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May 28th, 2020

Scientists Develop Tool to Sequence Circular DNA; New Method Will Provide Insight into Genomes of Bacteria and Viruses, As Well As Extrachromosomal Circular DNA (eccDNA) in Humans; SMRT Long-Range Sequencing from Pacific Biosciences Employed

University of Alberta (Canada) biologists have invented a new way for sequencing circular DNA, according to a new study. The tool, called CIDER-Seq, will give other scientists rich, accurate data on circular DNA in any type of cell. The article describing the new method was published online on April 3, 2020 in Nature Protocols. The article is titled “Full-Length Sequencing of Circular DNA Viruses and Extrachromosomal Circular DNA Using CIDER-Seq.” While our own DNA is linear, circular DNA is common in the genomes of bacteria and viruses. Scientists have also discovered circular DNA within the nuclei of human and plant cells, called extrachromosomal circular DNA (eccDNA). Recently, research has begun to investigate the role of eccDNA in human cancer--but progress has been hampered due to the lack of effective methods for studying and sequencing eccDNA. "Our key advance is that, through our method, scientists can finally gain an unbiased, high-resolution understanding of circular DNA in any type of cell," explained Devang Mehta, PhD, postdoctoral fellow in the Department of Biological Sciences at the University of Alberta and lead author. "With our invention of CIDER-Seq, we can start to begin to understand the function of these mysterious circular DNAs in human and plant cells." CIDER-Seq uses DNA sequencing technology called single-molecule real-time (SMRT) long-read sequencing from Pacific Biociences to obtain full-length sequences without the need for PCR or restriction digestion. The method includes a web-lab protocol, as well as a new computational pipeline. It is optimized to examine both viral genomes and eccDNA and is made accessible to other scientists online.

May 27th

New Evidence for Blood-Based Biomarker (Neurofilament Light Chain) (NfL) for Alzheimer's Disease; Findings Made in MGH-Led Study of Over 2,000 Members of Colombian Kindred with Familial Alzheimer’s Due to Same Mutation (PSEN1 E280A)

A potential blood-based biomarker for Alzheimer's and other neurodegenerative diseases seems even more promising thanks to new research from a Massachusetts General Hospital (MGH)-led study. According to this team's work, neurofilament light chain (NfL) has great potential as a biomarker for early detection of Alzheimer's disease and could be also useful for monitoring treatment response for that condition. The study was carried out by a team co-led by Yakeel T. Quiroz, PhD, Assistant Professor at Harvard Medical School, and Director of the Familial Dementia Neuroimaging Lab at MGH. Their work was published in the June 1, 2020 issue of The Lancet Neurology. The article is titled “Plasma Neurofilament Light Chain in the Presenilin 1 E280A Autosomal Dominant Alzheimer's Disease Kindred: A Cross-Sectional and Longitudinal Cohort Study.” Additional co-first authors were Henrik Zetterberg, PhD, of Sahlgrenska University Hospital in Sweden, and Eric Reiman, MD, from the University of Arizona. "We wanted to determine the earliest age at which plasma NfL levels could distinguish individuals at high risk of Alzheimer's," says Dr. Quiroz, who is also an MGH Research Scholar 2020-2025. The researchers found that NfL levels increased with age among people at genetic risk because of a specific mutation (PSEN1 E280A) and began to differentiate carriers from noncarriers at age 22, an average of 22 years before their estimated age of cognitive impairment (age 44). Neurofilament light chain (NfL) is a biomarker of neurodegeneration-- damage to neurons. Measures of NfL concentrations in cerebral spinal fluid (CSF) and blood have been used to detect and track neurodegeneration in individuals with Alzheimer's disease and other brain disorders.

