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February 8th, 2020

Combination of Cryo-EM and Mass Spec Reveals New Insights into Post-Translational Modifications (PTMs) of Tau Protein; PTMs Mediate Structural Diversity of Toxic Tau Protein in Various Tauopathies Such As Alzheimer’s Disease

The tau protein has long been implicated in Alzheimer's disease and a host of other debilitating brain diseases. But scientists have struggled to understand exactly how tau converts from its normal, functional form into a misfolded, harmful one. Now, researchers at Columbia University's Zuckerman Institute and the Mayo Clinic in Florida, together with colleagues at Emory University and Arizona State University, have used cutting-edge technologies to see tau in unprecedented detail. By analyzing brain tissue from patients, this research team has revealed that modifications to the tau protein may influence the different ways it can misfold in a person's brain cells. These differences are closely linked to the type of neurodegenerative disease that will develop -- and how quickly that disease will spread throughout the brain. The study, published online on February 6, 2020 in Cell, employed two complementary techniques to map the structure of tau and decipher the effects of additional molecules, called post-translational modifications (PTMs), on its surface. These new structural insights could accelerate the fight against neurodegenerative diseases, by helping researchers identify new biomarkers that detect these disorders before symptoms arise and design new drugs that target specific PTMs, preventing the onset of disease before it wreaks havoc on the brain. The Cell article is titled “"Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains." "Tau has long been a protein of significant interest due to its prevalence in disease," said Anthony Fitzpatrick, PhD, a Principal Investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute, who led the study.

February 6th

Mayo Researchers Discover Way to Prime Cancer Tumors for Immunotherapy

A cancer tumor's ability to mutate allows it to escape from chemotherapy and other attempts to kill it. So, encouraging mutations would not seem to be a logical path for cancer researchers. Yet a Mayo Clinic team and their collaborators took that counterintuitive approach and discovered that, while it created resistance to chemotherapy, it also made tumors sensitive to immunotherapy. They also found that this approach worked successfully across tumor types and individual patient genomes. Their findings, involving mouse models and human cells, were published online on February 7, 2020 in Nature Communications. The open-access article is titled “APOBEC3B-Mediated Corruption of the Tumor Cell Immunopeptidome Induces Heteroclitic Neoepitopes for Cancer Immunotherapy.” The international team of researchers based in Rochester, Minnesota and London, and led by Richard Vile (photo), PhD, a Mayo Clinic Professor of Pediatric Oncology, studied models of both pediatric brain tumors and melanoma. They found that, in mice, high levels of the protein APOBEC3B drove a high rate of tumor mutations. Yet, at the same time, these levels of APOBEC3B also sensitized cells to treatment with immune checkpoint blockade, a major mechanism of immunotherapy. "When you put that in the context of vaccine therapy, the mutations generate neoepitopes, a type of peptide that is a prime target for killer T cells," says Dr. Vile. "So that, combined with the checkpoint blockade, make for a potential cross-tumor therapy." The results showed a high rate of cures in subcutaneous melanoma and brain tumor models, and effectiveness no matter the tumor type or location. The results also showed that an individualized approach for each patient is not required.

Breakthrough in Study of Age-Related Macular Degeneration (AMD), the Most Common Cause of Blindness: Complement System-Activating Protein (FHR4) Shown to Be Closely Linked to AMD; Finding May Enable Both Risk Assessment & Treatment

An international team of scientists has identified a protein that is strongly linked to the commonest cause of blindness in developed countries when its levels are raised in the blood. The discovery is a major step forward in the understanding of age-related macular degeneration (AMD), which affects 1.5 million people in the UK alone. The study, carried out by a team from the Universities of Manchester, Cardiff, London, and Nijmegen, and Manchester Foundation NHS Trust was published online on February 7, 2020 in Nature Communications. The open-access article is titled “"Increased Circulating Levels of Factor H Related Protein 4 Are Strongly Associated with Age-Related Macular Degeneration." The protein, Factor H-Related Protein 4 (FHR4), was found by the team to be present at higher levels in the blood of patients with AMD compared to individuals of a similar age without the disease. The findings were confirmed in 484 patient and 522 control samples from two independent collections across Europe. Analyses of eyes donated for research after life also revealed the Factor FHR4 protein was present in the AMD-affected parts of the eye. FHR4 was shown by the team to activate part of the immune system -called the complement system; over-activation of the complement system was already known to be a major causal factor of AMD. FHR4 is one of a group of proteins that regulate the complement system and the genes encoding these proteins are tightly clustered on chromosome 1, the largest human chromosome. When the team investigated a set of genetic variants across the human genome, they found that genetic variants in this region on chromosome 1 determined the levels of FHR4 in the blood. And they found that the same genetic variants were associated with AMD.

