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Antiviral Response: Eosinophils Active in Immediate Defense During Influenza A Infection; Possible Implications for Understanding SARS-CoV-2 Infection in Asthmatic Patients

For the first time in published literature, Le Bonheur Children's Hospital and University of Tennessee Health Science Center (UTHSC) researchers have shown that a variety of white blood cells known as eosinophils (image) modify the respiratory barrier during influenza A virus (IAV) infection, according to a paper published online on February 27, 2021 in Cells. This research could have implications in understanding SARS-CoV-2 (COVID-19) infection in asthmatic patients. The open-access article is titled “Eosinophil Responses at the Airway Epithelial Barrier During the Early Phase of Influenza A Virus Infection in C57BL/6 Mice” (https://www.mdpi.com/2073-4409/10/3/509). The Le Bonheur/UTHSC study found that eosinophils immunomodulate airway epithelial cells during IAV infection, helping to neutralize the virus and protect the airway. The study was led by University of Tennessee Health Science Center Postdoctoral Fellow Meenakshi Tiwary, PhD, from the lab of Director of the Pediatric Asthma Research Program and Plough Foundation Chair of Excellence in Pediatrics, Amali Samarasinghe, PhD, in collaboration with Robert Rooney, PhD, Assistant Professor of Pediatrics at the University of Tennessee Health Science Center and Director of the Biorepository and Integrative Genomics Initiative at Le Bonheur, and Swantje Liedmann, PhD, a postdoctoral fellow at St. Jude Children's Research Hospital. "We examined eosinophil responses to influenza A virus during the early phase of infection and found that eosinophils exhibit multiple functions as active mediators of antiviral host defense," said Dr. Samarasinghe.

A New Perspective on the Genomes of Archaic Humans; Significant Expression Differences Detected in Homo sapiens Genes of Vocal Tract and Cerebellum Versus Those of Ancestors

A genome by itself is like a recipe without a chef--full of important information, but in need of interpretation. So, even though we have sequenced genomes of our nearest extinct relatives--the Neanderthals and the Denisovans--there remain many unknowns regarding how differences in our genomes actually lead to differences in physical traits. "When we're looking at archaic genomes, we don't have all the layers and marks that we usually have in samples from present-day individuals that help us interpret regulation in the genome, like RNA or cell structure," said David Gokhman, PhD, a postdoctoral fellow in biology at Stanford University. "We just have the naked DNA sequence, and all we can really do is stare at it and hope one day we'd be able to understand what it means," he said. Motivated by such hopes, a team of researchers at Stanford and the University of California, San Francisco (UCSF), have devised a new method to harvest more information from the genomes of archaic humans to potentially reveal the physical consequences of genomic differences between us and them. Their work, published online on April 22, 2021 in eLife, focused on sequences related to gene expression--the process by which genes are activated or silenced, which determines when, how, and where DNA's instructions are followed. Gene expression tends to be the genetic detail that determines physical differences between closely related groups. The open-access eLife article is titled “The Cis-Regulatory Effects of Modern Human-Specific Variants” (https://elifesciences.org/articles/63713).

Hungry Fruit Flies Are Extreme Ultramarathon Fliers; In Search of Food, a Fly Can Travel Six Million Times Its Body Length

In 2005, an ultramarathon runner ran continuously 560 kilometers (350 miles) in 80 hours, without sleeping or stopping. This distance was roughly 324,000 times the runner's body length. Yet this extreme feat pales in comparison to the relative distances that fruit flies can travel in a single flight, according to new research from Caltech. Caltech scientists have now discovered that fruit flies can fly up to 15 kilometers (about 9 miles) in a single journey--6 million times their body length, or the equivalent of over 10,000 kilometers for the average human. In comparison to body length, this is farther than many migratory species of birds can fly in a day. To discover this, the team conducted experiments in a dry lakebed in California's Mojave Desert, releasing flies and luring them into traps containing fermenting juice in order to determine their top speeds. The research was conducted in the laboratory of Michael Dickinson, PhD, Esther M. and Abe M. Zarem Professor of Bioengineering and Aeronautics and executive officer for biology and biological engineering. A paper describing the study was published online on April 27, 2021 PNAS. The article is titled “The Long-Distance Flight Behavior of Drosophila Supports an Agent-Based Model for Wind-Assisted Dispersal in Insects” (https://www.pnas.org/content/118/17/e2013342118). The work was motivated by a longstanding paradox that was identified in the 1940s by legendary geneticist Theodosius Dobzhansky and other pioneers of population genetics who studied Drosophila species across the Southwest United States. Dobzhansky and others found that fly populations separated by thousands of kilometers appeared much more genetically similar than could be easily explained by their estimates of how far the tiny flies could actually travel.

