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Archive - 2019

August 16th

Oxygen-Sensing Mechanism Based on Small RNA (sRNA) Is Key to E. coli Locating Region of Colon in Which to Set Up Most Threatening Infections; Discovery May Ultimately Enable Avoidance of These Food-Borne Infections

A pair of University of Virginia (UVA) School of Medicine scientists has revealed how E. coli seeks out the most oxygen-free crevices of the colon to cause the worst infection possible. The discovery could one day let doctors prevent the infection by allowing E. coli to pass harmlessly through the body. The new discovery shows just how the food-borne pathogen knows where and when to begin colonizing the colon on its way to making you sick. By recognizing the low-oxygen environment of the large intestine, the dangerous bacterium gives itself the best odds of establishing a robust infection - one that is punishing for the host. "Bacterial pathogens typically colonize a specific tissue in the host. Therefore, as part of their infection strategies, bacterial pathogens precisely time deployment of proteins and toxins to these specific colonization niches in the human host. This allows the pathogens to save energy and avoid detection by our immune systems and ultimately cause disease," said researcher Melissa Kendall (left in photo), PhD, of UVA's Department of Microbiology, Immunology, and Cancer Biology. "By knowing how bacterial pathogens sense where they are in the body, we may one day be able to prevent E. coli, as well as other pathogens, from knowing where it is inside a human host and allow it (the E. coli) to pass through the body without causing an infection." The UVA research was published in the July 9, 2019 issue of PNAS. The article is titled “The sRNA DicF Integrates Oxygen Sensing to Enhance Enterohemorrhagic Escherichia coli Virulence via Distinctive RNA Control Mechanisms.” E. coli naturally lives in our colons, and most strains do us no harm. But there are several strains that can cause cramps, diarrhea, vomiting, even kidney failure and death. Children are at particular risk. As such, E.

From the Tiny Testes of Flies, Rockefeller Scientists Derive Insights into How New Genes Arise

In the battle of the sexes, males appear to have the innovative edge--from a genetic standpoint, at least. Scientists are finding that the testes are more than mere factories for sperm; these organs also serve as hotspots for the emergence of new genes, the raw material for the evolution of species. Using fruit flies, a Rockefeller University team has gained key insight into how nature's attempts at innovation play out during the development of sperm. In research published online on August 16, 2019 in eLife, they mapped the presence of mutations to DNA at the single-cell level, and the activity of new genes arising from such changes. The open-access article is titled “Testis Single-Cell RNA-Seq Reveals the Dynamics of De Novo Gene Transcription and Germline Mutational Bias in Drosophila.” "Our work offers an unprecedented perspective on a process that enables living things to adapt and evolve, and that ultimately contributes to the diversity of life on Earth," says Rockefeller Assistant Professor Li Zhao, PhD, who led the research. In recent years, studies in animals from flies to humans have turned up a number of young genes that originated in the testes. These and other discoveries suggest that the testes rank among the most productive sites in the body--male or female--for genetic innovation. This mass production of genetic novelties comes with significant risks, however. In humans, for example, a father's sperm acquires two to three times more new mutations than do a mother's eggs in the course of normal development, leaving the sperm riddled with genetic mistakes. In some cases, such mistakes may harm the faather’s offspring, or even derail the prospect of fatherhood altogether.

August 15th

FDA Approves New Drug (Pretomanid) for Treatment-Resistant Forms of Tuberculosis That Affects the Lungs; Approval Signals FDA’s Continued Focus on Facilitating Development of New Treatments to Fight Antimicrobial-Resistant Infections

On August 14, 2019, the U.S. Food and Drug Administration announced approval of Pretomanid Tablets, in combination with bedaquiline and linezolid, for the treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs. “The threat of antimicrobial-resistant infections is a key challenge we face as a public health agency,” said FDA Principal Deputy Commissioner Amy Abernethy, MD, PhD. “The bacterium that causes tuberculosis can develop resistance to the antibiotics used to treat it. Multidrug-resistant TB and extensively drug-resistant TB are public health threats due to limited treatment options. New treatments are important to meet patient national and global health needs. That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections. This approval also marks the second time a drug is being approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, a pathway, advanced by Congress, to spur development of drugs targeting infections that lack effective therapies. We hope we continue to see more development of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs.” Pretomanid (image shows structure), in combination with bedaquiline and linezolid, is approved for treating a limited and specific population of adult patients with extensively drug-resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary TB. Multidrug-resistant TB and extensively drug-resistant TB are difficult to treat due to resistance to available therapies.

