Two Mammalian Models Can Use Their Intestines to Breathe; Finding May Be Applicable to Humans with Respiratory Failure, Including Those with COVID-19

Rodents and pigs share with certain aquatic organisms the ability to use their intestines for respiration, finds a study published online on May 14, 2021 in the journal Med. The article is titled “Mammalian Enteral Ventilation Ameliorates Respiratory Failure.” The researchers demonstrated that the delivery of oxygen gas or oxygenated liquid through the rectum provided vital rescue to two mammalian models of respiratory failure. “Artificial respiratory support plays a vital role in the clinical management of respiratory failure due to severe illnesses such as pneumonia or acute respiratory distress syndrome (ARDS),” says senior study author Takanori Takebe (@TakebeLab), MD, PhD, of the Tokyo Medical and Dental University and the Cincinnati Children’s Hospital Medical Center. “Although the side effects and safety need to be thoroughly evaluated in humans, our approach may offer a new paradigm to support critically ill patients with respiratory failure.” Several aquatic organisms have evolved unique intestinal breathing mechanisms to survive under low-oxygen conditions using organs other than lungs or gills. For example, sea cucumbers, freshwater fish called loaches, and certain freshwater catfish use their intestines for respiration. But it has been heavily debated whether mammals have similar capabilities. In the new study, Dr. Takebe and his collaborators provide evidence for intestinal breathing in rats, mice, and pigs. First, they designed an intestinal gas ventilation system to administer pure oxygen through the rectum of mice. They showed that without the system, no mice survived 11 minutes of extremely low-oxygen conditions. With intestinal gas ventilation, more oxygen reached the heart, and 75% of mice survived 50 minutes of normally lethal low-oxygen conditions. Because the intestinal gas ventilation system requires abrasion of the intestinal muscosa, it is unlikely to be clinically feasible, especially in severely ill patients–so the researchers also developed a liquid-based alternative using oxygenated perfluorochemicals. These chemicals have already been shown clinically to be biocompatible and safe in humans.

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New Research Optimizes Body’s Own Immune System to Fight Solid Cancers; First-of-Its-Kind study Shows How Immune Cells Can Be Engineered for Enhanced Migration Through Complex Tumor Microenvironments

A ground-breaking study led by engineering and medical researchers at the University of Minnesota Twin Cities shows how engineered immune cells used in new cancer therapies can overcome physical barriers to allow a patient’s own immune system to fight tumors. The research could improve cancer therapies in the future for millions of people worldwide. The research was published online on May 14, 2021 in Nature Communications, a peer-reviewed, open-access, scientific journal published by Nature Research. The article is titled “Engineering T Cells to Enhance 3D Migration Through Structurally and Mechanically Complex Tumor Microenvironments.” Instead of using chemicals or radiation, immunotherapy is a type of cancer treatment that helps the patient’s immune system fight cancer. T cells are a type of white blood cell that are of key importance to the immune system. Cytotoxic T cells are like soldiers who search out and destroy the targeted invader cells. While there has been success in using immunotherapy for some types of cancer in the blood or blood-producing organs, a T cell’s job is much more difficult in solid tumors. “The tumor is sort of like an obstacle course, and the T cell has to run the gauntlet to reach the cancer cells,” said Paolo Provenzano, PhD, the senior author of the study and a Biomedical Engineering Associate Professor in the University of Minnesota College of Science and Engineering. “These T cells get into tumors, but they just can’t move around well, and they can’t go where they need to go before they run out of gas and are exhausted.” In this first-of-its-kind study, the researchers are working to engineer the T cells and develop engineering design criteria to mechanically optimize the cells or make them more “fit” to overcome the barriers. If these immune cells can recognize and get to the cancer cells, then they can destroy the tumor. In a fibrous mass of a tumor, the stiffness of the tumor causes immune cells to slow down about two-fold–almost as if they are running in quicksand.

