Syndicate content

Archive - 2020

December 16th

Scientists Map Network of Over 100 SARS-Cov-2’s Helper Proteins Inside Human Cells; One (TMEM41B) Is Absolutely Required by Four Tested Coronaviruses, As Well As by Three Deadly Flaviruses—Yellow Fever, West Nile, and Zika

As all viruses, SARS-CoV-2 is in the grey zone between a chemical and a living being. Its biological machinery is too scant to propagate on its own, and instead the virus hijacks proteins of the host to generate new copies of itself. Scientists hope that by developing drugs that disrupt such proteins, it might become possible to deal a fatal blow to the virus. Now a new study (titled “Genome-Scale Identification of SARS-Cov-2 and Pan-Coronavirus Host Factor Networks”) maps out this intricate network of helpers for SARS-CoV-2 and three other coronaviruses that cause the common cold. The results identify over a hundred human proteins without which these viruses cannot replicate inside the cells and cause disease.Among them is a protein that stands out because it is an absolute requirement for infection by the four coronaviruses. Moreover, it is also needed by viruses from an entirely different family, flaviviruses, including those that cause yellow fever, West Nile, and Zika disease, according to results of a second study (titled “TMEM41B Is a Pan-Flavivirus Host Factor”). “The fact that this protein is important to multiple different viruses makes it a promising and high-priority target for drug development efforts,” says Charles M. Rice, PhD, Professor of Virology at Rockefeller University, who co-led the studies with John Poirier, PhD, Assistant Professor, Medicine, at New York University. Both studies were published in Cell. The TMEM41B article was published online on December 8, 2020, and the Genome-Scale Identification article was published online on December 9, 2020. Once it has entered a host cell, SARS-CoV-2 co-opts hundreds of molecules to make copies of the viral RNA and wrap them up as thousands of new viruses.

Potentially Useful Existing Drugs Suggested After GWAS Identification of Five Genes Associated with Most Severe Form of COVID-19; Work Called “Stunning Realization of the Promise of Human Genetics to Help Understand Critical Illness”

Existing drugs that could be repurposed to treat COVID-19 have been identified in a study highlighting genes linked to severe forms of the disease. Genes involved in antiviral immunity and lung inflammation have been pinpointed in the research, led by a scientist from the Roslin Institute of Scotland’s University of Edinburgh. The breakthrough should help doctors understand how COVID -19 damages lungs at a molecular level, and points towards existing drugs that could be effective against severe illness. Scientists studied the DNA of 2,700 patients in 208 intensive care units (ICUs) in the UK. Researchers from the GenOMICC (Genetics of Mortality in Critical Care) consortium--a global collaboration to study genetics in critical illness—used genome-wide association studies (GWAS) to compare the genetic information of COVID -19 patients in ICU with samples provided by healthy volunteers from other studies. The scientists found key differences in five genes--known as IFNAR2, TYK2, OAS1, DPP9, and CCR2--which may underlie why some people become severely sick with COVID -19, while others are not affected, or only moderately affected. Scientists were then able to predict the effect of drug treatments on patients, because some variations of the identified genes are known to respond in a similar way to particular drugs. For example, the scientists showed that a reduction in the activity of the TYK2 gene protects against COVID-19. A class of anti-inflammatory drugs called JAK inhibitors, which includes the drug baricitinib, produces this effect. The researchers also discovered that a boost in the activity of the gene INFAR2 could create protection, because it is likely to mimic the effect of treatment with interferon—a protein released by cells of the immune system to defend against viruses.