Antibody Designed to Detect & Quantify Toxic Amyloid-Beta Oligomers in Alzheimer's Disease; May Help Enable Early Disease Diagnosis, Disease Monitoring, and Drug Design

Researchers have found a way to design an antibody that can identify the toxic particles that destroy healthy brain cells in Alzheimer’s disease--a potential advance in the fight against this dire disease. The new method is able to recognize these toxic particles, known as amyloid-beta oligomers (image shows solution form of amyloid-beta peptide 1-42), which are the hallmark of the disease, leading to hope that new diagnostic methods can be developed for Alzheimer's disease and other forms of dementia. The team, from the University of Cambridge, University College London, and Lund University, designed an antibody that is highly accurate at detecting toxic oligomers and quantifying their numbers. Their results are reported in PNAS. "There is an urgent unmet need for quantitative methods to recognize oligomers--which play a major role in Alzheimer's disease, but are too elusive for standard antibody discovery strategies," said Professor Michele Vendruscolo, PhD, from Cambridge's Centre for Misfolding Diseases (https://www.cmd.ch.cam.ac.uk/) in the UK, who led the research. "Through our innovative design strategy, we have now discovered antibodies to recognize these toxic particles." Dementia is one of the leading causes of death in the UK and costs more than £26 billion (~$32 billion) each year, a figure which is expected to more than double in the next 25 years. Estimates put the current cost to the global economy at nearly £1 trillion (~$1.2 trillion) per year.

Codiak Presents New Preclinical Data Demonstrating Potential of EngEx™-Engineered Exosomes to Drive New Class of Molecular Medicines That Can Carry Specific Cargo to Targeted Cells

On May 15, 2020, Codiak BioSciences, Inc., a company at the forefront of advancing engineered exosomes as a new class of biologic medicines, announced new preclinical data on programs using its proprietary engEx Platform. Highlights included new preclinical data demonstrating the powerful adaptive immune response driven by its exoVACC™ vaccine platform compared to standard vaccine approaches and the first data on Codiak’s ability to utilize engEx to direct tropism for multiple cell types in vitro and in vivo. These data, which were presented at the 23rd Annual Meeting of the American Society of Gene & Cell Therapy (ASCGT) (https://annualmeeting.asgct.org/am20/), demonstrate the broad potential of engineered exosomes to serve as a foundation for new classes of molecular medicines to address complex, immune-mediated diseases. Exosomes are an important intercellular communication system, facilitating the transfer of molecular payloads between cells. They are mediated by a complex network of proteins and glycoproteins on the exosome surface that play a role in cellular tropism, uptake, and immune cell signaling. Utilizing its engEx Platform, Codiak can engineer exosomes with distinct properties, load them with various types of therapeutic molecules and alter tropism so they reach specific cell targets. Codiak is developing exosome product candidates to target multiple pathways throughout the body to treat various forms of cancer and, through its exoVACC modular vaccine platform, to enhance the immune response against a broad array of antigens. “The results that we are generating across our engEx Platform continue to confirm the potential of our engEx-engineered exosomes to be an entirely new modality capable of addressing diseases with unmet needs,” said Douglas E.

Prostaglandin Pair Activates Nurr1 Nuclear Receptor Transcription Factor & Boosts Dopamine Production, Offers Potential for Parkinson’s Disease Treatment, According to Results of NTU-Singapore & Harvard Study

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 7 to 10 million people worldwide. Patients with the illness have reduced levels of dopamine in the brain, causing them to have difficulty controlling motor movements, with symptoms such as tremor and rigidity of muscles in hands, arms, and legs. They can also develop some non-motor symptoms, like sleep disturbance, depression, and loss of smell. Through laboratory investigations and in vivo experiments, a team led by Professor Yoon HoSup, PhD, from the Nanyang Technological University (NTU) School of Biological Sciences in Singapore, and Professor Kwang-Soo Kim, PhD, from McLean Hospital and Harvard Medical School in the United States found that the “molecular pair,” prostaglandin E1 (PGE1), a type of hormone, and prostaglandin A1 (PGA1), can be the key to boosting dopamine levels and slowing Parkinson’s disease. PGE1 and PGA1 do this by binding to Nurr1, a class of proteins crucial to the development and maintenance of dopamine in the brain. [Editor’s Note: The nuclear receptor related 1 protein (Nurr1), also known as NR4A2 (nuclear receptor subfamily 4, group A, member 2) is a protein that in humans is encoded by the NR4A2 gene.[5] Nurr1 is a member of the nuclear receptor family of intracellular transcription factors. Image shows Nurr1 interacting with DNA.] The binding of these prostaglandins causes Nurr1 to be activated, resulting in a marked increase in dopamine production, while preventing dopamine-producing brain cells from dying. After activation of Nurr1, mice with a model of Parkinson’s disease showed significant improvements in their motor functions.

