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Archive - Sep 2020

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September 17th

Yale Researchers ID Target Region in Key Molecule in Duchenne Muscular Dystrophy (DMD); Tyrosine Phosphatase Molecule (MKP5) Previously Thought “Undruggable”—Finding Suggests Possible Treatment Strategy for DMD & Possibly Broader Applications in Fibrosis

Researchers at Yale University have identified a possible treatment for Duchenne muscular dystrophy (DMD), a rare genetic disease for which there is currently no cure or treatment, by targeting an enzyme that had been considered "undruggable." The finding appears in the August 25, 2020 issue of Science Signaling. The article is titled “An Allosteric Site on MKP5 Reveals a Strategy for Small-Molecule Inhibition.” DMD is the most common form of muscular dystrophy, a disease that leads to progressive weakness and eventual loss of the skeletal and heart muscles. It occurs in 16 of 100,000 male births in the U.S. People with the disease exhibit clumsiness and weakness in early childhood and typically need wheelchairs by the time they reach their teens. The average life expectancy is 26. While earlier research had revealed the crucial role played by an enzyme called MKP5 in the development of DMD, making it a promising target for possible treatment, scientists for decades had been unable to disrupt this family of enzymes, known as protein tyrosine phosphatases, at the enzymes' "active" site where chemical reactions occur. In the new study, Anton Bennett, PhD, the Dorys McConnell Duberg Professor of Pharmacology and Professor of Comparative Medicine at the Yale School of Medicine, and his team screened over 162,000 compounds. They identified one molecular compound that blocked the enzyme's activity by binding to a previously undiscovered allosteric site--a spot near the enzyme's active site. "There have been many attempts to design inhibitors for this family of enzymes, but those compounds have failed to produce the right properties," Dr. Bennett said.

Princeton Research Team ID’s Recycling Enzymes That Can Control SNA12 Levels; SNA12 Can Drive Breast Cancer Metastasis

By isolating the enzymes responsible for recycling a dangerous protein, Princeton's Yibin Kang (photo), PhD, has identified a promising new target for cancer treatments. "Do not erase." "Recycle me." "Free to a good home." Humans post these signs to indicate whether something has value or not, whether it should be disposed of or not. Inside our cells, a sophisticated recycling system uses its own enzymatic signs to flag certain cells for destruction -- and a different set of enzymes can remove those flags. Changing the balance between those two groups might provide a way to control a dangerous protein called SNAI2 that helps cancers metastasize, said Dr. Kang, Princeton University's Warner-Lambert/Parke-Davis Professor of Molecular Biology, who has spent his career studying the cells and molecules behind metastatic cancers. His team has a pair of papers coming out in next month's issue of Genes & Development, released online on Septemer 17, 2020. The key is the cell's recycling system. In 2004, the Nobel Prize ( was awarded to the three scientists who discovered that the body will shred proteins into tiny pieces after they are tagged with a "recycle me" sign ( by a molecule called "ubiquitin." Some scientists refer to ubiquitin as the "kiss of death," because once a protein has enough ubiquitin tags, that protein is headed on a one-way trip to the shredder -- unless another enzyme comes along to remove its "recycle me" sign.

September 16th

Gilead Acquires Immunomedics for $21 Billion; Gilead Thus Adds Trodelvy, First-in-Class Antibody-Drug Conjugate Approved to Treat Triple-Negative Breast Cancer, with Promise in Other Forms of Breast Cancer and Additional Solid Tumors

On September 13, 2020, Gilead Sciences, Inc. (Nasdaq: GILD) and Immunomedics (Nasdaq: IMMU) announced that the companies have entered into a definitive agreement pursuant to which Gilead will acquire Immunomedics for $88.00 per share in cash. The transaction, which values Immunomedics at approximately $21 billion, was unanimously approved by both the Gilead and Immunomedics Boards of Directors and is anticipated to close during the fourth quarter of 2020. The agreement will provide Gilead with TrodelvyTM (sacituzumab govitecan-hziy), a first-in-class Trop-2 directed antibody-drug conjugate (ADC) that was granted accelerated approval by the U.S. FDA in April for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. Immunomedics plans to submit a supplemental Biologics License Application (BLA) to support full approval of Trodelvy in the United States in the fourth quarter of 2020. Immunomedics is also on track to file for regulatory approval in Europe in the first half of 2021.

