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High-Throughput Proteomics Strategy Used in Effort to Identify Multiple Highly Potent & Specific Nanobodies from Llamas; Possible Uses of Such Nanobodies, Which Can Be Identified Quickly and Inexpensively, Are “Tremendous,” Author States

By capitalizing on a convergence of chemical, biological, and artificial intelligence advances, University of Pittsburgh (Pitt) School of Medicine scientists, and colleagues from Hebrew University in Jerusalem, have developed an unusually fast and efficient method for discovering tiny antibody fragments with big potential for development into therapeutics against deadly diseases. The technique, published online on February 15, 2021 in the journal Cell Systems, is the same process the Pitt team used to extract tiny SARS-CoV-2 antibody fragments from llamas, which could become an inhalable COVID-19 treatment for humans. The new article is titled “Integrative Proteomics Identifies Thousands of Distinct, Multi-Epitope, and High-Affinity Nanobodies.” This approach has the potential to quickly identify multiple potent nanobodies that target different parts of a pathogen--thwarting variants. "Most of the vaccines and treatments against SARS-CoV-2 target the spike protein, but if that part of the virus mutates, which we know it does, those vaccines and treatments may be less effective," said senior author Yi Shi, Ph.D., Assistant Professor of Cell Biology at Pitt. "Our approach is an efficient way to develop therapeutic cocktails consisting of multiple nanobodies that can launch a multipronged attack to neutralize the pathogen." Dr. Shi and his team specialize in finding nanobodies--which are small, highly specific fragments of antibodies produced by llamas and other camelids. Nanobodies are particularly attractive for development into therapeutics because they are easy to produce and bioengineer. In addition, they feature high stability and solubility, and can be aerosolized and inhaled, rather than administered through intravenous infusion, like traditional antibodies.

New Immunotherapy Target (CD161) Discovered for Malignant Brain Tumors

Scientists say they have discovered a potential new target for immunotherapy of malignant brain tumors, which so far have resisted the ground-breaking cancer treatment based on harnessing the body's immune system. The discovery, reported online on February 15, 2021 in CELL, emerged from laboratory experiments and has no immediate implications for treating patients. The article is titled “Inhibitory CD161 Receptor Identified in Glioma-Infiltrating T Cells by Single-Cell Analysis.” Scientists from Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard said the target they identified is a molecule that suppresses the cancer-fighting activity of immune T cells, the white blood cells that seek out and destroy virus-infected cells and tumor cells. The scientists said the molecule, called CD161, is an inhibitory receptor that they found on T cells isolated from fresh samples of brain tumors called diffuse gliomas. Gliomas include glioblastoma, the most aggressive and incurable type of brain tumor. The CD161 receptor is activated by a molecule called CLEC2D on tumor cells and immune-suppressing cells in the brain, according to the researchers. Activation of CD161 weakens the T cell response against tumor cells. To determine if blocking the CD161 pathway could restore the T cells' ability to attack the glioma cells, the researchers disabled it in two ways: they knocked out the gene called KLRB1 that codes for CD161, and they used antibodies to block the CD161-CLEC2D pathway. In an animal model of gliomas, this strategy strongly enhanced the killing of tumor cells by T cells, and improved survival of the animals.

Avian Model Allows Insights into Human Ciliopathies; Ciliopathic Micrognathia (Underdeveloped Lower Jaw) in Chick Model Results from Abnormal Skeletal Differentiation & Remodeling

