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November 15th, 2019

Genome-Wide Screen of Malaria Parasite Genome with Corresponding Metabolic Models Represents Major Breakthrough in Malaria Research; Allows Researchers to Focus on Essential Genes

Despite great efforts in medicine and science, more than 400,000 people worldwide are still dying of malaria. The infectious disease is transmitted by the bite of mosquitoes infected with the malaria parasite Plasmodium (image). The genome of the parasite is relatively small, with about 5,000 genes. In contrast to human cells, Plasmodium parasites only have a single copy of each individual gene. If one removes a gene from the entire genome of the parasite, this leads therefore directly to a change in the phenotype of the parasite. An international consortium led by Professors Volker Heussler from the Institute of Cell Biology (ICB) at the University of Bern and Oliver Billker from the Umeå University in Sweden and formerly at the Sanger Institute in Great Britain has taken advantage of this fact. The researchers have carried out a genome-wide gene deletion study on malaria parasites: They specifically removed over 1300 individual genes, observed the effects during the entire life cycle of the parasite and were thus able to identify many new targets in the pathogen. The present study was published in the November 14, 2019 issue of Cell. The open-access article is titled “Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage.” The researchers used a malaria mouse model established at the Institute of Cell Biology at the University of Bern. Each of the 1,300 parasite genes was replaced by an individual genetic code to analyze how the removal of the individual genes affects the parasite. The use of individual codes allows the scientists to study many parasites simultaneously and thus drastically shortens the time of their analysis.

November 13th

Phage Therapy Shows Promise for Alcoholic Liver Disease; Gut Bacteria Toxin Linked to Worse Clinical Outcomes; Treatment With Bacteriophages Clears the Harmful Bacteria and Eliminates Disease In Mice

Bacteriophages (phages) are viruses that specifically attack and destroy bacteria. In the early 20th century, researchers experimented with phages as a potential method for treating bacterial infections. But then antibiotics emerged and phages fell out of favor. With the rise of antibiotic-resistant infections, however, researchers have renewed their interest in phage therapy. In limited cases, patients with life-threatening multidrug-resistant bacterial infections have been successfully treated with experimental phage therapy after all other alternatives were exhausted. Researchers at the University of California San Diego School of Medicine and their collaborators have now, for the first time, successfully applied phage therapy in mice for a condition that's not considered a classic bacterial infection: alcoholic liver disease. The study was published in the November 13, 2019 issue of Nature. The article is titled “Bacteriophage Targeting of Gut Bacterium Attenuates Alcoholic Liver Disease.” "We not only linked a specific bacterial toxin to worse clinical outcomes in patients with alcoholic liver disease, we found a way to break that link by precisely editing gut microbiota with phages," said senior author Bernd Schnabl, MD, Professor of Medicine and Gastroenterology at UC San Diego School of Medicine and Director of the NIH-funded San Diego Digestive Diseases Research Center. Up to 75 percent of patients with severe alcoholic hepatitis, the most serious form of alcohol-related liver disease, die within 90 days of diagnosis. The condition is most commonly treated with corticosteroids, but these drugs are not highly effective. Early liver transplantation is the only cure, but is only offered at select medical centers to a limited number of patients.

After Decades of Little Progress, Researchers May Be Catching Up to Sepsis; PERSEVERE Platform Assays Five Risk-Associated Biomarkers