KSQ Therapeutics Uses CRISPR Approach to Study Role of Every Human Gene In Disease Biology

CRISPR’s potential to prevent or treat disease is widely recognized. But the gene-editing technology can also be used as a research tool to probe and understand diseases. That’s the basic insight behind KSQ Therapeutics. The company uses CRISPR (clustered regularly interspaced short palindromic repeats) to alter genes across millions of cells. By observing the effect of turning on and off individual genes, KSQ can decipher their role in diseases like cancer. The company uses those insights to develop new treatments. The approach allows KSQ to evaluate the function of every gene in the human genome. The approach was developed at MIT by KSQ co-founder Tim Wang (photo), PhD ’17, in the labs of professors Eric Lander, PhD, and David Sabatini, MD, PhD. “Now we can look at every single gene, which you really couldn’t do before in a human cell system, and therefore there are new aspects of biology and disease to discover, and some of these have clinical value,” says Dr. Sabatini, who is also a KSQ co-founder. KSQ’s product pipeline includes small-molecule drugs as well as cell therapies that target genetic vulnerabilities identified from their experiments with cancer and tumor cells. KSQ believes its CRISPR-based methodology gives it a more complete understanding of disease biology than other pharmaceutical companies and thus a better chance of developing effective treatments to cancer and other complex diseases. KSQ’s scientific co-founders had been studying the function of genes for years before advances in CRISPR allowed them to precisely edit genomes about 10 years ago.

Lobster Underbelly Serves As Model for Synthesis of Gelatin-Like Material (Nanofibrous Hydrogel) That Mimics Underbelly’s Remarkable Stretch and Strength Characteristics; Material May Be Useful in Robust Artificial Tissues Such As Tendons & Ligaments

A lobster’s underbelly is lined with a thin, translucent membrane that is both stretchy and surprisingly tough. This marine under-armor, as MIT engineers reported in 2019 (https://news.mit.edu/2019/lobster-underbelly-tough-industrial-rubber-0219), is made from the toughest known hydrogel in nature, which also happens to be highly flexible. This combination of strength and stretch helps shield a lobster as it scrabbles across the seafloor, while also allowing it to flex back and forth to swim. Now, a separate MIT team has fabricated a hydrogel-based material that mimics the structure of the lobster’s underbelly. The researchers ran the material through a battery of stretch and impact tests, and showed that, similar to the lobster underbelly, the synthetic material is remarkably “fatigue-resistant,” able to withstand repeated stretches and strains without tearing. If the fabrication process could be significantly scaled up, materials made from nanofibrous hydrogels could be used to make stretchy and strong replacement tiss es such as artificial tendons and ligaments. The team’s results were u published online on April 23, 2021 in the journal Matter. The article is titled “Strong Fatigue-Resistant Nanofibrous Hydrogels Inspired by Lobster Underbelly” (https://www.cell.com/matter/fulltext/S2590-2385(21)00161-2). The paper’s MIT co-authors include postdocs Jiahua Ni and Shaoting Lin; graduate students Xinyue Liu and Yuchen Sun; Professor of Aeronautics and Astronautics Raul Radovitzky; Professor of Chemistry Keith Nelson; Mechanical Engineering Professor Xuanhe Zhao; and former Research Scientist David Veysset PhD 2016, now at Stanford University; along with Zhao Qin, Assistant Professor at Syracuse University, and Alex Hsieh of the Army Research Laboratory.