September 15th

Dyslexia Problems Reduced by Non-Invasive Electrical Stimulation of Brain’s Left Auditory Cortex

Dyslexia is a frequent disorder of reading acquisition that affects up to 10% of the population, and is characterized by lifelong difficulties with written material. Although several possible causes have been proposed for dyslexia, the predominant one is a phonological deficit, a difficulty in processing language sounds. The phonological deficit in dyslexia is associated with changes in rhythmic or repetitive patterns of neural activity in a sound-processing region of the brain, the left auditory cortex. Neuroscientists from the University of Geneva (UNIGE) have demonstrated, in a study published on line on September 8, 2020 in Plos Biology, a causal relationship between brain oscillations at a specific frequency (30 Hz) and the ability to process phonemes that is essential for reading. Using a non-invasive electrical stimulation technique capable of synchronizing neural activity at the stimulation frequency, phonological deficits and reading accuracy could be improved in adults with dyslexia. Silvia Marchesotti, PhD, and Anne-Lise Giraud, PhD, respectively researcher and professor in the Department of Basic Neurosciences of the Faculty of Medicine at UNIGE, together with their colleagues, investigated the main possible cause of dyslexia: the phonological deficit. The article is titled “Selective Enhancement of Low-Gamma Activity by tACS Improves Phonemic Processing and Reading Accuracy in Dyslexia.” "We know that during brain development, when children start to read, some experience tremendous difficulties matching speech sounds with letters," explains Dr. Marchesotti. These specific difficulties are associated with anomalies of neural activity synchronization in the left auditory cortex at the frequency of 30 Hz.

September 9th

Brain & Type 2 Diabetes—Introduction of Fibroblast Growth Factor 1 into Brain Can Induce Sustained Remission of Type 2 Diabetes in Rodents; Nature Medicine & Nature Metabolism Articles Report on How This Remission May Occur

In rodents with type 2 diabetes, a single surgical injection of a protein called fibroblast growth factor 1 can restore blood sugar levels to normal for weeks or months--yet how this growth factor acts in the brain to generate this lasting benefit has been poorly understood. Clarifying how this occurs might lead to more effective diabetes treatments that tap into the brain's inherent potential to ameliorate the condition. "Until recently, the brain's ability to normalize elevated blood sugar levels in diabetic animals was unrecognized," said Michael Schwartz, MD, Professor of Medicine at the University of Washington (UW) School of Medicine and Co-Director of the UW Medicine Diabetes Institute. "By interrogating cellular and molecular responses induced in the hypothalamus by a brain peptide called fibroblast growth factor 1, our international teams' latest findings chart a path towards a more complete understanding how this effect is achieved.” “These insights," he said, "may one day inform therapeutic strategies for inducing sustained diabetes remission, rather than simply lowering blood sugar levels on a day-to-day basis as current treatments do." Type 2 diabetes affects 10% of the U.S. population. It is closely tied to obesity and causes serious health problems including heart disease, vision loss, kidney failure, dementia, difficult-to-cure infections, and nerve damage. It also increases the risk of needing amputations. Control of blood sugar levels can prevent these problems, but is often hard to achieve and becomes an ongoing struggle for many patients. In two companion papers, published online on September 7, 2020 in Nature Communications and Nature Metabolism, international teams of researchers describe the intricate biology of the brain's response to fibroblast growth factor 1.

September 8th

Researchers Show How Mutations in DNA Packaging Machines (SWI/SNF Complexes) Can Cause Cancer

Like wrenches made of Legos, SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes ( tighten or loosen DNA in our cells to control how genes are turned on and made into proteins. When assembled correctly, these complexes play a crucial role in the development of normal tissues, and when broken, they can lead to the development of cancer. These complexes are commonly disrupted by mutations in the genes that encode them--but how this leads to cancer is poorly understood. New research from the Children’s Medical Center Research Institute (CRI) at the University of Texas (UT) Southwestern ( has determined how mutations in two key SWI/SNF proteins, ARID1A and ARID1B, can drive cancer development by disrupting the assembly of SWI/SNF complexes. The study (, published online on September 7, 2020 in Nature Cancer, addresses fundamental questions about SWI/SNF biology, as well as therapeutic strategies designed to kill cancer cells by targeting this complex. The article is titled “Dual ARID1A/ARID1B Loss Leads to Rapid Carcinogenesis and Disruptive Redistribution of BAF complexes.” "While it is abundantly clear that SWI/SNF components are defective in almost all cancer types, it is still fuzzy how mutations in components lead to broken SWI/SNF complexes, and how broken complexes cause disease," says study leader Hao Zhu ( (photo), MD, an Associate Professor at CRI.

September 8th

Birth of a Male Sex Chromosome in Atlantic Herring

The evolution of sex chromosomes is of crucial importance in biology as it stabilizes the mechanism underlying sex determination and usually results in an equal sex ratio. An international team of scientists, led by researchers from Uppsala University in Sweden, now reports that they have been able to reconstruct the birth of a male sex chromosome in the Atlantic herring. The male-specific region is tiny and contains only three genes: a sex-determining factor and two genes for sperm proteins. The study was publishd recently in PNAS. It is hard to study the early evolution of sex chromosomes because it usually happened a long time ago and the sex-determining chromosomes usually rapidly degenerate and accumulate repetitive sequences. For instance, humans have an X/Y system of sex determination and the presence of Y determines male sex. The human Y chromosome, which was established more than 100 million years ago, evolved from a chromosome identical to the X chromosome, but has since lost most of the genes present on X and is now only about a third the size of the X chromosome. The Atlantic herring also has an X/Y system but it is young and evolved much more recently. In the herring, X and Y are almost identical in gene content, the only difference being that the Y has three additional genes: a sex-determining factor (BMPR1BBY) and two sperm protein genes predicted to be essential for male fertility. “The unique feature of this study is that we have been able to reconstruct the birth of a sex chromosome. The evolution of the herring Y chromosome in fact resembles the process when my son makes a construction with pieces of Lego,” says Nima Rafati, PhD, a bioinformatician at Uppsala University and first author on the paper.