February 6th

Yale Researchers Find That Ubiquitous Cellular Protein, Polycystin 2, When Unmutated, Plays Lead Role In Cell Survival; When Mutated, It Can Cause Polycystic Kidney Disease (PKD)

The protein known as polycystin 2 is present in every cell in the body, but, until now, scientists knew little about its purpose. Yale researchers; together with colleagues at the University of Illinois at Urbana, the Washington University School of Medicine in St. Louis, and Heidelberg University; have discovered that it protects against cell death, making it a potential target for therapies to treat a variety of diseases of the liver and kidneys, as well as for brain aneurysms, heart disease, and cancer. Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant transient receptor potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. The new research on polycystin 2 was reported online on January 15, 2020 in Scientific Reports. The open-access article is titled “Polycystin 2 Is Increased in Disease to Protect Against Stress-Induced Cell Death.” There are over 6 million protein species in the human body, and scientists are still learning the key roles these proteins play. In the case of polycystin 2, researchers had almost exclusively focused on the protein’s role in polycystic kidney disease (PKD), specifically autosomal dominant PKD (AD-PKD), from which the protein draws its name. When polycystin 2 is mutated, it triggers the disease, which is characterized particularly by the development of large, fluid-filled cysts in the kidney, causing renal failure that necessitates a kidney transplant. “No one knew any function for this protein other than when it was mutated,” said Barbara Ehrlich (at left in photo), PhD, Yale Professor of Pharmacology and of Cellular and Molecular Physiology, who co-led the study with graduate student Allison Brill (at right in photo), 2020 Yale Graduate School of Arts & Sciences (GSAS).

Unprecedented Analyses of More Than 2,600 Whole Genome Sequences from 38 Different Tumor Types Results in 21 Studies Published Simultaneously in Nature Journals; One Suggests Many Cancer Mutations Occur Years Before the Cancer Develops

In a virtually unprecedented event, 21 open-access research papers arising from the monumental efforts of the ICGC/TCGA consortium on whole genome sequencing and integrative analysis of cancer have been published simultaneously online on February 5, 2020, in the following journals published by Nature: Nature Communications (8), Nature (6), Nature Genetics (5), Nature Biotechnology (1), and Communications Biology (1). The work is based on an international collaboration of over 1,300 scientists and clinicians from 37 countries known as the Pan-Cancer Analysis of Whole Genomes (PCAWG). The effort involved analysis of more than 2,600 genomes of 38 different tumor types, creating a huge resource of primary cancer genomes. The flagship paper is titled “Pan-Cancer Analysis of Whole Genomes.” In this BioQuick post, another one of the 21 articles (“The Evolutionary History of 2,658 Cancers”) is described. The the titles and links for all 21 articles are provided following description of the Evolutionary History article. In addition, related articles, including editorials and a News & Views article are provided at the end. Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI) and the Francis Crick Institute in the UK have analyzed the whole genomes of over 2r,600 tumors from 38 different cancer types to determine the chronology of genomic changes during cancer development. Cancer occurs as part of a lifelong process in which our genome changes over time. As we age, our cells cannot maintain the integrity of the genome after cell division without making some errors (mutations). This process can be accelerated by various genetic predispositions and environmental factors, such as smoking. Over our lifetimes, these mutations build up and cells may be mis-programmed, leading to cancer.

