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Archive - Jul 2020

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July 2nd

RNA Structures Revealed by the Thousands Using Lead (Pb+2) Sequencing Approach

Researchers from Bochum and Münster in Germany have developed a new method to determine the structures of all RNA molecules in a bacterial cell at once. In the past, this had to be done individually for each molecule. Besides their exact composition, their structure is crucial for the function of the RNAs. The team describes the new high-throughput structure mapping method, termed Lead-Seq for lead (Pb) sequencing in an article published online on May 28, 2020 in Nucleic Acids Research. The article is titled “Lead-Seq: Transcriptome-Wide Structure Probing in Vivo Using Lead (II) Ions.” Christian Twittenhoff, Vivian Brandenburg (at right in photo), Francesco Righetti, PhD, and Professor Franz Narberhaus (at left in photo), PhD, from the Chair of Microbial Biology at Ruhr-Universität Bochum (RUB) collaborated with the Bioinformatics Group headed by Professor Axel Mosig, PhD, at RUB and the team led by Professor Petra Dersch, PhD, at the University of Münster, previously from the Helmholtz Centre for Infection Research in Braunschweig. In all living cells, genetic information is stored in double-stranded DNA and transcribed into single-stranded RNA, which then serves as a blueprint for proteins. However, RNA is not only a linear copy of the genetic information, but often folds into complex structures. The combination of single-stranded and partially folded double-stranded regions is of central importance for the function and stability of RNAs. "If we want to learn something about RNAs, we must also understand their structure," says Professor Narberhaus. With lead sequencing, the authors present a method that facilitates the simultaneous analysis of all RNA structures in a bacterial cell.

CAR-T Cells Recognize & Attack Human and Mouse Solid-Tumor Cancer Cells in Vitro; CAR-T Cell Therapy Has Previously Shown Effectiveness Against Blood Cancers, But Not Against Solid Tumors; Current Approach Targets Glycosylated Peptides on Solid Tumors

A method known as CAR-T (chimeric antigen receptor T cells) therapy (https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell) has been used successfully in patients with blood cancers such as lymphoma and leukemia. The approach modifies a patient's own T-cells by adding a piece of an antibody that recognizes unique features on the surface of cancer cells. The potency of adoptive T cell therapies targeting the cell surface antigen CD19 has been demonstrated in hematopoietic cancers. In a new study, researchers report that they have dramatically broadened the potential targets of this approach--their engineered T-cells attack a variety of solid-tumor cancer cells from humans and mice. Heretofore, CAR-T therapy had not demonstrated effectiveness against solid tumors. The researchers, led by a team from the University of Illinois at Urbana-Champaign, and including scientists from the University of Chicago and the University of Copenhagen, reported their findings online on June 30, 2020 in the Proceedings of the National Academy of Sciences (https://www.pnas.org/content/117/26/15148). The article is titled "Structure-Guided Engineering of the Affinity and Specificity of CARs Against Tn-Glycopeptides." [Editor’s Note: Tn antigen refers to the monosaccharide structure N-acetylgalactosamine (GalNAc) linked to serine or threonine by a glycosidic bond (https://en.wikipedia.org/wiki/Tn_antigen)] "Cancer cells express on their surface certain proteins that arise because of different kinds of mutations," said Preeti Sharma, PhD, a postdoctoral researcher at the University of Illinois at Urbana-Champaign who led the research, together with Biochemistry Professor David Kranz (http://mcb.illinois.edu/faculty/profile/d-kranz/), PhD, a member of the Cancer Center at Illinois and an affiliate of the Carl R.

