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Archive - 2021

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February 17th

Cone Snail Venom Shows Potential for Treating Severe Malaria

Severe forms of malaria such as that caused by Plasmodium falciparum may be deadly even after treatment with current parasite-killing drugs. This is due to persistent cyto-adhesion of infected erythrocytes even though existing parasites within the red blood cells are dead. As vaccines for malaria have proved less than moderately effective, and to treat these severe cases of P. falciparum malaria, new avenues of treatmen are urgently needed. Latest estimates indicate that more than 500 million cases of malaria and more than 400,000 deaths are reported worldwide each year. Anti-adhesion drugs may hold the key to significantly improving survival rates. Using venom from the Conus nux, a species of sea snail, a first-of-its-kind study from Florida Atlantic University's Schmidt College of Medicine in collaboration with FAU's Charles E. Schmidt College of Science and the Chemical Sciences Division, National Institute of Standard and Technology, United States Department of Commerce, suggests that these conotoxins could potentially treat malaria caused by P. falciparum. The study provides important leads toward the development of novel and cost-effective anti-adhesion or blockade-therapy pharmaceuticals aimed at counteracting the pathology of severe malaria. Results, published online on December 26, 2020 for the March 15, 2021 issue of the Journal of Proteomics, expand the pharmacological reach of conotoxins/conopeptides by revealing their ability to disrupt protein-protein and protein-polysaccharide interactions that directly contribute to malaria. Similarly, mitigation of emerging diseases like AIDS and COVID-19 also could benefit from conotoxins as potential inhibitors of protein-protein interactions as treatment.

February 17th

People with Loss-of-Function Gene Variant for ACTN3 Muscle Protein Tolerate Cold Temperatures Better; Variant May Have Been Protective During Human Migration from Africa to Europe

A gene variant that affects skeletal muscle function may have protected humans against lower temperatures as they migrated from Africa to Europe more than 50,000 years ago, suggests a study published online on February 17, 2021 in the American Journal of Human Genetics. The loss-of-function (LOF) variant of the ACTN3 gene is known to result in the loss of a skeletal muscle protein called α-actinin-3 and to have become more prevalent as modern humans moved to colder environments. Researchers now show that α-actinin-3 deficiency improves cold tolerance in humans by increasing muscle tone. "Our study shows an improved cold tolerance in people lacking α-actinin-3, which would have been an evolutionary survival advantage when moving to colder climates," says co-senior study author Professor Håkan Westerblad, PhD, of the Karolinska Institutet. "Our study also highlights the great importance of skeletal muscle as a heat generator in humans." The open-access AJHG article is titled “Loss of α-Actinin-3 During Human Evolution Provides Superior Cold Resilience and Muscle Heat Generation.” Approximately 1.5 billion people worldwide (~20%) carry the ACTN3 LOF variant and therefore lack α-actinin-3. Although deficiency in this protein is not associated with muscle disease, such deficiency impairs performance during power and sprint activities. Because the LOF variant became more abundant as humans moved to colder climates, Professor Westerblad and co-senior study author Marius Brazaitis, PhD, of Lithuanian Sports University suspected that it might play a role in improving cold tolerance.

Genetic Variant Inherited from Neanderthals Reduces Risk of Severe COVID-19 by Approximately 20%

SARS-CoV-2, the virus that causes COVID-19, impacts people in different ways after infection. Some experience only mild or no symptoms at all, while others become sick enough to require hospitalization and may develop respiratory failure and die. Now, researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) in Japan and the Max Planck Institute for Evolutionary Biology in Germany have found that a group of genes that reduces the risk of a person becoming seriously ill with COVID-19 by approximately 20% is inherited from Neanderthals. “Of course, other factors such as advanced age or underlying conditions such as diabetes have a significant impact on how ill an infected individual may become,” said Professor Svante Pääbo, PhD, who leads the Human Evolutionary Genomics Unit (https://groups.oist.jp/heg) at OIST. “But genetic factors also play an important role and some of these have been contributed to present-day people by Neanderthals.” Last year, Professor Pääbo and his colleague Professor Hugo Zeberg reported in Nature (https://www.oist.jp/news-center/press-releases/ancient-neanderthal-hand-...) that the greatest genetic risk factor so far identified, doubling the risk to develop severe COVID-19 when infected by the virus, had been inherited from Neanderthals. Their latest research builds on a new study, published in December last year from the Genetics of Mortality in Critical Care (GenOMICC) consortium in the UK, which collected genome sequences of 2,244 people who developed severe COVID-19. This UK study pinpointed additional genetic regions on four chromosomes that impact how individuals respond to the virus.