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High Genomic Diversity Is Good News for California Condor; First Complete Genome Reveals High Genetic Diversity Despite Recent Brush with Extinction

Despite having been driven nearly to extinction, the California condor has a high degree of genetic diversity that bodes well for its long-term survival, according to a new analysis by University of California (UC) researchers. Nearly 40 years ago, the state’s wild condor population was down to a perilous 22. That led to inbreeding that could have jeopardized the population’s health and narrowed the bird’s genetic diversity, which can reduce its ability to adapt to changing environmental conditions. In comparing the complete genomes of two California condors with those of an Andean condor and a turkey vulture, UC San Francisco and UC Berkeley scientists did find genetic evidence of inbreeding over the past few centuries, but, overall, a wealth of diversity across most of the genome. “You need genetic diversity in order to adapt, and the more genetic diversity they (California condors) have, hopefully, the more chance they have to adapt and persist,” said Jacqueline Robinson, PhD, a UCSF postdoctoral fellow and first author of a paper about the analysis published online on May 13, 2021 in Current Biology. The open-access article is titled “Genome-wide diversity in the California condor tracks its prehistoric abundance and decline” (www.cell.com/current-biology/fulltext/S0960-9822(21)00548-0). “Our study is the first to begin quantifying diversity across the entire California condor genome, which provides us a lot of baseline information and will inform future research and conservation.” The health of the bird’s genome is probably due to the species’ great abundance in the past. Dr. Robinson and her colleagues, including Rauri Bowie, PhD, UC Berkeley Professor of Integrative Biology, used statistical techniques to estimate the bird’s historical population and found that it was far more abundant across the United States a million years ago than even the turkey vulture, America’s most common vulture today. The California condor likely numbered in the tens of thousands, soaring and scavenging from New York and Florida to California and into Mexico.

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Evolutionary Biologists Discover Mechanism That Enables Anolis Lizards to Breathe Underwater

A team of evolutionary biologists from the University of Toronto has shown that Anolis lizards, or anoles, are able to breathe underwater with the aid of a bubble clinging to their snouts. Anoles are a diverse group of lizards found throughout the tropical Americas. Some anoles are stream specialists, and these semi-aquatic species frequently dive underwater to avoid predators, where they can remain submerged for as long as 18 minutes. “We found that semi-aquatic anoles exhale air into a bubble that clings to their skin,” says Chris Boccia, a recent Master of Science graduate from the Faculty of Arts & Science’s Department of Ecology & Evolutionary Biology (EEB). Boccia is lead author of a paper describing the finding published online on May 12, 2021 in Current Biology. The open-access article is titled “Repeated Evolution of Underwater Rebreathing in Diving Anolis Lizards” (www.cell.com/current-biology/fulltext/S0960-9822(21)00575-3). “The lizards then re-inhale the air,” says Boccia, “a maneuver we’ve termed ‘rebreathing’ after the scuba-diving technology.” The researchers measured the oxygen (O2) content of the air in the bubbles and found that it decreased over time, confirming that rebreathed air is involved in respiration. Rebreathing likely evolved because the ability to stay submerged longer increases the lizard’s chances of eluding predators. The authors studied six species of semi-aquatic anoles and found that all possessed the rebreathing trait, despite most species being distantly related. While rebreathing has been studied extensively in aquatic arthropods like water beetles, it was not expected in lizards because of physiological differences between arthropods and vertebrates.

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Horseradish Flea Beetle Protected by Weapons of Its Food Plant; Researchers Elucidate How Insect Regulates Accumulation of Plant Toxins Via Special Transporters

When horseradish flea beetles (photo) feed on their host plants, they take up not only nutrients but also mustard oil glucosides, the characteristic defense compounds of horseradish and other brassicaceous plants. Using these mustard oil glucosides, the beetles turn themselves into a “mustard oil bomb” and so deter predators. A team of researchers from the Max Planck Institute for Chemical Ecology in Jena, Germany, has now been able to demonstrate how the beetle regulates the accumulation of mustard oil glucosides in its body. The beetles have special transporters in the excretory system that prevent the excretion of mustard oil glucosides. This mechanism enables the horseradish flea beetle to accumulate high amounts of the plant toxins in its body, which it uses for its own defense. The new results were published online on May11, 2021 in Nature Communications. The open-access article is titled “Sugar Transporters Enable a Leaf Beetle to Accumulate Plant Defense Compounds” (www.nature.com/articles/s41467-021-22982-8). Many animals use chemical defense compounds to deter predators. These defense compounds are either produced by the animal itself or by symbionts of the animal, or they are acquired from the diet. The ability to acquire defense compounds from the diet is particularly widespread in insects that feed on toxic plants. One example is the horseradish flea beetle (Phyllotreta armoraciae), which can sequester mustard oil glucosides, also known as glucosinolates, in its body. “The horseradish flea beetle belongs to an economically important group of insects, because several Phyllotreta species are crop pests. This beetle, which can accumulate vast amounts of host plant glucosinolates, regulates the levels and composition of glucosinolates in the body at least partially by excretion. This suggested that Phyllotreta armoraciae possesses very efficient transport and storage mechanisms, which we wanted to uncover,” says first author Zhi-Ling Yang, PhD, explaining the goal of the new study.