Ciliopathies are genetic disorders caused by defects in the structure and function of cilia, microtubule-based organelles present on the surface of almost every cell in the human body which play crucial roles in cell signaling. Ciliopathies present a wide range of often severe clinical symptoms, frequently affecting the head and face and leading to conditions such as cleft palate and micrognathia (an underdeveloped lower jaw that can impair feeding and breathing). In addition, the human ciliopathies include autosomal dominant polycystic kidney disease (ADPKD), a serious disease that affects approximately 600,000 in the United States, and autosomal recessive PKD, which is rare, affecting just 1 in 20,000 births, but also very serious. While we understand many of the genetic causes of human ciliopathies, they are only half the story: the question remains as to why, at a cellular level, defective cilia often cause developmental craniofacial abnormalities. Researchers have now discovered that ciliopathic micrognathia in an animal model results from abnormal skeletal differentiation and remodeling. The work from Christian Bonatto Paese, PhD, Evan Brooks, and others from Samantha Brugmann's (photo) (PhD) lab at the Cincinnati Children's Hospital Medical Center in the USA is published in Development. The article is titled “Ciliopathic Micrognathia Is Caused by Aberrant Skeletal Differentiation and Remodeling.” The researchers used the avian ta2 mutant as a model for Oral-Facial-Digital syndrome subtype 14 (OFD14), a rare human ciliopathy characterized by micrognathia. They observed defective formation of the jaw bone (mandible) at early stages of development in ta2 mutants. These defects correlated with unchecked progression through the cell cycle and over-proliferation in skeletal progenitor cells.

Robert Weinberg and Bert Vogelstein Share 2021 Japan Prize for Medical Science and Medicinal Science

In a January 29, 2021 announcement, the Japan Prize Foundation named MIT Professor Robert Weinberg (photo), PhD, as one of the recipients of its 2021 awards in the category of Medical Science and Medicinal Science, citing Dr. Weinberg’s contributions to the development of a multi-step model of how cancer begins and progresses, and the application of that model to improve cancer treatments and outcomes. Dr. Weinberg, along with co-recipient Bert Vogelstein (photo below), MD, of the Johns Hopkins University School of Medicine, will receive the award in April at a presentation ceremony attended by the emperor and empress of Japan. “Dr. Weinberg’s work has led to the identification of critical genes for cancer development that have subsequently been approved as therapeutic targets, resulting in thousands of lives being saved,” writes the Japan Prize Foundation in its news release. “This award is a tribute to the brilliant scientists who have worked alongside me during my time at the Whitehead Institute,” says Dr. Weinberg, a Whitehead Institute founding member who is the Daniel K. Ludwig Professor for Cancer Research at MIT, as well as an extramural member of the David H. Koch Institute for Integrative Cancer Research at MIT. In 1979, Dr. Weinberg and his lab discovered the first gene associated with tumor formation in humans, also known as an oncogene. In the decades since, he has devoted his career to studying not only the genetic basis of cancer, but also the ways in which cancerous cells spread and proliferate throughout the body. His work, along with Dr. Vogelstein’s, is credited with the development of new areas of cancer research, including the idea of targeted cancer therapies, and the broader field of precision medicine.

Tuning the Circadian Clock; Boosting Rhythms May Be Key to Future Treatments and Medicines; New Article Unravels Remarkable Relationship Between Time-of-Day and Physiology

Subconsciously, our bodies keep time for us through an ancient means--the circadian clock. A new University of California, Irvine (UCI)-led article reviews how the clock controls various aspects of homeostasis, and how organs coordinate their function over the course of a day. "What is fascinating is that nearly every cell that makes up our organs has its own clock, and thus timing is a crucial aspect of biology," said Kevin B. Koronowski, PhD, lead author and a postdoctoral fellow in Biological Chemistry at the UCI School of Medicine. "Understanding how daily timing is integrated with function across organs has implications for human health, as disruption of the clock and circadian rhythms can be both a cause and effect of diseases from diabetes to cancer." The circadian clock generates a ~24-hour rhythm that controls behavior, hormones, the immune system, and metabolism. Using human cells and mice, researchers from the Paolo Sassone-Corsi Laboratory at UCI's Center for Epigenetics and Metabolism aim to uncover the physiological circuits, for example between the brain and liver, whereby biological clocks achieve coherence. The scientists’ work, titled, "Communicating Clocks Shape Circadian Homeostasis," was published in the February 12, 2021 issue of Science.Circadian clocks align internal processes with external time, which enables diverse lifeforms to anticipate daily environmental changes such as the light-dark cycle. In complex organisms, clock function starts with the genetically encoded molecular clock or oscillator within each cell and builds upward anatomically into an organism-wide system. Circadian misalignment, often imposed in modern society, can disrupt this system and induce adverse effects on health if prolonged.