February 5th

New Route Developed for Synthesis of Deadly Mushroom Toxin Amanitin, Which Is Potentially Useful Therapeutically; Method May Allow Toxin to Be Produced at Industrial Scale, Thus Enabling Possibly Rapid Research Advances

The death cap mushroom (Amanita phalloides) is highly toxic. However, some of its toxins can also be healing when used appropriately: for instance, amanitins are potential components for antibody-based cancer treatments. In the journal Angewandte Chemie, German, in an article published online on December 17, 2019, scientists have now described a new synthetic route for α-amanitin. The open-access article is titled “A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin.” Their method seems suitable for production on a larger scale, finally making enough of the toxin available for further research. Amanitins inhibit the enzyme RNA polymerase II with high selectivity, which leads to cell death. When transported into tumor cells by antibodies, the toxin could fight tumors. Until recently, however, the only source of amanitins was the mushrooms (Amanita phalloides) themselves, which limited the possibilities for experimentation. Some time ago, a total synthesis was reported for α-amanitin, the most powerful amanitin. Researchers working with Roderich D. Süssmuth, PhD, at the Technical University of Berlin have now introduced an alternative route for a total synthesis that occurs entirely in the liquid phase, allows for the possibility of producing different structural variants, and can be implemented on a larger scale. “We decided to use a convergent route, meaning that several components are first synthesized independently and then finally put together to form the target molecule,” explains Dr. Süssmuth. The building blocks are three peptide fragments made of five, one, and two amino acids. The researchers refer to their method as a [5+1+2] synthesis.

Unlocking the Secrets of Cell Regulation: Researches at University of Bonn Investigate Structure of Long RNAs; Develop New Method to Accurately Measure RNA Lengths

Ribonucleic acids (RNA) ensure that the blueprint in the cell nucleus is translated into vital proteins and that cell functions are regulated. However, little is known about the structure and function of particularly long RNAs, which consist of hundreds or thousands of building blocks. Chemists at the University of Bonn have now developed a new method for this purpose: They mark the complex molecules with tiny "flags" and measure the distances between them with a "molecular ruler". The results are published online on January 25, 2020 in Angewandte Chemie International Edition. The article is titled “EPR Distance Measurements on Long Non-Coding RNAs Empowered by Genetic Alphabet Expansion Transcription.” In living cells, everything follows a plan: The blueprints for all building and operating materials are stored in the cell nucleus. If, for example, a certain protein is required, the genetic information is read from the DNA and translated into ribonucleic acid (RNA). The RNA transmits the blueprint to the cell's "protein factories", the ribosomes. "However, more than 80 percent of ribonucleic acids are not involved in the production of proteins at all," says Dr. Stephanie Kath-Schorr (photo) from the LIMES Institute at the University of Bonn. This so-called "non-coding" RNA is probably involved in various regulatory processes in the cell. Scientists would like to gain a much better understanding of the control processes that non-coding RNA is responsible for. "To do this, however, we must first understand the structures of ribonucleic acids and how they are folded," says Kath-Schorr. The spatial structure seems to have an important role in the function of RNA. It determines which molecules a certain RNA binds to and therefore triggers important processes in the cell.

Scientists Find Long Non-Coding RNA (lncRNA) Affecting Skin Cancer Progression; PRECSIT lncRNA Promotes Growth & Spread of Cutaneous Squamous Cell Carcinoma

Researchers at the University of Turku, Turku University Central Hospital, and Western Cancer Center (FICAN West) have discovered a newly identified long non-coding (lnc) RNA molecule (PRECSIT) that regulates the growth and invasion of squamous cell carcinoma of the skin. In the future, PRECSIT lnc RNA could potentially serve as a new marker for the detection of rapidly advancing or spreading squamous cell carcinoma and as a target for new therapies. Skin cancers are the most common cancers in the world and their incidence is increasing. Squamous cell carcinoma is the most common metastatic skin cancer and its incidence is increasing worldwide. Long-term exposure to the sun's ultraviolet radiation is the most important risk factor for the development of this type of cancer. Squamous cell carcinoma of the skin is characterized by a significant gene mutation burden of cancer cells resulting from long-term exposure to the sun's ultraviolet radiation. Several gene mutations predisposing to skin cancer are known, but the importance of non-coding RNA molecules of the so-called dark side of the genome in the development of squamous cell carcinoma is still unclear, says Professor Veli-Matti Kähäri, MD, PhD, from the Department of Dermatology at the University of Turku in Finland. The majority of the human genome contains genes that do not produce protein, but their role as regulators of cellular functions is still essential. Long non-coding RNAs (lncRNAs) are a largely unknown set of RNAs and recent studies have found that they play a role in regulating signaling pathways, particularly in cancer, says researcher Minna Piipponen, PhD, one of the authors of the study. Thus, RNA molecules could be utilized in cancer diagnostics as specific marker molecules and as targets for new therapies.