Researchers Expose Power of Histone Modifier Enzyme (DOT1L) on Key Immune Cells

Communication, serendipity, and a histone modifier enzyme called DOT1L (disruptor of telomeric silencing 1-like) have all combined to produce some exciting findings on the immune system's B cells and T cells by two groups of Monash Biomedicine Discovery Institute (BDI) (Australia) scientists. The new results could result in further studies into a target for asthma and allergies, and fundamental work exploring the formation of immunity itself. Two papers on DOT1L by teams led by BDI’s Professor Colby Zaph and Associate Professor Kim Good-Jacobson--whose labs are next door to each other--were both published online on December 16, 2020 in Cell Reports. Dr. Zaph’s article is titled “The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells During Infection and Inflammation" (https://www.cell.com/cell-reports/pdf/S2211-1247(20)31494-7.pdf). Dr. Good-Jacobson’s article is titled “The Histone Methyltransferase DOT1L Is Essential for Humoral Immune Responses” (https://www.cell.com/cell-reports/pdf/S2211-1247(20)31493-5.pdf). Professor Zaph and colleagues found that the DOT1L enzyme was critical in controlling how T cells (white blood cells critical for immunity to infections) (image) make the choice to develop into distinct subsets. T cells have the ability to adopt a variety of fates that depend on the type of infection they face. Type 1 T cells (Th1) for example are critical for clearing viral infections, while type 2 T cells (Th2) are required for immunity to worm parasites. Critically, dysregulated Th1 cells can cause diseases such as inflammatory bowel disease, diabetes, and arthritis, and uncontrolled Th2 cell responses can lead to asthma and allergies.

December 15th

Immune Cell (Treg) That Drives Breast Cancer Could Be Useful Target In Novel Immunotherapies

Breast cancer is the most common cancer in women worldwide, but many immunotherapies have had limited success in treating aggressive forms of the disease. "A deeper understanding of the immunobiology of breast cancer is critical to the success in harnessing immunotherapeutic approaches to improve breast cancer survival," said Paula Bos (photo), PhD, member of the Cancer Biology research program at he Virginia Commonwealth University (VCU) Massey Cancer Center and Assistant Professor in the Department of Pathology at the VCU School of Medicine. New research findings from Dr. Bos, published online in the December 8, 2020 issue of Cell Reports, identified a type of immune cells that acts as a major driver of breast cancer growth by preventing the accumulation of a specific protein that induces anti-tumor responses. This new knowledge could be utilized for the development of novel immunotherapeutic approaches to treat the disease. The article is titled “Regulatory T Cells Support Breast Cancer Progression by Opposing IFN-γ-Dependent Functional Reprogramming of Myeloid Cells.” Regulatory T cells (Treg cells) are a special class of immune cells that possess a unique ability to suppress the function of other immune cells. This function serves to protect the organism from overreacting to certain molecules created within the body; however, in many cases it subdues the immune system's ability to attack cancer cells. Therefore, Treg cells are often abundant in solid tumors, particularly breast cancers, and are commonly associated with worse outcomes. In previous research, Dr. Bos demonstrated that targeting Treg cells in breast cancer models significantly reduced tumor growth and metastasis; however, it remained unclear on a molecular level why this tumor reduction was happening.

Two Analyses of Dallas Heart Study Data Yield New Insights on Depression

In analyses of Dallas Heart Study Data, researchers at the University of Texas (UT) Southwestern (UTSW) have found links between inflammation, menopause, and depressive disorder and published their findings in two articles. One article (https://www.psychiatrist.com/JCP/article/Pages/association-between-glyca...), published recently in the Journal of Clinical Psychiatry, shows a link between an inflammatory molecule (GlycA) in the blood and a person’s likelihood of depressive symptoms. This open-action article is titled “An Association Between the Inflammatory Biomarker GlycA and Depressive Symptom Severity.” The other article (https://www.maturitas.org/article/S0378-5122(20)30384-4/fulltext), published online on September 30, 2021 in the journal Maturitas, indicates which symptoms of menopause are most predictive of depression. This article is titled “Association of Menopause Symptoms with Depressive Symptom Severity in a Diverse Community-Based Sample.” Both studies are based on data from the Dallas Heart Study (DHS) (https://www.utsouthwestern.edu/research/translational-medicine/doing-res...), which, since 2000, has tracked the health of thousands of participants with the goal of improving the diagnosis, prevention, and treatment of heart disease. “The DHS dataset is an extraordinary resource at UT Southwestern,” says Sherwood Brown (photo) (https://profiles.utsouthwestern.edu/profile/10878/sherwood-brown.html?&s...), MD, PhD, senior author of both depression papers and Professor of Psychiatry and Vice Chair for Clinical Research at UTSW. In the first two years of the study, more than 6,000 residents of Dallas County completed a detailed medical survey; 3,500 of them, aged 30 to 65, provided blood samples and underwent imaging studies.