February 16th

Combination Treatment for Common Glioma Type Shows Promise in Mice

Gliomas are common brain tumors that constitute approximately one third of all cancers of the nervous system. In a study funded by the National Institutes of Health (NIH), researchers tested a novel combination treatment approach on mice with tumors with characteristics similar to human astrocytomas--a type of slow-growing glioma--and found tumor regression in 60 percent of the mice treated. These encouraging results, published online on December 17, 2020 in the Journal of Clinical Investigation, could be the first step toward developing a treatment for this type of brain cancer. The open-access article is titled “Inhibition of 2-Hydroxyglutarate Elicits Metabolic Reprogramming and Mutant IDH1 Glioma Immunity in Mice.” Led by senior authors Maria Castro, PhD, and Pedro Lowenstein, MD, PhD, together with a team of researchers at the University of Michigan Rogel Cancer Center in Ann Arbor specifically tested inhibitors of the compound D-2-Hydroxyglutarate (D-2-HG), which is produced by cancer cells, on a mouse version of astrocytoma carrying mutations in the genes IDH1 and ATRX, along with an inactivated form of the tumor suppressor protein 53 (TP53) gene. When the implanted mice were treated with a drug to block the production of D-2-HG along with standard of care radiation and temozolomide (chemotherapy) treatments, their survival significantly improved. Looking more closely at tumor cells grown in dishes, the researchers saw that blocking D-2-HG caused the cells to become more susceptible to radiation treatment. However, the treatment also increased the amount of an "immune checkpoint" protein, which tumors use to turn off T cells and evade the immune system.

Breakthrough in Fight Against Spruce Bark Beetles; Scientists Identify 73 Different Odorant Receptors in Beetle Antennae and Characterize the Odorant Response in Two; Findings May Enable Efforts to Interfere with Bark Beetles to Save Spruce Trees

For the first time, a research team led by scientists at Lund University in Sweden has mapped out exactly what happens when spruce bark beetles use their sense of smell to find trees and partners to reproduce with. The hope is that the results will lead to better pest control and protection of the forest in the future. The Eurasian spruce bark beetle uses its sense of smell to locate trees and partners. The odors are captured via odorant receptors (proteins) in their antennae. Researchers have long understood the connection, but so far they have not known exactly which receptors bind to what pheromones. This is key knowledge for the long-term development of more effective and environmentally friendly pesticides and bark beetle traps used to protect the forest. The research team was able to characterize the response of odorant receptors in bark beetles for the first time. They identified 73 different receptors in the antennae of the Eurasian spruce bark beetle (Ips typographus), and succeeded in characterizing the odor response in two of the receptors. One responds to the pheromone ipsenol, the other to ipsdienol. “A large number of different bark beetle species use these pheromones when communicating with scents, so the fact that we have been able to characterize them is a breakthrough,” says Martin N. Andersson, PhD, at Lund University, who led the research group consisting of researchers in Sweden, Germany and the Czech Republic. The new research was published online on January 26, 2021 in BMC Biology. The open-access article is titled “Putative Ligand Binding Sites of Two Functionally Characterized Bark Beetle Odorant Receptors.”