Blood Test of Moms Who Had Gestational Diabetes Could Predict Type 2 Diabetes Years Before It Strikes; Test Represents “Holy Grail of Personalized Medicine to Find Molecular Differences in Seemingly Healthy People & Predict Which Will Develop a Disease"

Scientists have identified metabolites in the blood that accurately predict whether a woman will develop type 2 diabetes after experiencing a transient form of illness (gestational diabetes) during pregnancy. This discovery could lead to a test that would help doctors identify patients at greatest risk and help them potentially avert the disease through interventions including diet and exercise. The research was led by Michael Wheeler, PhD, a Professor of Physiology at the University of Toronto’s Faculty of Medicine, in collaboration with Hannes Röst, PhD, an Assistant Professor of Molecular Genetics and Computer Science at the Donnelly Centre for Cellular and Biomolecular Research, Feihan Dai, PhD, a research scientist of physiology and Erica Gunderson, a research scientist at the Kaiser Permanente Division of Research in Northern California. Mi Lai, PhD, a post-doctoral fellow in Wheeler's group performed much of the analyses. "There is a metabolic dysregulation that occurs in the group of women that will go on to develop type 2 diabetes that is present in the early postpartum period, suggesting that there is an underlying problem that exists already and we can detect it," says Dr. Wheeler, who is also a senior scientist at Toronto General Hospital Institute at University Health Network. The identified metabolic signature can predict with over 85 per cent accuracy if a woman will develop type 2 diabetes (T2D), as described in a study published online on May 20, 2020 in PLOS Medicine.

Michigan State Scientists Solve Half-Century-Old Magnesium Dimer Mystery

Magnesium dimer (Mg2) is a fragile molecule consisting of two weakly interacting atoms held together by the laws of quantum mechanics. It has recently emerged as a potential probe for understanding fundamental phenomena at the intersection of chemistry and ultracold physics, but its use has been thwarted by a half-century-old enigma--five high-lying vibrational states that hold the key to understanding how the magnesium atoms interact but have eluded detection for 50 years. The lowest fourteen Mg2 vibrational states were discovered in the 1970s, but both early and recent experiments should have observed a total of nineteen states. Like a quantum cold case, experimental efforts to find the last five failed, and Mg2 was almost forgotten. Until now. Piotr Piecuch, PhD, Michigan State University (MSU) Distinguished Professor and MSU Foundation Professor of Chemistry, along with College of Natural Science Department of Chemistry graduate students Stephen H. Yuwono and Ilias Magoulas, developed new, computationally derived evidence that not only made a quantum leap in first-principles quantum chemistry, but finally solved the 50-year-old Mg2 mystery. Their findings were published in the April 3, 2020 issue of Science Advances. The open-access article is titled “Quantum Computation Solves a Half-Century-Old Enigma: Elusive Vibrational States of Magnesium Dimer Found.” "Our thorough investigation of the magnesium dimer unambiguously confirms the existence of 19 vibrational levels," said Dr. Piecuch, whose research group has been active in quantum chemistry and physics for more than 20 years.

May 26th

Results Suggest Organisms Have “Memory” of Their Ancestral Environments; Adjustments When Returned to Original Homeland Made Via “Plastic” Phenotypic Changes, Rather Than Mutations