First-Ever in Vitro Culture Method for Monkey Malaria Parasite Should Allow Rapid, High-Throughput Testing of Possible Drugs for Relapsing Malaria in Humans & Endangered Penguins

A breakthrough in monkey malaria research by two University of Otago (New Zealand) scientists could help scientists diagnose and treat a relapsing form of human malaria. Malaria is a mosquito-borne infectious disease that affects humans and other animals with more than 200 million cases annually, particularly in Asia, the Pacific, and South America. Symptoms include fever, tiredness, vomiting and headaches and, in severe cases, it can cause seizures, coma, or death. Relapsing malaria is caused by the vivax malaria parasite, which is also the most widely distributed and difficult to treat cause of human malaria. Current efforts to develop new drugs and vaccines against vivax have been stymied by lack of a test tube (in vitro) cultured method. However, in a world-first discovery, Dr. Adelina Chua and Jessica Ong have developed an in vitro method for culturing a monkey malaria parasite which is closely related to the relapsing vivax parasite. "We can't culture vivax malaria, but now we can culture its almost identical sister species which gives us an unprecedented opportunity to develop and rapidly test new antimalarials," explained Ms. Ong, a doctoral candidate from the University of Otago Department of Microbiology and Immunology. An interesting spinoff from this research is that the drugs developed against human relapsing malaria also have a good chance of working against bird malaria, which has been killing the endangered yellow-eyed penguin (image) on the New Zealand mainland. "Before our model there was no high throughput model to screen new antimalarials targeting relapsing malaria," Ms. Ong says. "Our model will play a significant part in not only drug development, but also vaccine and diagnostic research."

August 15th

Study Identifies Gene Mutation (in RABL3 Gene) Linked to Hereditary Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers with limited treatment options. It typically comes with an especially poor prognosis due to its lack of symptoms until advanced stages and its ability to resist many anticancer therapies. Identifying genes involved in its development may lead to earlier diagnoses and improved treatments. Now, a research team led by investigators at Massachusetts General Hospital (MGH), Brigham and Women's Hospital, and Dana-Farber Cancer Institute has found that a mutation in a particular gene is associated with hereditary forms of pancreatic cancer in one family studied. Approximately 10% of pancreatic cancer is believed to be hereditary (see discussion of pancreatic cancer in former US President Jimmy Carter's family below). The research group also uncovered a mechanism by which mutations such as the one they identified may contribute to the development of tumors. In their study, which was published online on August 12, 2019 in Nature Genetics, the researchers sequenced the genomes of a family in which multiple members had pancreatic cancer. The analyses revealed a mutation in the RAS oncogene family-like 3 (RABL3) gene. The article is titled “Mutations in RABL3 Alter KRAS Prenylation and Are Associated with Hereditary Pancreatic Cancer.” To assess the effects of this gene mutation, the investigators recapitulated it in zebrafish, a model which offers large populations for studying the impact of newly discovered genetic mutations on cancer risk. The fish carrying the mutation developed cancers at an accelerated rate and with greater frequency. Additional studies revealed that the protein expressed by RABL3 interacts with components of the RAS signaling pathway, which has been implicated in various forms of cancer and other conditions.

Variants in MS4A4A Gene Influence Levels of Soluble TREM2 and Affect Susceptibility to Alzheimer’s Disease; Results Suggest Increased Focus on Brain’s Immune Cells (Microglia)

An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer's disease. Most genes implicated thus far in Alzheimer's affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain's immune cells. The findings, published online on August 14, 2019 in Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer's symptoms. The article is titled “The MS4A Gene Cluster Is a Key Modulator of Soluble TREM2 and Alzheimer’s Disease Risk.” The identified genes -- known as MS4A4A and TREM2 -- operate in the microglia (image), the brain's immune cells. The genes influence Alzheimer's risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins beta-amyloid and tau from the brain. "The findings point to a new therapeutic strategy," said co-senior investigator Carlos Cruchaga, PhD, a Professor of Psychiatry and Director of the NeuroGenomics and Informatics Group at Washington University School of Medicine. "If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer's disease or slow its development." In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer's disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment.

Lost in Translation: Researchers Discover Surprising Amount of Variation in tRNA Genes; Suggest Possible Role in Disease

A molecule called transfer ribonucleic acid (tRNA), is an essential component of the human genome that acts as a translator. It reads the genetic code and translates it into proteins - one of the key building blocks of the human body. When researchers and clinicians investigate the genome's relation to disease, they have traditionally focused on mutations in the code for proteins. But now researchers at Western University in Canada have shown that the genes encoding tRNAs can also have mutations that cause the code to be misread, and in greater numbers than previously thought. Think of it like a translator app on your phone - if it has errors in its software, the output is going to be all wrong, even if the original text is correct. The results of the new study were published online on August 13, 2019 in RNA Biology. The article is titled “Targeted Sequencing Reveals Expanded Genetic Diversity of Human Transfer RNAs.” "This actually changes the way we think about the genetic code," said lead author Mathew Berg, a PhD Candidate at Western's Schulich School of Medicine & Dentistry.