Pigs Show Potential for “Remarkable” Level of Behavioral, Mental Flexibility in New Study; Researchers Teach Four Animals to Play Rudimentary Joystick-Enabled Video Game That Demonstrates Conceptual Understanding Beyond Simple Chance

Pigs will probably never be able to fly, but new research is revealing that some species within the genus Sus may possess a remarkable level of behavioral and mental flexibility. A study published online on February 11, 2021 in Frontiers in Psychology tested the ability of four pigs to play a simple joystick-enabled video game. The article is titled “Acquisition of a Joystick-Operated Video Task by Pigs (Sus scrofa).” “Each animal demonstrated some conceptual understanding despite limited dexterity on tasks normally given to non-human primates to analyze intelligence. The study involved two Yorkshire pigs named Hamlet and Omelette, and two Panepinto micro pigs, Ebony and Ivory. All four animals were trained to approach and manipulate a joystick with their snouts in front of a computer monitor during the first phase of the experiment. They were then taught how to play a video game in which the goal was to move a cursor using the joystick toward up to four target walls on the screen. Each pig performed the tasks well above chance, indicating the animal understood that the movement of the joystick was connected to the cursor on the computer screen. The fact that these far-sighted animals with no opposable thumbs could succeed at the task is "remarkable," according to the researchers. "It is no small feat for an animal to grasp the concept that the behavior they are performing is having an effect elsewhere. That pigs can do this to any degree should give us pause as to what else they are capable of learning and how such learning may impact them," said lead author Candace Croney, PhD, a professor at Purdue University and Director of the Purdue Center for Animal Welfare Science. Sarah T. Boysen, PhD, known for her work on chimpanzee cognition, co-authored the study.

Rabies Immune Globulin (Human) Treatment Demonstrated As Safe and Effective for Use in Children in First Pediatric Trial Study; Results Have Been Submitted to US FDA for Review

A treatment, known as KEDRAB (Rabies Immune Globulin [Human]), currently used in the prevention of rabies has been demonstrated to be safe and effective for patients age 17 and under. Results published online on February 10, 2021 in Human Vaccines & Immunotherapeutics report the first and only pediatric trial of any human rabies immunoglobulin (HRIG) currently available in the US. The open-access article is titled “Safety and Efficacy of Rabies Immunoglobulin in Pediatric Patients with Suspected Exposure.” Findings have been submitted to the US Food and Drug Administration (FDA) for review. In the United States, someone is treated for possible exposure to rabies every 10 minutes. Globally, the World Health Organization (WHO) estimates that rabies causes 59,000 human deaths annually in over 150 countries, with 95% of cases occurring in Africa and Asia—however, they concede it is likely a gross underestimate of the true burden of disease. The WHO also estimates that 40% of the global rabies disease burden occurs in children under 15 years of age, and that most encounters of the disease follow a dog bite. Once clinical symptoms appear; rabies is virtually 100% fatal. The current treatment for previously unvaccinated people potentially exposed to rabies is called rabies post-exposure prophylaxis (PEP), which includes thorough wound washing, passive neutralization of the virus with infiltration of human rabies immune globulin (HRIG) into and around the wound site, and a series of 4 doses of rabies vaccine given over a 2-week timeframe. And in this latest study carried out by a team of international experts from the US and Israel, KEDRAB® (HRIG150) has become the first HRIG shown to be safe and effective in children when administered promptly and properly as part of the rabies PEP process.

Novel Protein (NAMPT) Could Reverse Severe Muscle Wasting in Disease, Aging, and Trauma; NAMPT Triggers Muscle Stem Cells to Regenerate Muscle; Complete Muscle Replacement & Movement Achieved in Mouse Models