After decades of little or no progress, biomedical researchers are finally making some headway at detecting and treating sepsis, a deadly medical complication that sends a surge of pathogenic infection through the body and remains a major public health problem. Researchers at Cincinnati Children's Hospital Medical Center report in the November 13, 2019 issue of Science Translational Medicine that they have developed and successfully tested a new rapid blood assay that measures five biomarkers and accurately predicts which patients are at low, medium, or high risk for death from sepsis (colloquially referred to as blood poisoning). Called PERSEVERE, the new test allows physicians to detect and stratify sepsis at its earliest moments, just as the body is about to unleash a storm of bacterial infection, according to study's senior investigator, Hector Wong (photo), MD, Director of Critical Care Medicine at Cincinnati Children's. By knowing which five proteins/genes make up the assay's five-biomarker blood panel, physicians should be able to start medical interventions much earlier and with greater precision. Dr. Wong said, not only can patients be stratified into low, medium and high-risk groups, the biomarker test allows physicians to pick the right interventions for specific patients, including which drugs and dosages. The article is titled “Prospective Clinical Testing and Experimental Validation of the Pediatric Sepsis Biomarker Risk Model.” "The PERSEVERE platform focuses on stratification and prognostication, not diagnostics," says Dr. Wong. "Prognostic enrichment is a fundamental tool of precision medicine.

Exosomes Enable Delivery of Severe Prostate Cancer-Promoting Transfer Factors; Inhibition of Exosome Release May Prove Helpful in Treatment

A transcription factor that aids neuron function also appears to enable a cell conversion in the prostate gland that can make an already recurrent cancer even more deadly, scientists say. The transcription factor BRN4 is mostly expressed in the central nervous system and inner ear, but now scientists have the first evidence it’s amplified and overexpressed in patients with the rare, but increasing, neuroendocrine prostate cancer, they report in an article published online on September 18, 2019 in the journal Clinical Cancer Research. The article is titled “BRN4 Is a Novel Driver of Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer and Is Selectively Released in Extracellular Vesicles with BRN2.” As their name implies, neuroendocrine cells also are more common in the brain, but the walnut-sized prostate gland also has a small percentage of them and they appear to become more numerous and deadly in the face of newer, more powerful hormone therapy. The sex hormone androgen is a major driver of prostate cancer so hormone therapy to suppress it or its receptor — called chemical castration — is a standard frontline therapy, says Sharanjot Saini (left in photo), PhD, a cancer biologist in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia (MCG) at Augusta University. Still, as high as 40 percent of patients develop castration-resistant prostate cancer within a few years. This more aggressive cancer is harder to treat, and patients may get a newer, more powerful hormone therapy like enzalutamide, which was first approved in 2012 for this recurring prostate cancer. It’s the far more common luminal cell type in the prostate gland that typically becomes cancerous, says Dr. Saini, the study’s corresponding author.

Research Points to Possible Treatment Target in Idiopathic Pulmonary Fibrosis (IPF); Targeting Mevalonate Pathway May Abrogate Role of Macrophages in Dysregulated Fibrotic Repair

Long-held dogma says lung fibrosis in diseases like idiopathic pulmonary fibrosis(IPF) results from recurrent injury to alveolar epithelium that is followed by dysregulated repair. Research at the University of Alabama at Birmingham (UAB) uproots that paradigm, and suggests a possible treatment target for IPF. A. Brent Carter(photo, courtesy of UAB), MD, and colleagues reported online on Octobr 14, 2019 in the Journal of Clinical Investigation that the recruited monocyte-derived macrophages, which have an increased flux in the mevalonate metabolic pathway -- without any experimental injury -- can induce lung fibrosis in a mouse model. When there is prior lung injury, the increased flux through the mevalonate pathway exacerbates the resulting fibrosis. The mechanism polarizes macrophages to a profibrotic state that causes pathogenic macrophage/fibroblast signaling. Furthermore, study of humans with IPF showed that three hallmarks of the mechanism that leads to lung fibrosis in the absence of injury in mice are also found in bronchoalveolar (BAL) cells from these patients, as compared to healthy individuals. These three hallmarks are 1) activation of the small GTPase protein Rac1 and its localization into the intermembrane space of mitochondria in the BAL cells, 2) increased production of mitochondrial reactive oxygen species by BAL cells from patients with IPF, and 3) evidence of increased flux through the non-sterol arm of the mevalonate pathway in the BAL cells results in the augmented activation of Rac1. "Here, we show a paradigm shift that indicates a critical and essential role for monocyte-derived macrophage/fibroblast crosstalk in the development and progression of fibrosis in the absence of epithelial injury," said Dr.