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A Comprehensive Map of the SARS-CoV-2 Genome; MIT-Led Research Team Uses Comparative Genomics of Closely Related Viruses to Determine the SARS-CoV-2 Protein-Coding Gene Set and to Analyze New Mutations’ Likelihood of Helping the Virus Adapt

In early 2020, a few months after the COVID-19 pandemic began, scientists were able to sequence the full genome of SARS-CoV-2, the virus that causes the COVID-19 infection. While many of its genes were already known at that point, the full complement of protein-coding genes was unresolved. Now, after performing an extensive comparative genomics study, MIT researchers have generated what they describe as the most accurate and complete gene annotation of the SARS-CoV-2 genome. In their study, the results of which were published online on May 11, 2021 in Nature Communications, the scientists confirmed several protein-coding genes and found that a few others that had been suggested as genes do not code for any proteins. “We were able to use this powerful comparative genomics approach for evolutionary signatures to discover the true functional protein-coding content of this enormously important genome,” says Manolis Kellis, PhD, who is the senior author of the study and a Professor of Computer Science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) as well as a member of the Broad Institute of MIT and Harvard. The research team also analyzed nearly 2,000 mutations that have arisen in different SARS-CoV-2 isolates since the virus began infecting humans, allowing them to rate how important those mutations may be in changing the virus’ ability to evade the immune system or become more infectious. The open-access Nature Communications article is titled “Conflicting and Ambiguous Names of Overlapping ORFs in the SARS-CoV-2 Genome: A Homology-Based Resolution.” The SARS-CoV-2 genome consists of nearly 30,000 RNA bases. Scientists have identified several regions known to encode protein-coding genes, based on their similarity to protein-coding genes found in related viruses. A few other regions were suspected to encode proteins, but they had not been definitively classified as protein-coding genes.

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CytoDyn Reaches Agreement with Albert Einstein Israelite Hospital in Brazil to Conduct Two COVID-19 Trials–Small Trial in Critically Ill and Large Trial in Severely Ill Populations

On May 5, 2021, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (Vyrologix or PRO 140), a chemokine receptor type 5 (CCR5) antagonist with the potential for multiple therapeutic indications, announced the agreement to partner with Academic Research Organization (ARO)–Albert Einstein Israelite Hospital (AEIH) in São Paulo, Brazil for two COVID-19 trials. The COVID-19 trials in Brazil are intended to provide the Brazilian regulatory authority, ANVISA, with the requisite data to consider advancing the availability of leronlimab to thousands of Brazilians infected with COVID-19. These two Phase 3 trials will be conducted in up to 45 clinical sites. Chris Recknor, MD, CytoDyn’s Chief Operating Officer and Head of Clinical Development, commented, “We are pleased to partner with one of the best hospitals in Latin America, the Albert Einstein Israelite Hospital, and their affiliated academic research organization network. This ARO has conducted multiple large-scale COVID trials for many pharmaceutical companies. CytoDyn is utilizing their extensive experience to develop and conduct our CD16 and CD17 COVID-19 trials. With approximately 1,500 patients in total for both trials, we anticipate having adequate power in each trial to achieve a significant p-value for our endpoints and will be performing an interim analysis after 40% of the critically ill patients are enrolled. In Brazil, the P1 COVID variant is fueling a second wave worse than the initial outbreak. In April, more than 78,000 people lost their lives from COVID and ICU capacity in 15 of Brazil’s 26 states, is at or above 90% full. Vyrologix is variant agnostic. We expect an interim analysis will be conducted in October-November of this year. We look forward to accelerating these trials for the benefit of the Brazilian people.”