Experimental Drug Boosts Brain Cell Cleaning to Reverse Alzheimer’s Disease Symptoms in Mice; Deficient Cell-Cleaning Mechanism (Chaperone-Mediated Autophagy, CPG) Interacts Synergistically with Alzheimer’s Pathology to Greatly Accelerate Disease Progress

Researchers at Albert Einstein College of Medicine have designed an experimental drug that reversed key symptoms of Alzheimer’s disease in a mouse model of the disease. The drug works by reinvigorating a cellular cleaning mechanism that gets rid of unwanted proteins by digesting and recycling them. The study was published online April 22, 2021 in Cell. The article is titled “Chaperone-Mediated Autophagy Prevents Collapse of the Neuronal Metastable Proteome” (https://www.cell.com/cell/fulltext/S0092-8674(21)00379-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867421003792%3Fshowall%3Dtrue). “Discoveries in mice don’t always translate to humans, especially in Alzheimer’s disease,” said study Co-Leader Ana Maria Cuervo (photo) (https://einsteinmed.org/faculty/8784/ana-maria-cuervo/) MD, PhD, the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, Professor of Developmental and Molecular Biology, and Co-Director of the Institute for Aging Research at Einstein. “But we were encouraged to find in our study that the drop-off in cellular cleaning that contributes to Alzheimer’s in mice also occurs in people with the disease, suggesting that our drug may also work in humans.” In the 1990s, Dr. Cuervo discovered the existence of this cell-cleaning process, known as chaperone-mediated autophagy (CMA) and she has published 200 papers on its role in health and disease. CMA becomes less efficient as people age, increasing the risk that unwanted proteins will accumulate into insoluble clumps that damage cells. In fact, Alzheimer’s and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in patients’ brains. The Cell paper reveals a dynamic interplay between CMA and Alzheimer’s disease, with loss of CMA in neurons contributing to Alzheimer’s and vice versa.

Improving Survival in Pancreatic Cancer--TUG1 lncRNA Enhances Breakdown of Chemotherapy Drug; Scientists Use Anti-Sense Oligo to Suppress TUG1 Gene Expression & Enhance the Effects of Chemotherapy

Nagoya University researchers and colleagues in Japan have uncovered a molecular pathway that enhances chemotherapy resistance in some pancreatic cancer patients. Targeting an RNA to interrupt its activity could improve patient response to therapy and increase their overall survival. "Pancreatic cancer is one of the most aggressive human malignancies, with an overall median survival that is less than five months," says cancer biologist Yutaka Kondo, PhD, of Nagoya University Graduate School of Medicine. "This poor prognosis is partially due to a lack of potent therapeutic strategies against pancreatic cancer, so more effective treatments are urgently needed." Dr. Kondo and his colleagues focused their attention on a long noncoding RNA (lncRNA) called taurine upregulating gene 1 (TUG1). lncRNAs are gene regulators, several of which have recently been identified for helping some cancers resist chemotherapy. TUG1 is already known for being overexpressed in gastrointestinal cancers that have poor prognosis and are resistant to chemotherapy. The researchers found that TUG1 was overexpressed in a group of patients with pancreatic ductal adenocarcinoma. These patients were resistant to the standard chemotherapy treatment 5-fluorouracil (5-FU), and died much sooner compared to cancer patients with low TUG1 expression levels. Further laboratory tests showed that TUG1 counteracts a specific microRNA, leading to increased activity of an enzyme, called dihydropyrimidine dehydrogenase, which breaks down 5-FU into a compound that can't kill cancer cells. Dr. Kondo and his team found they could suppress TUG1 during 5-FU treatment of mice with pancreatic cancer by using antisense oligonucleotides attached to a specially designed cancer-targeting drug delivery system. Antisense oligonucleotides interfere with gene expression.

Scientists Discover “Jumping” Genes That Can Protect Against Blood Cancers—LINE-1 Retrotransposons Protect Against Myeloid Leukemia

New research has uncovered a surprising role for so-called “jumping” genes that are a source of genetic mutations responsible for a number of human diseases. In the new study from Children’s Medical Center Research Institute at UT Southwestern (CRI), scientists made the unexpected discovery that these DNA sequences, also known as transposons, can protect against certain blood cancers. These findings, published online on April 8, 2021 in Nature Genetics, led scientists to identify a new biomarker that could help predict how patients will respond to cancer therapies and find new therapeutic targets for acute myeloid leukemia (AML), the deadliest type of blood cancer in adults and children. The article is titled “Silencing of LINE-1 Retrotransposons Is a Selective Dependency of Myeloid Leukemia” (https://www.nature.com/articles/s41588-021-00829-8). Transposons are DNA sequences that can move, or jump, from one location in the genome to another when activated. Though many different classes of transposons exist, scientists in the laboratory of Jian Xu (at right in photo), PhD (https://cri.utsw.edu/scientists/jian-xu-lab/) focused on a type known as long interspersed element-1 (L1) retrotransposons. L1 sequences work by copying and then pasting themselves into different locations in the genome, which often leads to mutations that can cause diseases such as cancer. Nearly half of all cancers contain mutations caused by L1 insertion into other genes, particularly lung, colorectal, and head-and-neck cancers. The incidence of L1 mutations in blood cancers such as AML is extremely low, but the reasons why are poorly understood. When researchers screened human AML cells to identify genes essential for cancer cell survival, they found MPP8, a known regulator of L1, to be selectively required by AML cells.