Engineers Develop Novel Method to Produce NO2 Gaseous Messenger Molecule at Precise Locations in Body; Approach Could Illuminate NO2’s Roles in Neural, Circulatory, & Immune Systems; Work Described As “Milestone in Bioelectronics”

Nitric oxide (NO2) is an important signaling molecule in the body, with a role in building nervous system connections that contribute to learning and memory. It also functions as a messenger in the cardiovascular and immune systems. But it has been difficult for researchers to study exactly what its role is in these systems and how it functions. Because it is a gas, there has been no practical way to direct it to specific individual cells in order to observe its effects. Now, a team of scientists and engineers at MIT, and elsewhere, has found a way of generating the gas at precisely targeted locations inside the body, potentially opening new lines of research on this essential molecule’s effects. The findings were published online on June 29, 2020 reported in Nature Nanotechnology, in a paper by MIT Professors Polina Anikeeva (photo), PhD, Karthish Manthiram, PhD, and Yoel Fink, PhD; graduate student Jimin Park; postdoc Kyoungsuk Jin, PhD; and 10 others at MIT, and in Taiwan, Japan, and Israel. The article is titled “In Situ Electrochemical Generation of Nitric Oxide for Neuronal Modulation.” “It’s a very important compound,” Dr. Anikeeva says. But figuring out the relationships between the delivery of nitric oxide to particular cells and synapses, and the resulting higher-level effects on the learning process has been difficult. So far, most studies have resorted to looking at systemic effects, by knocking out genes responsible for the production of enzymes the body uses to produce nitric oxide where it’s needed as a messenger. But that approach, Dr. Anikeeva says, is “very brute force.

Certain Bacteria Are Circumventing Plant Defenses, Causing Foodborne Illnesses; Salmonella Can Enter Plants by Opening the Stomates in Plant Leaves

As the world wrestles with the coronavirus (COVID-19) pandemic, which arose after the virus jumped from an animal species to the human species, University of Delaware researchers are learning about new ways other pathogens are jumping from plants to people. Opportunistic bacteria--Salmonella, Listeria, and E. coli, for example--often piggy-back on raw vegetables, poultry, beef, and other foods to gain entry into a human host, causing millions of food-borne illnesses each year. But University of Delaware researchers Harsh Bais, PhD, and Kali Kniel, PhD, and their collaborators now have found that wild strains of Salmonella can circumvent a plant's immune defense system, getting into the leaves of lettuce by opening up the plant's tiny breathing pores called stomates (image). The plant shows no symptoms of this invasion and once inside the plant, the pathogens cannot just be washed off. Stomates are little kidney-shaped openings on leaves that open and close naturally and are regulated by circadian rhythm. They open to allow the plant to cool off and breathe. They close when they detect threats from drought or plant bacterial pathogens. Some pathogens can barge into a closed stomate using brute force, Dr. Bais said. Fungi can do that, for example. Bacteria don't have the enzymes needed to do that, so they look for openings--in roots or through stomates, he said. Plant bacterial pathogens have found a way to reopen those closed stomates and gain entry to the plant's internal workings, Dr. Bais said. But now, in research published online on April3, 2020 in Frontiers in Microbiology (https://www.frontiersin.org/articles/10.3389/fmicb.2020.00500/full), Dr. Bais and Dr. Kniel have shown that some strains of the human pathogen salmonella have developed a way to reopen closed stomates, too.

CytoDyn Releases Mechanism-of-Action Animation for Leronlimab in Immuno-Oncology

On July 2, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced the public release of the animation for leronlimab in immuno-oncology. Click here (https://www.dropbox.com/s/2uu5xp6fffzpwew/CytoDyn%20Leronlimab.mp4?dl=0) to view the animation. CytoDyn is encouraged by the potential of leronlimab to positively influence the tumor microenvironment by inhibiting T-reg infiltration, conversion of M2 macrophages (protumor macrophages) into M1 macrophages (antitumor macrophages), decreasing tumor angiogenesis, and inhibiting metastasis through CCR5 overexpression. CytoDyn is currently exploring the efficacy of leronlimab for several immuno-oncology indications, including metastatic triple-negative breast cancer, a mechanism of action basket trial for 22 solid tumors, and a Phase 2 combination therapy for metastatic colorectal cancer. The FDA has granted leronlimab Fast Track designation for metastatic triple-negative breast cancer. “We appreciate the work of Nucleus Medical Media to capture the potential benefits of leronlimab in the tumor microenvironment. The control of the tumor microenvironment is critical in the ultimate determination of clinical patient outcomes. We believe leronlimab may help leverage the immune system’s natural ability to fight cancer. Leronlimab’s safety profile and potential synergistic effects with current oncology treatments may prove to be an exciting opportunity within immuno-oncology,” said Scott A. Kelly, MD, Chief Medical Officer and Chairman of the Board of CytoDyn. CytoDyn has met its 75-patient enrollment target in its Phase 2 clinical trial for COVID-19, a randomized clinical trial for mild-to-moderate COVID-19 population in the U.S.