February 4th

11th Annual Precision Medicine World Conference (PMWC 2020) Opens with Awards Ceremony at Genentech Hall, UCSF Mission Bay; Awards Given to Three Major Contributors to Advance of Precision Medicine—Philip Greenberg, Laura van’t Veer, & Brook Byers

The Precision Medicine World Conference (PMWC 2020) opened its eleventh annual meeting ("How Do We Accelerate Precision Medicine and Deliver on Its Promises?”) centered in Silicon Valley on Tuesday evening, January 21, with an awards ceremony at Genentech Hall at UCSF Mission Bay in South San Francisco. (Editor’s Note: Including smaller regional meetings, the PMWC has organized 17 precision medicine meetings in total, since its inaugural Silicon Valley conference in 2009). UCSF was one of three co-hosts of this conference. The other hosts were Stanford Health and the Institute for Precision Medicine, a partnership of the University of Pittsburgh and the University of Pittsburgh Medical Center. The Awards ceremony honored three distinguished contributors to the advance of precision medicine. The MC of the PMWC Awards ceremony was Keith Yamamoto, PhD, Chancellor for Research, Executive Vice Dean of the School of Medicine, and Professor of Cellular and Molecular Pharmacology at UCSF. PMWC Luminary Awards were presented to Philip Greenberg (photo here, see additional event photos at end), MD, Head, Program in Immunology, Fred Hutchinson Cancer Research Center; Professor of Medicine and Immunology, University of Washington; and Member, Parker Institute for Cancer Immunology; and to Laura J. van’t Veer, PhD., Inventor, MammaPrint; Professor of Laboratory Medicine, and Director, Applied Genomics, UCSF Helen Diller Family Comprehensive Cancer Center. The PMWC Luminary Award recognizes individuals who have made significant contributions to accelerate personalized medicine within the clinical setting. Dr. Greenberg received his Luminary Award for “discoveries that led to adoptive immunotherapy with genetically engineered T cells.” Dr.

Developing Brain Is Key Regulator of Innate Immunity in Embryo; Brain Somehow “Senses” Bacterial Pathogens and Sends Signals to Immune Cells Directing Them to Site of Infection

Researchers led by biologists at Tufts University in Boston have discovered that the brains of developing embryos provide signals to a nascent immune system that help it ward off infections and significantly improve the embryo's ability to survive a bacterial challenge. Using frog embryos, which continue to develop with their brains removed, the researchers found that embryos without a brain are not able to marshal the forces of immune cells to an injury or infection site, leading the embryo to succumb to an infection more quickly. By contrast, the presence of a brain crucially helps direct immune cells to the site of injury to overcome the bacterial threat. The study was published online on February 4, 2020 in NPJ Regenerative Medicine. The open-access article is titled “An In Vivo Brain-Bacteria Interface: The Developing Brain As a Key Regulator of Innate Immunity." In a developing embryo, both brain and immune system are not fully formed. The immune system, for its part, consists mostly of an "innate" system of cells that respond immediately to infection and do not require training or produce antibodies. Nevertheless, these cells require signals that prompt them to move toward an infection site and trigger a response. The research team found that the brain appears to contribute to the signals that guide the nascent immune system. When brainless frog embryos were infected with E. coli, only about 16% of embryos survived, while the presence of a brain protected more than 50% from the infection. By following markers of immune cells, researchers confirmed that the effect is not due to the missing brain somehow hampering immune system development because the composition of the immune cells remained the same with or without a brain.