Green Tea Compound (EGCG) Aids Tumor-Suppressing, DNA-Repairing Protein p53; Research Offers New Lead for Cancer Drug Discovery

An antioxidant found in green tea may increase levels of p53, a natural anti-cancer protein, known as the "guardian of the genome" for its ability to repair DNA damage or destroy cancerous cells. Published online on February 12, 2021 in Nature Communications, a study of the direct interaction between p53 and the green tea compound, epigallocatechin gallate (EGCG), points to a new target for cancer drug discovery. The open-access article is titled "EGCG Binds Intrinsically Disordered N-Terminal Domain of p53 and Disrupts p53-MDM2 Interaction." "Both p53 and EGCG molecules are extremely interesting. Mutations in p53 are found in over 50% of human cancer, while EGCG is the major anti-oxidant in green tea, a popular beverage worldwide," said Chunyu Wang, PhD, corresponding author and a Professor of Biological Sciences at Rensselaer Polytechnic Institute in Troy, New York. "Now we find that there is a previously unknown, direct interaction between the two, which points to a new path for developing anti-cancer drugs. Our work helps to explain how EGCG is able to boost p53's anti-cancer activity, opening the door to developing drugs with EGCG-like compounds." Dr. Wang, a member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies, is an expert in using nuclear magnetic resonance (NMR) spectroscopy to study specific mechanisms in Alzheimer's disease and cancer, including p53, which he described as "arguably the most important protein in human cancer." P53 has several well-known anti-cancer functions, including halting cell growth to allow for DNA repair, activating DNA repair, and initiating programmed cell death--called apoptosis--if DNA damage cannot be repaired. One end of the protein, known as the N-terminal domain, has a flexible shape, and therefore, can potentially serve several functions depending on its interaction with multiple molecules.

February 15th

New Skin Patch Brings Us Closer to Wearable, All-in-One Health Monitor

Engineers at the University of California San Diego (UCSD) have developed a soft, stretchy skin patch (photo at left and below) that can be worn on the neck to continuously track blood pressure and heart rate while measuring the wearer's levels of glucose as well as lactate, alcohol, or caffeine. It is the first wearable device that monitors cardiovascular signals and multiple biochemical levels in the human body at the same time. "This type of wearable would be very helpful for people with underlying medical conditions to monitor their own health on a regular basis," said Lu Yin, a nanoengineering PhD student at UCSD and co-first author of the study published online on February 15, 2021 in Nature Biomedical Engineering. The open-access article is titled "An Epidermal Patch for the Simultaneous Monitoring of Haemodynamic and Metabolic Biomarkers." "It would also serve as a great tool for remote patient monitoring, especially during the COVID-19 pandemic when people are minimizing in-person visits to the clinic." Such a device could benefit individuals managing high blood pressure and diabetes--individuals who are also at high risk of becoming seriously ill with COVID-19. It could also be used to detect the onset of sepsis, which is characterized by a sudden drop in blood pressure accompanied by a rapid rise in lactate level. One soft skin patch that can do it all would also offer a convenient alternative for patients in intensive care units, including infants in the NICU, who need continuous monitoring of blood pressure and other vital signs. These procedures currently involve inserting catheters deep inside patients' arteries and tethering patients to multiple hospital monitors.

High-Throughput Proteomics Strategy Used in Effort to Identify Multiple Highly Potent & Specific Nanobodies from Llamas; Possible Uses of Such Nanobodies, Which Can Be Identified Quickly and Inexpensively, Are “Tremendous,” Author States