New Method Reveals How Parkinson's Disease Protein Damages Cell Membranes; Alpha-Synclein Binds to Membranes of Mitochondria-Like Vesicles, Which Then Deform Asymmetrically and Leak Their Contents

The reNew Method Reveals How Parkinson's Disease Protein Damages Cell Membranes; alpha-Synclein Binds to Membranes of Mitochondria-Like Vesicles, Which Then Deform Asymmetrically and Leak Their Contentssearchers found that the Parkinson's protein would bind to both vesicle types, but only caused structural changes to the mitochondrial-like vesicles, which deformed asymmetrically and leaked their contents. In sufferers of Parkinson's disease, clumps of α-synuclein (alpha-synuclein), sometimes known as the “Parkinson's protein,” are found in the brain. These destroy cell membranes, eventually resulting in cell death. Now, a new method developed at Chalmers University of Technology (photo), in Gothenberg, Sweden, reveals how the composition of cell membranes seems to be a decisive factor for how small quantities of α-synuclein cause damage. Parkinson's disease is an incurable condition in which neurons, the brain's nerve cells, gradually break down and brain functions become disrupted. Symptoms can include involuntary shaking of the body, and the disease can cause great suffering. To develop drugs to slow down or stop the disease, researchers try to understand the molecular mechanisms behind how α-synuclein contributes to the degeneration of neurons. It is known that mitochondria (image below), the energy-producing compartments in cells, are damaged in Parkinson's disease, possibly due to “amyloids” of α-synuclein. Amyloids are clumps of proteins arranged into long fibers with a well-ordered core structure, and their formation underlies many neurodegenerative disorders. Amyloids or even smaller clumps of α-synuclein may bind to and destroy mitochondrial membranes, but the precise mechanisms are still unknown.

MIT Engineers Use “DNA Origami” to Identify Vaccine Design Rules; In Lab Tests, Virus-Like DNA Structures Coated with Viral Proteins Provoke Strong Immune Response in Human B Cells

By folding DNA into a virus-like structure, MIT researchers have designed HIV-like particles that provoke a strong immune response from human immune cells grown in a lab dish. Such particles might eventually be used as an HIV vaccine. Currently, no effective vaccine exists for HIV. The DNA particles, which closely mimic the size and shape of viruses, are coated with HIV proteins, or antigens, arranged in precise patterns designed to provoke a strong immune response. The researchers are now working on adapting this approach to develop a potential vaccine for SARS-CoV-2, and they anticipate it could work for a wide variety of viral diseases. “The rough design rules that are starting to come out of this work should be generically applicable across disease antigens and diseases,” says Darrell Irvine, PhD, who is the Underwood-Prescott Professor with appointments in the Departments of Biological Engineering and Materials Science and Engineering; an Associate Director of MIT’s Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard. Dr. Irvine and Mark Bathe, PhD, an MIT Professor Of Biological Engineering and an Associate Member of the Broad Institute of MIT and Harvard, are the senior authors of the study, which was published online on June 29, 2020 in Nature Nanotechnology. The paper’s lead authors are former MIT postdocs Dr. Rémi Veneziano and Dr. Tyson Moyer.

July 1st

Solving the CNL6 Mystery in Batten Disease: CLN6 and CLN8 Interact with Each Other, Forming Molecular Complex That Collects Lysosomal Enzymes at Endoplasmic Reticulum and Mediates Their Trafficking Towards Lysosomes

