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Archive - Feb 6, 2018

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More Structured Senescence May Be Another Clue to Long Life Span and Cancer Resistance of Naked Mole Rat

With their large buck teeth and wrinkled, hairless bodies, naked mole rats won't be winning any awards for cutest rodent. But their long life span--they can live up to 30 years, the longest of any rodent--and remarkable resistance to age-related diseases, offer scientists key clues to the mysteries of aging and cancer. That's why University of Rochester biology professors Vera Gorbunova, PhD, and Andrei Seluanov, PhD, and postdoctoral associate Yang Zhao, PhD, studied naked mole rats to see if the rodents exhibit an anticancer mechanism called cellular senescence--and, if so, "how the mechanism might work differently than in short-lived animals, like mice," says Dr. Zhao, the lead author of the study, published online on February 5, 2018 in PNAS. The article is titled “Naked Mole Rats Can Undergo Developmental, Oncogene-Induced and DNA Damage-Induced Cellular Senescence.” Cellular senescence is an evolutionary adaptation that prevents damaged cells from dividing out of control and developing into full-blown cancer. However, senescence has a negative side too: by stopping cell division in order to prevent potential tumors, it also accelerates aging. Previous studies indicated that when cells that had undergone senescence were removed from mice, the mice were less frail in advanced age as compared to mice that aged naturally with senescent cells intact. Researchers therefore believed senescence held the key to the proverbial fountain of youth; removing senescent cells rejuvenated mice, so perhaps it could work with human beings. Companies began investigating drugs--known as senolytic agents--that would kill senescent cells and translate the anti-aging effects to humans.

Structure of Full-Length Serotonin Receptor Imaged for First Time by Cryo-EM; Results May Drive “Targeted Drug Design and Better Therapeutic Strategies”

A team of researchers from Case Western Reserve University School of Medicine has used Nobel-prize-winning electron microscope technology (cryo-EM) to image full-length serotonin receptors for the first time. The tiny proteins--approximately a billionth of a meter long--are common drug targets, despite limited available information about their structure. Now, new images published online on February 6, 2018 in Nature Communications provide snapshots of the receptors, including details about molecular binding sites that could lead to more precise drug design. The open-access article is titled “Cryo-EM Structure of 5-HT3A Receptor in Its Resting Conformation.” Serotonin receptors sit in cell membranes throughout the body, including membranes in the brain, stomach, and nerves. These receptors are highly dynamic with many moving parts, making them difficult subjects to capture in images. Researchers commonly break the receptor into pieces to study it. But by studying full-length serotonin receptors, researchers in the new study showed how its different portions interact. The researchers describe "a finely-tuned orchestration of three domain movements" that allows the receptors to elegantly control passageways across cell membranes. The study reveals how serotonin receptors work, says study first author Sandip Basak, PhD, a postdoctoral fellow in the Department of Physiology and Biophysics at Case Western Reserve University School of Medicine. "The serotonin receptor acts as a gateway, or channel, from outside the cell to inside," he says. "When serotonin binds onto the receptor, the channel switches conformation from closed to open. It eventually twists into a 'desensitized' state, where the channel closes but serotonin remains attached.

New CRISPR/Cas9 Gene-Editing Technique Abolishes Splice Sites for Frequently Mutated Exons in Duchenne Muscular Dystrophy (DMD) Heart Muscle Cells

