings suggest that fenofibrate therapy may be beneficial in the way the researchers hoped: by reducing cardiovascular events in patients with type 2 diabetes who take statins but still have especially high triglycerides levels and low HDL cholesterol levels. However, a randomized study is needed to confirm these findings, according to the authors.

[Press release] [JAMA Cardiology abstract]

Pharmacologic Advance Targets Glioblastoma Multiforme

The National Foundation for Cancer Research (NFCR) has congratulated Dr. Web Cavenee and Dr. Paul B. Fisher on their discovery of a new pharmacological agent to treat glioblastoma multiforme (GBM), the deadliest brain cancer, which they have been developing together with NFCR support. This new pharmacological agent could - with additional chemistry - lead to a new drug to prevent radiation-induced invasion of GBM cells. The researchers have tested their pharmacological agent in combination with radiation with profound survival benefits in pre-clinical models. Click here to read the full report by the scientists: The article is titled “Inhibition of Radiation-Induced Glioblastoma Invasion By Genetic and Pharmacological Targeting of MDA-9/Syntenin.” Paul B. Fisher, M.Ph., Ph.D., Director of the Virginia Commonwealth University's (VCU) Institute of Molecular Medicine (VIMM), focuses on cancer genetics and Web Cavenee Ph.D., Director of the Ludwig Institute for Cancer Research at the University of California at San Diego focuses on GBM. An exciting breakthrough for the treatment of GBM, this is about collaboration between two scientists on opposite coasts and shows how NFCR research may lead to tangible therapies for multiple cancers. NFCR has been funding Dr. Fisher's research since 2008, and Dr. Cavenee's research starting in 2002. "NFCR scientists are making headway in the fight against one of the most aggressive form of cancer, GBM, by working together on vital pre-clinical models," said Franklin C. Salisbury, Jr., NFCR CEO. "For years, discoveries from NFCR-funded research have led to better treatments today - and this latest discovery by two incredibly talented scientists gives us proof there will be improved therapies for GBM and multiple cancers in the foreseeable future." Dr.

Portion of a Long-Coding RNA Codes for Small Polypeptide with Tissue-Specific Role in Muscle Regeneration and Cancer; Work Reveals “New and Startling Mechanism”

Scientific research over the past decade has concentrated almost exclusively on the 2 percent of the genome's protein-coding regions, virtually ignoring the other 98 percent, a vast universe of non-coding genetic material previously dismissed as nothing more than “junk.” Now, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) reveals that one type of this “junk DNA”-- called long non-coding RNA (lncRNA) -- may be critically important for controlling cellular components in a tissue-specific manner. Published online on December 26, 2016 in the journal Nature, the new research points to lncRNA's key role in helping control processes related to muscle regeneration and cancer. The Nature article is titled “mTORC1 and Muscle Regeneration Are Regulated by the LINC00961-Encoded SPAR Polypeptide Long non-coding RNAs appear to be transcribed from our DNA in a similar manner to coding messenger RNAs, but are not translated into proteins. While lncRNA molecules do not produce correspondingly lengthy proteins, researchers have wondered whether some of these molecules may contain segments of sequences that can code for very short proteins, or polypeptides. "Whether such small, hidden polypeptides are actually functional, or represent 'translational noise' within the cell is still relatively unclear," said senior author Pier Paolo Pandolfi (photo), M.D., Ph.D., Director of the Cancer Center and Cancer Research Institute at BIDMC.