Batten disease is a family of 13 rare, genetically distinct conditions. Collectively, they are the most prevalent cause of neurodegenerative disease in children, affecting 1 in 12,500 live births in the U.S. One of the Batten disease genes is CLN6. How mutations in this gene lead to the disease has been a mystery, but a study, led by researchers at Baylor College of Medicine and published online on June 29, 2020, in the Journal of Clinical Investigation (https://www.jci.org/articles/view/130955), reveals how defective CLN6 can result in Batten disease. The open-access article is titled “A CLN6-CLN8 Complex Recruits Lysosomal Enzymes at the ER for Golgi Transfer.” “People with Batten disease have problems with their cells' ability to clear cellular waste, which then accumulates to toxic levels," said first author Lakshya Bajaj (http://www.sardiellolab.com/lakshya-bajaj.html), DDS/PhD, who was working on this project while a doctorate student in the laboratory of Marco Sardiello (https://www.bcm.edu/research/baylor-research/faculty-recognition/debakey...), PhD, at Baylor. Dr. Bajaj is currently a post-doctoral associate at Harvard Medical School (https://www.linkedin.com/in/lakshya-bajaj-3637661a/). In cells, lysosomes process cellular waste. They are sacs containing enzymes, a type of proteins that break down waste products into its constituent components that the cell can recycle or discard. In Batten disease caused by mutations in CLN6 (ceroid lipofuscinosis, neuronal 6), the lysosomes do not process waste effectively for unknown reasons. This results in waste accumulation. Batten disease is a type of lysosomal storage disorder.

New Study from Cedars-Sinai Shows That SARS-CoV-2 Can Infect Heart Cells in Vitro; Results Suggest Possibility That SARS-CoV-2 Can Directly Infect Heart Cells in COVID-19 Patients

A new study shows that SARS-CoV-2, the virus that causes COVID-19 (coronavirus 2019), can infect heart cells in a lab dish, indicating it may be possible for heart cells in COVID-19 patients to be directly infected by the virus. The discovery, published online on June 25, 2020 in Cell Reports Medicine (https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(20)30068-9) (see graphic abstract of article below), was made using heart muscle cells that were produced by stem cell technology. The article is titled “Human iPSC-Derived Cardiomyocytes, Are Susceptible to SARS-CoV-2 Infection.” Although many COVID-19 patients experience heart problems, the reasons are not entirely clear. Pre-existing cardiac conditions or inflammation and oxygen deprivation that result from the infection have all been implicated. But, until now, there has been only limited evidence that the SARS-CoV-2 virus directly infects the individual muscle cells of the heart. “We not only uncovered that these stem cell-derived heart cells are susceptible to infection by novel coronavirus, but that the virus can also quickly divide within the heart muscle cells,” said Arun Sharma, PhD, a Senior Research Fellow at the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the first and co-corresponding author of the study. “Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection.” The study also demonstrated that human stem-cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile, further confirming that the cells can be actively infected by the virus and activate innate cellular “defense mechanisms” in an effort to help clear out the virus.

Novel Function for Platelets: Nucleus-Free Cell Fragments Can Reduce Metastasis by Helping Preserve Vascular Barrier, Making Blood-Vessel Wall Selectively Impermeable, Thereby Reducing Spread of Tumor Cells to Other Parts of Body

Scientists at Uppsala University in Sweden have discovered a hitherto unknown function of blood platelets in cancer. In mouse models, these platelets have proved to help preserve the vascular barrier which makes blood-vessel walls selectively impermeable, thereby reducing the spread of tumor cells to other parts of the body. The study results were published online on June 25, 2020 in Cancer Research. The article is titled “Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis.” Platelets (https://en.wikipedia.org/wiki/Platelet), also known as thrombocytes, are tiny cell fragments, without a nucleus, that form in the bone marrow and circulate in the blood. If we are injured and start bleeding, platelets clump together, sealing off the wound while also helping the blood to coagulate. When the platelets are activated--which occurs not only in wounds, but also in tumors--the substances known as growth factors contained in the platelets are released into their immediate surroundings. One of these growth factors is platelet-derived growth factor B (PDGFB). In the Uppsala study, the researchers investigated what happens when the PDGFB in platelets, but not in other cell types, is deleted in individuals with cancer. PDGFB from platelets was found to be essential, to attract supporting cells to the tumor blood vessels. In healthy tissue, on the other hand, the platelets did not to perform this function. If PDGFB was lacking in platelets, the quantity of circulating tumor cells increased and they spread to other parts of the body to a much higher degree. Previous studies have shown that PDGFB from cells of another kind, endothelial cells that line the inside of blood vessels, is necessary to attract supporting cells to the vessels when they form.