Compound Derived from Thunder God Vine Could Help Pancreatic Cancer Patients; Triptolide Appears to Attack “Super Enhancers” in Pancreatic Cancer DNA

The results of a pre-clinical study led by researchers at the Translational Genomics Research Institute (TGen), a Phoenix-based affiliate of California’s City of Hope, suggest how a compound derived from the thunder god vine (photo)--an herb used in China for centuries to treat joint pain, swelling and fever--is able to kill cancer cells and potentially improve clinical outcomes for patients with pancreatic cancer. The medicinal plant's key ingredient, triptolide, is the basis of a water-soluble prodrug called Minnelide, which appears to attack pancreatic cancer cells and the cocoon of stroma surrounding the tumor that shields it from the body's immune system. Investigators recently published their study results online on November 9, 2020 in Oncogenesis. The open-access article (https://www.nature.com/articles/s41389-020-00285-9) is titled “Triptolide Targets Super-Enhancer Networks in Pancreatic Cancer Cells and Cancer-Associated Fibroblasts.” The study found that the compound's mechanism of action is the ability of triptolide (Minnelide) to disrupt what are known as super-enhancers, strings of DNA needed to maintain the genetic stability of pancreatic cancer cells and the cancer-associated-fibroblasts that help make up the stroma surrounding the cancer. "The cancer cells rely on super-enhancers for their growth and survival," said Haiyong Han, PhD, a Professor in TGen's Molecular Medicine Division and one of the study's senior authors. "We found that, by disrupting these super-enhancers, triptolide not only attacks the cancer cells, but also the stroma, which helps accelerate cancer cell death.

December 11th

High-Throughput Mapping of Phage Resistance Landscape of Bacteria Offers Avenue to Illuminating “Dark Matter” of Microorganism-Phage Interactions Throughout the Biological World

Scientists are continually searching for new and improved ways to deal with bacteria, be it to eliminate disease-causing strains or to modify potentially beneficial strains. And despite the numerous clever drugs and genetic engineering tools humans have invented for these tasks, those approaches can seem clumsy when compared to the finely tuned attacks waged by phages--the viruses that infect bacteria. Phages, like other parasites, are continually evolving ways to target and exploit their specific host bacterial strain, and in turn, the bacteria are continually evolving means to evade the phages. These perpetual battles for survival yield incredibly diverse molecular arsenals that researchers are itching to study, yet doing so can be tedious and labor-intensive. To gain insight into these defensive strategies, a team led by scientists at the Lawrence Berkeley National Laboratory (Berkeley Lab) has just developed an efficient and inexpensive new method. As reported online on October 13, 2020 in PLOS Biology (https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.30...), the team showed that a combination of three techniques can reveal which bacterial receptors phages exploit to infect the cell, as well as what cellular mechanisms the bacteria use to respond to a phage infection. The open-access article is titled “High-Throughput Mapping of the Phage Resistance Landscape in E. coli.” "Despite nearly a century of molecular work, the underlying mechanisms of phage-host interactions are only known for a few pairs, where the host is a well-studied model organism that can be cultured in a lab," said corresponding author Vivek Mutalik, PhD, a research scientist in Berkeley Lab's Environmental Genomics and Systems Biology (EGSB) Division.

December 10th

Genetics of Vascular Smooth Muscle Cells May Play Key Role in Coronary Artery Disease (CAD); Study Identifies One Gene (MIA3) with Protective Effect in CAD Plaque Formation