Levels of Free, Precursor Form of Vitamin D in Circulating Blood May Be Better Predictor of Future Health Risks and Death Than Oft-Measured Total Vitamin D, Observational Study Suggests

Free, circulating vitamin D levels in the blood may be a better predictor of future health risks than total vitamin D in aging men, according to a study (abstract #1044) presented at the European Society of Endocrinology (e-ECE 2020) annual meeting (September 5-9) ( These data suggest that the free, precursor form of vitamin D found circulating in the bloodstream is a more accurate predictor of future health and disease risk, than the often-measured total vitamin D. Because vitamin D deficiency is associated with multiple serious health conditions as people get older, this study suggests that further investigation into vitamin D levels and their link to poor health may be a promising area for further research. Vitamin D deficiency is common in Europe, especially in elderly people. It has been associated with a higher risk for developing many aging-related diseases, such as cardiovascular disease, cancer, and osteoporosis. However, there are several forms, or metabolites, of vitamin D in the body but it is the total amount of these metabolites that is most often used to assess the vitamin D status of people. The prohormone, 25-dihydroxyvitamin D is converted to 1,25-dihydroxyvitamin D, which is considered the active form of vitamin D in our body. More than 99% of all vitamin D metabolites in our blood are bound to proteins, so only a very small fraction is free to be biologically active. Therefore, the free, active forms may be a better predictor of current and future health. Dr.

Male-Specific Features Are Reduced in Mecp2-Null Mice; Mutations in Corresponding Human Gene (MECP2) Cause Rett Syndrome; Results Do Not Support Administering Oxytocin for Treatment of Rett Syndrome, Suggest Rett Is Not Autism Spectrum Disorder

Research conducted by the scientists at Spain’s University of Valencia (UV) and Jaume I University of Castellón (UJI), among other institutions, has found alterations to the structure of the brain’s nonapeptidergic systems, social behavior, and the production of pheromones--traits that reveal sexual dimorphism--in male mice with a lack of the Mecp2 gene. In humans, mutations of this gene cause Rett syndrome, a rare disease of neural development which causes, among other symptoms, a loss of speech and of the ability to walk, traits of autistic diseases, and epilepsy. Nonapeptides--peptide chains with nine amino acids such as oxytocin and vasopressin--are located in the cerebral nuclei that govern social behavior, which is why they, especially oxytocin, have been proposed, as possible therapies for autism disorders and related syndromes. Rett syndrome is a rare disease of neural development caused by mutations to human gene MECP2, which mainly affects young girls, and which had traditionally been classified under the umbrella of autism disorders. To study whether the nonapeptidergic systems are impaired in Rett syndrome, which would thus justify their use as therapeutic targets, the team has analyzed them in the brain of a Mecp2-null mouse brain. The research results were published online on August 4, 2020, in Brain Structure & Function. The article is titled “Male-Specific Features Are Reduced in Mecp2-Null Mice: Analyses of Vasopressinergic Innervation, Pheromone Production, and Social Behaviour.”

September 7th

Cell-Autonomous Immunity and the Pathogen-Mediated Evolution of Humans; How Our Prokaryotic and Single-Celled Origins Affect the Human Evolutionary Story

Although immune responses are generated by a complex, hierarchical arrangement of immune system organs, tissues, and components, the unit of the cell has a particularly large effect on disease progression and host survival. These cell-level defense mechanisms, known as cell-autonomous immunity, are among the most important determinants of human survival, and are millions to billions of years old, inherited from our prokaryotic and single-celled ancestors. The authors of a new paper published in the September 2020 issue of The Quarterly Review of Biology argue that understanding how cell-autonomous immunity has evolved in primates is crucial to understanding human evolution, not only because infectious agents thought to have affected human genomic evolution are excellent manipulators of cell-autonomous immunity, but because these defenses are found in every cell in every body system. In "Cell-Autonomous Immunity and the Pathogen-Mediated Evolution of Humans: Or How Our Prokaryotic and Single-Celled Origins Affect the Human Evolutionary Story," Jessica F. Brinkworth, PhD, and Alexander S. Alvarado, PhD, both from the Department of Anthropology and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, discuss how the ubiquity of cell-autonomous immunity highlights a biological reality not commonly addressed in human evolutionary studies--pathogens can mediate the evolution of all body cells, and therefore, all human body systems.