Scientists have developed a CRISPR/Cas9 gene-editing technique that can potentially correct a majority of the 3,000 mutations that cause Duchenne muscular dystrophy (DMD) by making a single cut at strategic points along the patient’s DNA, according to a study from the University of Texas (UT) Southwestern Medical Center. The method, successfully tested in heart muscle cells from patients, offers an efficient alternative to the daunting task of developing an individualized molecular treatment for each gene mutation that causes DMD. It also opens up possible new treatment approaches for other diseases that have thus far required more intrusive methods to correct single-gene mutations. Scientists say the new strategy enhances the accuracy for surgical-like editing of the human genome, correcting mistakes in the DNA sequence that cause devastating diseases like DMD, a deadly condition caused by defects in the dystrophin gene. Normally, the dystrophin protein helps strengthen muscle fibers. “This is a significant step,” said Dr. Eric Olson, Director of UT Southwestern’s Hamon Center for Regenerative Science and Medicine. “We’re hopeful this technique will eventually alleviate pain and suffering, perhaps even save the lives, of DMD patients who have a wide range of mutations and, unfortunately, have had no other treatment options to eliminate the underlying cause of the disease.” A study published online on January 31, 2018 in Science Advances documents the success of the new CRISPR/Cas9 gene-editing technique designed to treat DMD. The open-access article is titled “Correction of Diverse Muscular Dystrophy Mutations in Human Engineered Heart Muscle by Single-Site Genome Editing.” In the article abstract, the authors, including Dr. Olson, state the following.

Arginine May Have Played Key Role in Origin of Life; Finding Would Put Constraints on Types of Scenarios That Could Have Given Rise to the Genetic Code

Life as we know it originated roughly 3.5 to 4 billion years ago in the form of a prebiotic soup of organic molecules that somehow began to replicate themselves and pass along a genetic formula--or so goes the thinking behind the RNA World, one of the most robust hypotheses on the origin of life. Researchers at the University of California-Santa Barbara (UCSB) have now found evidence that the amino acid arginine (or its prebiotic world equivalent) may have been a more important ingredient in this soup than previously thought. "People tend to think of arginine as not being prebiotic," said Irene Chen, MD, PhD, a biophysicist whose research focuses on the chemical origins of life. "They tend to think of the simpler amino acids as being plausible, such as glycine and alanine." Arginine, by contrast, is relatively more complex, and was therefore thought to have entered the game at a later stage. Primordial Earth, according to the RNA World theory, had the conditions to host several types of biomolecules, including nucleic acids (which become genetic material), amino acids (which eventually link to form the proteins that are responsible for structure and function of cells), and lipids (which store energy and protect cells). Under what circumstances and how these biomolecules worked together is a source of ongoing investigation for researchers of the origins of life. For their investigation, the UCSB scientists analyzed a dataset of in vitro evolved complexes of proteins and aptamers (short RNA and DNA molecules that bind to specific target proteins).

Exosomes from Non-Metastatic Melanoma Can Stimulate Immune Response That Prevents Metastasis, Study Shows

Northwestern Medicine scientists have demonstrated that tiny vesicles (exosomes) released from non-metastatic melanoma cells trigger an immune response that prevents the cancer from spreading throughout the body. Michael Plebanek, a doctoral student in Feinberg’s Driskill Graduate Program in Life Sciences (DGP) at Northwestern Medicine, is the first author of the study, published on November 6, 2017 in Nature Communications. The open-access article is titled “Pre-Metastatic Cancer Exosomes Induce Immune Surveillance by Patrolling Monocytes at the Metastatic Niche.” Exosomes are nano-sized delivery vehicles that are released by cells into the bloodstream. In recent years, significant research has focused on the role of exosomes released by cancer cells in promoting the spread of cancer. This study, however, is the first to demonstrate that exosomes can also suppress metastasis, depending on the state of the cancer cell. “Mike’s paper is important because it provides data on the mechanisms by which these natural nanovesicles enhance the ability of the immune system to clear tumor cells and prevent cancer from spreading,” said C. Shad Thaxton, MD, PhD, Associate Professor of Urology and a co-author of the Nature Communications paper. Dr. Thaxton is also Plebanek’s advisor and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “Because the spread of cancer cells throughout the body is devastating for cancer patients, developing a deeper understanding of the process is critically important and adds to the knowledge that may result in new treatments.” Previously, it had been established that exosomes released from highly metastatic tumor cells support the spread of cancer by traveling to other organs in the body, where the exosomes nurture an environment for incoming cancer cells.