Researchers ID Possible Target Matrix Protein (Perlecan) in Effort to Halt Spread of Pancreatic Cancer

An international team of researchers has revealed how aggressive pancreatic cancer cells change their environment to enable easy passage to other parts of the body (metastasis) - the main cause of pancreatic cancer-related death. The researchers discovered that some pancreatic tumors produce more of a molecule called “perlecan” to remodel the environment around them, which helps cancer cells spread more easily to other parts of the body, and also protects them against chemotherapy. In a mouse model, the researchers showed that lowering the levels of perlecan reduced the spread of pancreatic cancer and improved response to chemotherapy. Led by Associate Professor Paul Timpson, PhD, Head of the Invasion and Metastasis Laboratory, and Thomas Cox, PhD, Leader of the Matrix and Metastasis Group, both at the Garvan Institute of Medical Research in Australia, the research may provide a promising new path to more effective treatment options for individuals with pancreatic and other cancers. The findings were published online on August 12, 2019 in Nature Communications. The open-access article is titled “CAF Hierarchy Driven by Pancreatic Cancer Cell p53-Status Creates a Pro-Metastatic and Chemoresistant Environment via Perlecan.”"Pancreatic cancer is very aggressive, and, by the time most cases are diagnosed, the tumor is often inoperable," says Associate Professor Timpson. "What we've discovered in this study is a two-pronged approach for treating pancreatic cancer that we believe will improve the efficiency of chemotherapy and may help reduce tumor progression and spread." Pancreatic cancer is one of the most lethal forms of cancer, with a five-year survival of ~9% in Australia.

August 12th

Enterovirus Antibodies Detected in CSF of Acute Flaccid Myelitis (AFM) Patients; New Study Adds to Knowledge About Rare Condition

A new study analyzing samples from patients with and without acute flaccid myelitis (AFM) provides additional evidence for an association between the rare, but often serious, condition that causes muscle weakness and paralysis, and infection with non-polio enteroviruses. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded the research, which was conducted by collaborating investigators at Columbia University's Center for Infection and Immunity, the Centers for Disease Control and Prevention (CDC), and the University of California San Diego (UCSD). The findings were reported online on August 13, 2019 in the online journal mBio. The open-access article is titled “Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.” There have been 570 confirmed cases since the CDC began tracking AFM in August 2014. AFM outbreaks were reported to the CDC in 2014, 2016 and 2018. AFM affects the spinal cord and is characterized by the sudden onset of muscle weakness in one or more limbs. Spikes in AFM cases, primarily in children, have coincided in time and location with outbreaks of one enterovirus (EV) EV-D68 (image) and a related enterovirus, EV-A71. Both of these viruses typically cause mild respiratory illness from which most people recover fully. Despite the epidemiological link between enterovirus circulation and AFM cases, evidence of direct causality has not been found. The researchers first looked for direct evidence of enterovirus infection in the cerebrospinal fluid (CSF) of 13 children and one adult diagnosed with AFM in 2018. They also examined five CSF samples taken from people with other central nervous system diseases.

August 5th

Long-Term, Anti-Rejection-Drug-Free Tolearance of Pancreas Islets Cells Induced by Apoptotic Donor Leukocytes in Non-Human Primates; Anti-Rejection Drugs Completely Discontinued 21 Days After Transplant

For decades, immunologists have been trying to train the transplant recipient's immune system to accept transplanted cells and organs without the long-term use of anti-rejection drugs. New University of Minnesota preclinical research shows that this is now possible. In a study published online on August 2, 2019 in Nature Communications, researchers at the University of Minnesota Medical School's Department of Surgery and Schulze Diabetes Institute, collaborating with colleagues at Northwestern University, have maintained long-term survival and function of pancreatic islet transplants despite complete discontinuation of all anti-rejection drugs on day 21 after the transplant. The open-access article is titled “Long-Term Tolerance of Islet Allografts in Nonhuman Primates Induced by Apoptotic Donor Leukocytes.” This study was performed in a stringent preclinical transplant setting in nonhuman primates, one step away from humans. For many patients with end-stage organ failure, transplantation is the only effective and remaining treatment option. To prevent transplant rejection, recipients must take medications long-term that suppress the body's immune system. These immunosuppressive drugs are effective at preventing rejection over the short term; however, because anti-rejection drugs suppress all of the immune system nonspecifically, people taking these drugs face the risk of serious infections and even cancer. Additionally, non-immunological side effects of immunosuppression, such as hypertension, kidney toxicity, diarrhea, and diabetes diminish the benefits of transplantation.