By capitalizing on a convergence of chemical, biological, and artificial intelligence advances, University of Pittsburgh (Pitt) School of Medicine scientists, and colleagues from Hebrew University in Jerusalem, have developed an unusually fast and efficient method for discovering tiny antibody fragments with big potential for development into therapeutics against deadly diseases. The technique, published online on February 15, 2021 in the journal Cell Systems, is the same process the Pitt team used to extract tiny SARS-CoV-2 antibody fragments from llamas, which could become an inhalable COVID-19 treatment for humans. The new article is titled “Integrative Proteomics Identifies Thousands of Distinct, Multi-Epitope, and High-Affinity Nanobodies.” This approach has the potential to quickly identify multiple potent nanobodies that target different parts of a pathogen--thwarting variants. "Most of the vaccines and treatments against SARS-CoV-2 target the spike protein, but if that part of the virus mutates, which we know it does, those vaccines and treatments may be less effective," said senior author Yi Shi, Ph.D., Assistant Professor of Cell Biology at Pitt. "Our approach is an efficient way to develop therapeutic cocktails consisting of multiple nanobodies that can launch a multipronged attack to neutralize the pathogen." Dr. Shi and his team specialize in finding nanobodies--which are small, highly specific fragments of antibodies produced by llamas and other camelids. Nanobodies are particularly attractive for development into therapeutics because they are easy to produce and bioengineer. In addition, they feature high stability and solubility, and can be aerosolized and inhaled, rather than administered through intravenous infusion, like traditional antibodies.

New Immunotherapy Target (CD161) Discovered for Malignant Brain Tumors

Scientists say they have discovered a potential new target for immunotherapy of malignant brain tumors, which so far have resisted the ground-breaking cancer treatment based on harnessing the body's immune system. The discovery, reported online on February 15, 2021 in CELL, emerged from laboratory experiments and has no immediate implications for treating patients. The article is titled “Inhibitory CD161 Receptor Identified in Glioma-Infiltrating T Cells by Single-Cell Analysis.” Scientists from Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard said the target they identified is a molecule that suppresses the cancer-fighting activity of immune T cells, the white blood cells that seek out and destroy virus-infected cells and tumor cells. The scientists said the molecule, called CD161, is an inhibitory receptor that they found on T cells isolated from fresh samples of brain tumors called diffuse gliomas. Gliomas include glioblastoma, the most aggressive and incurable type of brain tumor. The CD161 receptor is activated by a molecule called CLEC2D on tumor cells and immune-suppressing cells in the brain, according to the researchers. Activation of CD161 weakens the T cell response against tumor cells. To determine if blocking the CD161 pathway could restore the T cells' ability to attack the glioma cells, the researchers disabled it in two ways: they knocked out the gene called KLRB1 that codes for CD161, and they used antibodies to block the CD161-CLEC2D pathway. In an animal model of gliomas, this strategy strongly enhanced the killing of tumor cells by T cells, and improved survival of the animals.

Avian Model Allows Insights into Human Ciliopathies; Ciliopathic Micrognathia (Underdeveloped Lower Jaw) in Chick Model Results from Abnormal Skeletal Differentiation & Remodeling

Ciliopathies are genetic disorders caused by defects in the structure and function of cilia, microtubule-based organelles present on the surface of almost every cell in the human body which play crucial roles in cell signaling. Ciliopathies present a wide range of often severe clinical symptoms, frequently affecting the head and face and leading to conditions such as cleft palate and micrognathia (an underdeveloped lower jaw that can impair feeding and breathing). In addition, the human ciliopathies include autosomal dominant polycystic kidney disease (ADPKD), a serious disease that affects approximately 600,000 in the United States, and autosomal recessive PKD, which is rare, affecting just 1 in 20,000 births, but also very serious. While we understand many of the genetic causes of human ciliopathies, they are only half the story: the question remains as to why, at a cellular level, defective cilia often cause developmental craniofacial abnormalities. Researchers have now discovered that ciliopathic micrognathia in an animal model results from abnormal skeletal differentiation and remodeling. The work from Christian Bonatto Paese, PhD, Evan Brooks, and others from Samantha Brugmann's (photo) (PhD) lab at the Cincinnati Children's Hospital Medical Center in the USA is published in Development. The article is titled “Ciliopathic Micrognathia Is Caused by Aberrant Skeletal Differentiation and Remodeling.” The researchers used the avian ta2 mutant as a model for Oral-Facial-Digital syndrome subtype 14 (OFD14), a rare human ciliopathy characterized by micrognathia. They observed defective formation of the jaw bone (mandible) at early stages of development in ta2 mutants. These defects correlated with unchecked progression through the cell cycle and over-proliferation in skeletal progenitor cells.