Researchers at the University of Virginia (UVA) have shed light on how our genes affect our risk for coronary artery disease, the most common form of heart disease. In addition to identifying gene variants that influence risk, they found that one gene in particular (MIA3) appears to have a protective effect. Doctors may be able to use the findings to identify people at high risk and to develop better treatments and preventative interventions. "Current drugs for coronary artery disease treat the risk factors, such as cholesterol or hypertension," said researcher Mete Civelek (photo), PhD, of UVA's Department of Biomedical Engineering and UVA's Center for Public Health Genomics. "Our studies used a genetic approach to identify the mechanisms in the wall of the blood vessels where the disease actually develops." Heart disease is the most common cause of death in the United States, killing one person every 36 seconds. About 18.2 million Americans have the form known as coronary artery disease, or CAD. The federal Centers for Disease Control and Prevention (CDC) estimates that more than 350,000 Americans died from CAD in 2017. Scientists have known that our risk for CAD is affected by diet, smoking, exercise, and other factors, including family history, but the role of our genes remains poorly understood. To better understand this, Dr. Civelek and his colleagues began by examining cells from 151 ethnically diverse heart donors. These cells, called vascular smooth muscle cells, can prove either beneficial or harmful in the buildup of fatty plaques inside our blood vessels. That buildup, known as atherosclerosis, causes CAD. The researchers examined the smooth muscle cells for 12 different characteristics that influence the stability of the plaque patches.

December 10th

Gene from Ancient Bacterium Helps Ticks Spread Lyme Disease

One of the reasons ticks spread Lyme disease so well goes back to a unique evolutionary event. In an article published in the December 10, 2020 issue of Cell, researchers report that an antibacterial enzyme in ticks, Dae2, protects them from bacteria found on human skin, while still allowing them to harbor Borrelia burgdorferi, the bacterium that causes Lyme disease. Ticks acquired the gene for this enzyme 40 million years ago from an unknown species of ancient bacterium through horizontal gene transfer. The open-access Cell article is titled "Ticks Resist Skin Commensals with Immune Factor of Bacterial Origin." Bacteria exchange DNA with each other all the time, but what's remarkable is that 40 million years ago a gene in bacteria jumped across kingdoms all the way into ticks," says senior author Seemay Chou, PhD, a Professor of Biochemistry at University of California San Francisco (UCSF). "The ticks effectively stole a page out of the bacteria's playbook, repurposing their arsenal to use against them." The relationship between ticks and the Lyme bacterium is an example of symbiosis, where two species live in harmony with one another, and often, one organism benefits from the other without harming it. But Dr. Chou's team found that ticks have a more adversarial relationship with with bacteria found on human skin, and ticks use Dae2--the enzyme stolen from ancient bacteria--as a defense agent to keep them safe. Because the ticks are so well protected against human skin bacteria, they can spread Lyme disease far and wide. However, without Dae2, the whole system falls apart. "When we blocked the enzyme, we found that ticks were actually dying from these bacteria." says Dr. Chou.

Subcompartments Discovered in Peroxisomes; Finding “Requires Us to Rethink Everything We Thought We Knew About Peroxisomes,” Lab Leader Says

In his first year of graduate school, Rice University biochemist Zachary Wright discovered something hidden inside a common piece of cellular machinery that's essential for all higher order life from yeast to humans. What Wright saw in 2015 --subcompartments inside organelles called peroxisomes is described in a study published online on December 4, 2020 in Nature Communications. The open-access article is titled “Peroxisomes Form Intralumenal Vesicles with Roles in Fatty Acid Catabolism and Protein Compartmentalization in Arabidopsis” (https://www.nature.com/articles/s41467-020-20099-y). "This is, without a doubt, the most unexpected thing our lab has ever discovered," said study co-author Bonnie Bartel, PhD, Wright's PhD advisor and a member of the National Academy of Sciences. "This requires us to rethink everything we thought we knew about peroxisomes." Dr.Bartel is the Ralph and Dorothy Looney Professor of BioSciences at Rice. Peroxisomes (https://en.wikipedia.org/wiki/Peroxisome)--are compartments where cells turn fatty molecules into energy and useful materials, like the myelin sheaths that protect nerve cells. In humans, peroxisome dysfunction has been linked to severe metabolic disorders, and peroxisomes may have wider significance for neurodegeneration, obesity, cancer, and age-related disorders. Much is still unknown about peroxisomes, but their basic structure--a granular matrix surrounded by a sack-like membrane--wasn't in question in 2015. Dr. Bartel said that's one reason Wright's discovery was surprising. "We're geneticists, so we're used to unexpected things. But usually they don't come in Technicolor," she said, referring to another surprising aspect of Wright's find: beautiful color images that show both the walls of the peroxisome subcompartments and their interiors.