Organisms carry long-term "memories" of their ancestral homelands that help them adapt to environmental change, according to a new study that involved raising chickens on the Tibetan Plateau and an adjacent lowland site. The study provides new insights into how creatures adapt to changing environments, a topic that's especially relevant today in the context of rapid climate change, which is creating challenges for plants and animals worldwide. The chicken was domesticated from the red jungle fowl (photo) in South Asia and Southeast Asia at least 4,000 to 4,500 years ago. It was brought to the Tibetan Plateau by about 1,200 years ago, where it acquired high-altitude adaptations such as an increase in oxygen-carrying red blood cells. In a set of experiments by University of Michigan (U-M) biologists and their Chinese colleagues, researchers hatched and reared hundreds of chickens on the Tibetan Plateau, at an elevation of nearly 11,000 feet, and at an adjacent lowland site in China's Sichuan Province. Some of the eggs from lowland chickens were hatched on the plateau, and some high-altitude eggs were hatched at a site 2,200 feet above sea level. The goal was to assess the relative contributions of two types of phenotypic change--meaning changes to an organism's observable physical characteristics or traits--to the process of environmental adaptation. "Plastic" phenotypic changes involve altered gene activity but no rewriting of the genetic code in DNA molecules, while mutations cause altered gene activity by modifying the sequence of letters in the code itself. Evolutionary biologists have debated the relative roles of plastic and mutation-induced changes in adaptation, and whether the former serve as stepping stones to the latter.

Merck and Ridgeback Bio Collaborate to Advance Development of Novel Antiviral Candidate, EIDD-2801, a Ribonucleoside Analog That Inihibits Replication of Viral RNA; Clinical Studies of EIDD-2801 for Treatment of Patients with COVID-19 Are Underway

On May 26, 2020, Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics LP (https://www.ridgebackbio.com/), a closely held biotechnology company,announ ced that the companies have entered into a collaboration agreement to develop EIDD-2801, an orally available antiviral candidate currently in early clinical development for the treatment of patients with COVID-19. “In addition to our efforts to develop potential vaccines to SARS-CoV-2, we have also been evaluating our own anti-viral assets and those from external sources for their potential to treat individuals with COVID-19,” said Roger M. Perlmutter, MD, PhD, President, Merck Research Laboratories. “Clinical evaluation of EIDD-2801 in COVID-19 patients is just beginning, now that phase 1 studies have demonstrated that the compound is well-tolerated. Because preclinical studies demonstrate that EIDD-2801 has potent antiviral properties against multiple coronavirus strains, including SARS-CoV-2, we are eager to advance the next phase of clinical studies as rapidly and responsibly as possible.” Under terms of the agreement, Merck, through a subsidiary, will gain exclusive worldwide rights to develop and commercialize EIDD-2801 and related molecules. Ridgeback Bio will receive an undisclosed upfront payment, specified milestones, and a share of the net proceeds of EIDD-2801 and related molecules, if approved. Merck will be responsible for clinical development, regulatory filings, and manufacturing. The transaction is subject to the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act, and other customary closing conditions.

Merck and IAVI Collaborate to Develop Vaccine Against SARS-CoV-2; New Collaboration to Leverage Complementary Expertise and Capabilities with rVSV Technology to Advance Novel Vaccine Candidate

On May 26, 2020, Merck (NYSE: MRK), known as MSD outside the United States and Canada, and IAVI (https://www.iavi.org/), a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges, announced a new collaboration to develop an investigational vaccine against SARS-CoV-2 to be used for the prevention of COVID-19. This vaccine candidate will use the recombinant vesicular stomatitis virus (rVSV) technology (image depicts VSV;see larger image below) that is the basis for Merck’s Ebola Zaire virus vaccine, ERVEBO® (Ebola Zaire Vaccine, Live), which was the first rVSV vaccine approved for use in humans. Merck has also signed an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response within an agency of the United States Department of Health and Human Services, to provide initial funding support for this effort. Under the agreement, IAVI and Merck will work together to advance the development and global clinical evaluation of a SARS-CoV-2 vaccine candidate designed and engineered by IAVI scientists. The vaccine candidate is in preclinical development, and clinical studies are planned to start later in 2020. Merck will lead regulatory filings globally. Both organizations will work together to develop the vaccine and make it accessible and affordable globally, if approved. “COVID-19 is an enormous scientific, medical, and global health challenge. Merck is collaborating with organizations around the globe to develop anti-infectives and vaccines that aim to alleviate suffering caused by SARS-CoV-2 infection,” said Roger M. Perlmutter, MD, PhD, President, Merck Research Laboratories.