Four Free Weekly Virtual Talks on COVID-19 by World Leaders in Science; Talks Intended to Make COVID-19 Situation Clear to the Public; Series Titled “The Science from Infection to Treatment”--First Talk on Wednesday, April 28, 7 pm EDT

The Minor Memorial Library in Roxbury, Connecticut is excited to welcome four renowned scientists for a series of four lectures to explain the underlying science in producing antibodies, therapies, and vaccines to thwart the COVID-19 pandemic. The COVID-19 lectures will be given on Wednesdays: April 28, May 5, 12, and 19 at 7 pm EDT on Zoom. There is no charge for these programs, but registration is required. RSVP online at (https://www.minormemoriallibrary.org/?tribe_events=covid-101-your-immune...) to receive the Zoom link. Descriptions of the scheduled lectures follow. WEDNESDAY APRIL 28 AT 7 PM EDT ON ZOOM: LECTURE 1: “How Your Immune System Responds to Viral Infection” Vaccines have great potential to end the COVID-19 pandemic and yet are controversial. Hear from Marc Jenkins, PhD, about how vaccines stimulate the immune system and why vaccines are such powerful tools in infection control. Dr. Jenkins is a Regents and Distinguished McKnight University Professor and heads the Center for Immunology at the University of Minnesota. In 2020, he was elected to the National Academy of Sciences. WEDNESDAY MAY 5 AT 7 PM EDT ON ZOOM: LECTURE 2: “Antibody Therapy: What Is It and Is It Safe? Amidst the COVID-19 crisis, Regeneron utilized its suite of technologies to rapidly develop and release the first antibody cocktail with Emergency Use Authorization (EUA) to treat SARS-CoV-2 infection. Learn how the antibody therapy works through mimicking a natural immune response and why it continues to be potently active against all known variants. Lecturer Benjamin Fulton, PhD, is a Scientist in the Infectious Disease Department at Regeneron and a member of the team that developed Regeneron’s COVID-19 antibody cocktail.

Ingredient in Indian Long Pepper Shows Promise Against Glioblastoma in Animal Models; Cryo-EM Illuminates Mechanism of Action; Piperlongumine Allosterically Inhibits TRPV2 Ion Channel Overexpressed in Glioblastoma

Piperlongumine, a chemical compound found in the Indian Long Pepper plant (Piper longum) (photo), is known to kill cancerous cells in many tumor types, including brain tumors. Now an international team including researchers from the Perelman School of Medicine at the University of Pennsylvania has illuminated one way in which the piperlongumine works in animal models--and has confirmed its strong activity against glioblastoma, one of the least treatable types of brain cancer. The researchers, whose findings were published online on April 14, 2021 in ACS Central Science, showed in detail how piperlongumine binds to--and hinders the activity of--a protein called TRPV2, which is overexpressed in glioblastoma in a way that appears to drive cancer progression. The scientists found that piperlongumine treatment radically shrank glioblastoma tumors and extended life in two mouse models of this cancer, and also selectively destroyed glioblastoma cells taken from human patients. The open-access article is titled “Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression” (https://pubs.acs.org/doi/10.1021/acscentsci.1c00070). "This study gives us a much clearer picture of how piperlongumine works against glioblastoma, and in principle enables us to develop treatments that can be even more potent," said study co-senior author Vera Moiseenkova-Bell, PhD, an Associate Professor of Pharmacology and Faculty Director of the Electron Microscopy Resource Laboratory and Beckman Center for Cryo-Electron Microscopy at Penn Medicine. The study was a collaboration led by the laboratory of co-senior author Gonçalo J. L. Bernardes, DPhil, of the Institute of Molecular Medicine, University of Lisbon and the University of Cambridge.

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