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New Preclinical Data Demonstrate Potential of Codiak’s Engineered Exosomes As Novel, Targeted Approaches in Multiple Disease Areas

On May 11, 2021, Codiak BioSciences, Inc. (Nasdaq: CDAK), a clinical-stage biopharmaceutical company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, announced new preclinical data from programs from its engEx™ Platform showing the broad potential therapeutic applications of engineered exosomes. The data, which include results from the investigational new drug (IND)-enabling studies for exoASO™-STAT6, immune evasion data from Codiak’s exoAAV™ gene therapy platform, data showing the versatility of Codiak’s exoVACC™ vaccine platform, and Codiak’s ability to engineer specific cell uptake were presented on May11, 2021 at the virtual 24th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) (annualmeeting.asgct.org/). “These data highlight the power and flexibility of our engineering platform to build on the natural biology of exosomes with distinct and intentionally-chosen features,” said Douglas E. Williams, PhD, President and Chief Executive Officer of Codiak. “By using exosomes to enhance the therapeutic index, we can pursue previously undruggable pathways and targets in multiple disease areas. Our lead programs are in immuno-oncology where we currently have two clinical trials underway in patients, and based on our continuing preclinical work, we see potential to advance programs in a broad array of therapeutic applications.” Codiak’s proprietary engEx Platform enables the company to engineer exosomes–naturally occurring, extracellular nanoparticle vesicles–with distinct properties, load them with various therapeutic molecules and alter tropism so they reach specific cellular targets. Codiak has two programs in clinical development and expects to file an IND for exoASO-STAT6–a novel exosome therapeutic carrying an antisense oligonucleotide (ASO) to target the transcription factor, STAT6–by the end of the year.

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Scientists at UW-Madison and Columbia University Lead Efffort to Engineer Peptide to Block Parainfluenza Virus (HPIV3) That Causes Childhood Respiratory Infections

By engineering a peptide that can prevent the attachment of human parainfluenza viruses (HPIVs) to cells, researchers have improved a method in rodent models intended to help keep children healthy. HPIVs are the leading cause of childhood respiratory infections, responsible for 30% to 40% of illnesses like croup and pneumonia. The viruses also affect the elderly and people with compromised immune systems. To sicken people, HPIVs must latch onto cells and inject their genetic material to start making new viruses. HPIV3 is the most prevalent among these viruses. There are currently no approved vaccines or antivirals for HPIV3 infection in people. In a study led by the Sam Gellman (photo), PhD, lab in the Chemistry Department at the University of Wisconsin-Madison, and the lab of Anne Moscona, MD, and Matteo Porotto, PhD, at Columbia University, researchers built upon years of work on peptide treatments to generate one capable of blocking the HPIV3 attachment process. The researchers’ work was published online on April 7, 2021 in the Journal of the American Chemical Society. The article is titled “Engineering Protease-Resistant Peptides to Inhibit Human Parainfluenza Viral Respiratory Infection” (pubs.acs.org/doi/10.1021/jacs.1c01565). To enter host cells, HPIVs use specialized fusion proteins that resemble three corkscrews laid side-by-side. Earlier work by the the Moscona-Porotto lab showed that scientists could derive a partial chunk of this corkscrew protein from HPIV3, introduce this peptide to the virus, and prevent the corkscrew from driving the infection process. The peptide, itself a corkscrew, essentially zippers up with the virus’s corkscrews, creating a tight bundle of six corkscrew shapes. The newly modified peptide persists longer in the body, making it about three times more effective at blocking infection in rodent models of disease than the original form.

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Exosomes Carrying Salmonella Antigens Stimulate Innate and Adaptive Immunity in Animal Model

With the COVID-19 vaccines on many people’s minds, some may be surprised to learn that we do not yet have vaccines for many common infectious diseases. Take Salmonella, for example, which can infect people through contaminated food, water, and animals. According to the World Health Organization, non-typhoidal Salmonella infection affects more than 95 million people globally each year, leading to an estimated 2 million deaths annually. There is no approved vaccine for Salmonella in humans, and some strains are antibiotic-resistant. But, just as scientists spent decades doing the basic research that made the eventual development of the COVID-19 vaccines possible, University of Florida researchers led by Mariola Edelmann, PhD, Assistant Professor in the Department of Microbiology and Cell Science, University of Florida/Institute of Food and Agricultural Sciences (UF/IFAS) College of Agricultural and Life Sciences, are laying the groundwork for an effective vaccine for Salmonella and other hard-to-treat bacterial infections. In their study, supported by the National Institutes of Health and published online on May 6, 2021 in PLoS Pathogens, the UF/IFAS scientists demonstrate a novel approach to triggering immunity against Salmonella. The open-access article is titled “Antigen-Encapsulating Host Extracellular Vesicles Derived from Salmonella-Infected Cells Stimulate Pathogen-Specific Th1-Type Responses in Vivo” (journals.plos.org/plospathogens/article?id=10.1371/journal.ppat….). This approach takes advantage of how cells communicate with each other, said Winnie Hui (photo), first author of the study, which was conducted while she was a doctoral candidate in microbiology and cell science.

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