November 12th

Batty Microbiomes Defy Predictions

Right now, there are trillions of bacteria living in your gut, making up about one percent of your body weight. They're supposed to be there--we need them to help us digest food and fight off diseases. The same is true for most mammals; in general, just about every mammal from dogs to dolphins relies on a community of helpful bacteria, called a microbiome, living inside them for health and survival. Many animals have even evolved along with their gut bacteria to work together better, to the point that closely related host species typically share more similar microbiomes. But a new study has identified one group of mammals that seems to buck that trend: bats. A new paper, published online on November 12, 2019 in mSystems, reveals that the microbiomes of closely-related bats can be totally different from each other, which suggests that having a community of helpful gut bacteria may not be so important for this already eccentric group of mammals. The open-access article is titled “Ecology and Host Identity Outweigh Evolutionary History in Shaping the Bat Microbiome.” "It shifts the paradigm we've been operating under, that animals require microbes for digestion and nutrient acquisition. That's true for us, but it may not be true for all species," says lead author Holly Lutz, PhD, a research associate at Chicago's Field Museum and post-doctoral researcher at the University of California, San Diego. "The trends we're seeing suggest that bats may not depend on bacteria the same way many other mammals do, and that they can survive just fine without a strict suite of bacteria in their guts to help them digest their food." To learn about the relationships between bats and their microbes, Dr. Lutz and her colleagues took samples of bacteria from the skin, tongues, and guts of 497 bats from 31 different species in Kenya and Uganda.

Anthrax Toxin May Be Effective Weapon in Fighting Bladder Cancer

Anthrax may soon help more people win the fight against bladder cancer, which the Centers for Disease Control and Prevention (CDC) says strikes approximately 72,000 Americans each year and kills about 16,000, and is one of the most expensive cancers to treat. The current treatments for bladder cancer are invasive for patients - who often must sit for hours at a time with a bladder full of an agent designed to kill cancer cells and tumors. Bladder cancer also is one of the most reoccurring for people diagnosed with the disease. Now, researchers at Purdue University have come up with a way to combine the anthrax toxin (image) with a growth factor to kill bladder cancer cells and tumors. The research was published online on October 4, 2019 in the International Journal of Cancer. "We have effectively come up with a promising method to kill the cancer cells without harming the normal cells in the bladder," said R. Claudio Aguilar, PhD, an Associate Professor and the Assistant Head of Biological Sciences in Purdue's College of Science. "It is basically like creating a special solution that targets cancer cells, while leaving healthy cells alone." Dr. Aguilar said the bladder has its own protective layer, which saves the good cells from the anthrax mixture but offers no protection for the cancer cells and tumors. He said the Purdue system works within minutes - instead of the usual hours for bladder cancer treatment - to target the cancer cells in the bladder. "We have seen outstanding results with our treatment," said Dr. Aguilar, who works as part of a team focused on cell identity and signaling at the Purdue University Center for Cancer Research. "It is fast and effective, both of which are critical for people dealing with this devastating disease." Dr. Aguilar and his group worked with the Purdue teams led by Dr.

Frequent Technical Bias Occurs in RNA-Seq Expression Studies, Leading to Widespread Misinterpretation of Gene Expression Data; Authors Present Approach to Removing This Bias