When a muscle is torn, stem cells within the muscle normally repair the problem. This occurs, not only in severe muscle wasting diseases such as muscular dystrophy and in war veterans who survive catastrophic limb injuries, but also in our day-to-day lives when we simply pull a muscle. Also, when we age and become frail, we lose much of our muscle and our stem cells don't seem to be able to work as well as they once did. The muscle stem cells are invisible engines that drive the tissue's growth and repair after muscle injuries and may, when working well, be able to also drive regeneration of muscle in the elderly when they are losing muscle and becoming frail. But growing muscle stem cells in the lab and then using them to therapeutically replace damaged muscle has been frustratingly difficult. Researchers at the Australian Regenerative Medicine Institute at Monash University in Melbourne, Australia have discovered a protein that triggers these muscle stem cells to proliferate and heal. In a mouse model of severe muscle damage, injections of this naturally occurring protein (NAMPT-- nicotinamide phosphoribosyltransferase) (image) led to the complete regeneration of muscle and the return of normal movement after severe muscle trauma. The research led by Professor Peter Currie, Director of Monash University's Australian Regenerative Medicine Institute, was published online on February 10, 2021 in Nature. The article is titled “Macrophages Provide a Transient Muscle Stem Cell Niche Via NAMPT Secretion.” The scientists studied the regeneration of skeletal muscle in zebrafish, fast becoming the go-to animal model for the study of stem cell regeneration because the fish are quick to reproduce, easier to experimentally manipulate, and share at least 70 percent of their genes with humans.

Unusual Characteristics of Certain Exosomes May Stem from Their Possible Ancient Evolutionary Origin Prior to Cells and Make Them Superior to Man-Made Nanoparticles for Therapeutic Purposes, Yale Professor Maintains

In a review article published online on January 31, 2021 in the International Journal of Molecular Sciences, Philip W. Askenase (photo), MD, Professor of Medicine and Pathology, Section of Rheumatology and Clinical Immunology, Department of Internal Medicine, Yale School of Medicine, (and former 30-Year Chief of Allergy & Immunology at Yale School of Medicine), strongly suggests that some cell-produced exosome subsets have a number of special properties that may be related to their hypothesized long evolution, perhaps ultimately traceable to before the origin of cells themselves. He argues that these special, long-evolved properties make these exosomes superior to man-made nanoparticles for the therapeutic purposes that artificial nanoparticles are developed for today, but which have seen little success. The open-access article by Dr. Askenase is titled “Ancient Evolutionary Origin and Properties of Universally Produced Natural Exosomes Contribute to Their Therapeutic Superiority Compared to Artificial Nanoparticles,” Int. J. Mol. Sci. 2021, 22, 1429. ( Askenase explains that exosomes are among a group of natural nano-sized extracellular vesicles (EVs) that are made by all cells of all species and are present in all bodily fluids so far examined. Exosomes are “newly recognized, fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases,” and are about a millionth the size of the donor cells they come from, he says. These tiny double-membrane-bounded EVs are present in the blood at concentrations of billions per milliliter, as they are contributed by virtually all the cells of the body, while leukocytes are present in the blood at concentrations of only thousands per milliliter.

Common Anti-Depressant (Paroxetine, an SSRI) May Be First-Ever Treatment for Osteoarthritis

A disease of the joints, osteoarthritis affects more than 30 million adults and is the fifth-leading cause of disability in the United States. In a new study, scientists have discovered the cellular pathway that leads to osteoarthritis and have identified a commonly used anti-depressant (paroxetine) that inhibits this pathway. The team found that paroxetine not only slows down cartilage degeneration, but also promotes cartilage health in both mice and human cartilage in vitro. The drug may be the first-ever treatment for this debilitating, degenerative disease. “Osteoarthritis destroys joint cartilage and results in pain and disability,” said Fadia Kamal, PhD, Assistant Professor of Orthopedics and Rehabilitation at Penn State College of Medicine. “Patients live with this pain until their cartilage is extremely degenerated. Unfortunately, an invasive artificial joint replacement surgery is the only treatment orthopedists are currently able to offer. There has been a dire need to identify novel therapeutic targets, [and] approaches or agents that can actively halt or reverse the osteoarthritis disease process.” In previous research, Dr. Kamal and her colleagues found that increased production and activity of a particular enzyme, G protein-coupled receptor kinase 2 (GRK2), led to harmful cell growth in heart and kidney disease. Dr. Kamal, who holds doctorate degrees in cell physiology and pharmacy, explained that osteoarthritis is similarly driven by uncontrolled growth of cartilage cells, a process called chondrocyte hypertrophy, but how this proliferation occurs had been a mystery. Given their knowledge of the role of GRK2 in heart and kidney disease, Dr. Kamal and her team decided to investigate the enzyme in osteoarthritis patients.

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