Reproducibility is a major challenge in experimental biology, and with the increasing complexity of data generated by genomic-scale, this concern is immensely amplified. RNA-seq, one of the most widely used methods in modern molecular biology, allows in a single test the simultaneous measurement of the expression level of all the genes in a given sample. New research, published online on November 12, 2019 in the open-access journal PLOS Biology by Shir Mandelbaum, Zohar Manber, Orna Elroy-Stein, and Ran Elkon from Tel Aviv University, identifies a frequent technical bias in data generated by RNA-seq technology, which recurrently leads to false results. The article is titled “Recurrent Functional Misinterpretation of RNA-Seq Data Caused By Sample-Specific Gene Length Bias.” Analyzing dozens of publicly available RNA-seq datasets, which profiled the cellular responses to numerous different stresses, Dr. Mandelbaum and colleagues noticed that sets of particularly short or long genes repeatedly showed changes in expression level (as shown by the apparent number of RNA transcripts from a given gene). Puzzled by this recurring pattern, the authors then asked whether it reflects some universal biological response common to many different triggers or if it, rather, stems from some experimental artefact. To tackle this question, they compared replicate samples from the same biological condition. Differences in gene expression between replicates can reflect technical effects that are not related to the experiment's biological factor of interest. Unexpectedly, the same pattern of particularly short or long genes showing changes in expression level was observed in these comparisons between replicates, demonstrating that this pattern is the result of a technical bias that seemed to be coupled with gene length.

November 11th

Biomarker Blood Test Could Reveal High-Risk Heart Patients in Need of Treatment

Without occasionally looking under the hood, it’s difficult topredict whether expensive car repairs lie ahead. In a similar way, preventive cardiologists are looking for ways to detect early-stage heart disease in people who aren’t currently in treatment. Preventive cardiology researchers at the University of Texas (UT) Southwestern Medical Center believe that a new blood test for protein biomarkers could identify these individuals. Their new study, published online on November 11, 2019 in Circulation, pooled patient data from three major patient populations including multiple ethnicities and totaling nearly 13,000 people. The team asked whether measuring levels of two biomarkers – proteins in the blood – would identify people in need of treatment. The researchers found that approximately one-third of adults with mild hypertension who are not currently recommended for treatment have slight elevations of one of these two biomarkers; these individuals were more likely to have heart attacks, strokes, or congestive heart failure over the next 10 years. In other words, these patients are “flying under the radar” and do not know that they are at greater risk of cardiovascular events. The Circulation article is titled “Incorporation of Biomarkers Into Risk Assessment for Allocation of Antihypertensive Medication According to the 2017 ACC/AHA High Blood Pressure Guideline: A Pooled Cohort Analysis.” Dr. Ambarish Pandey (left in photo) and Dr. Parag Joshi (right in photo) believe some patients at risk of heart disease could be helped by a biomarker blood test.“We think this type of test can help in the shared decision-making process for patients who need more information about their risk,” said preventive cardiologist Dr. Parag Joshi, Assistant Professor of Internal Medicine.

Study Reveals How Two Strains of One Bacterium Combine to Cause Flesh-Eating Infection

In recent years, scientists have found that serious infections that progress rapidly and resist treatment are often caused by multiple microbes interacting with one another. Very little is known about these so-called “polymicrobial infections,” but traditional diagnostic methods often misidentify them as monomicrobial, or single-microbe, infections. A new study by a team of scientists that included researchers from the University of Maryland, the University of Texas Medical Branch, and CosmosID, Inc., used genetic analysis to reveal how two different strains of a single species of flesh-eating bacteria worked in concert to become more dangerous than either one strain alone. The study was published online in the Proceedings of the National Academy of Sciences on November 11, 2019. The article is titled “T6SS and ExoA of Flesh-Eating Aeromonas Hydrophila In Peritonitis And Necrotizing Fasciitis During Mono- And Polymicrobial Infections.” "This research provides clear evidence that a very severe infection considered to be caused by a single species of a naturally occurring bacterium actually had two strains," said Rita Colwell (photo), PhD, a Distinguished University Professor in the University of Maryland Institute for Advanced Computer Studies and a co-author of the study. "One of the strains produces a toxin that breaks down muscle tissue and allows the other strain to migrate into the blood system and infect the organs." The original infection--cultured from a patient who developed the severe flesh-eating disease known as necrotizing fasciitis--was diagnosed as a monomicrobial disease. Traditional diagnostics could only determine that the infection was caused by a single species of bacteria called Aeromonas hydrophila.