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267 Genes Linked to Creativity May Have Been “Secret Weapon” in Survival of Homo sapiens

Creativity—the “secret weapon” of Homo sapiens—constituted a major advantage over Neanderthals and played an important role in the survival of the human species. This is the finding of an international team of scientists, led by the University of Granada (UGR), which has identified for the first time a series of 267 genes linked to creativity that differentiate Homo sapiens from Neanderthals. This important scientific finding, published online on April 21, 2021 in Molecular Psychiatry (Nature), suggests that it was these genetic differences linked to creativity that enabled Homo sapiens to eventually replace Neanderthals. It was creativity that gave Homo sapiens the edge, above and beyond the purely cognitive level, by facilitating superior adaptation to the environment compared to that of now-extinct hominids and providing greater resilience to aging, injury, and disease. The open-access Molecular Psychiatry article is titled “Evolution of Genetic Networks for Human Creativity” (https://www.nature.com/articles/s41380-021-01097-y). The research team comprises first author Igor Zwir, Coral del Val, Rocío Romero, Javier Arnedo, and Alberto Mesa from the UGR’s Department of Computer Science and Artificial Intelligence, the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), and the Biohealth Research Institute in Granada (ibs.GRANADA), together with senior author Robert Cloninger (photo) of Washington University in St. Louis and colleagues from the Young Finns Study (Finland), the American Museum of Natural History (New York), and the Menninger Clinic (Houston, Texas). Their findings are the result of an interdisciplinary study that brings together Artificial Intelligence (AI), Molecular Genetics, Neurosciences, Psychology, and Anthropology.

Plant Shrub Chemical (Curcusome D) Synthesized in Lab Offers Possibility of Targeting Previously “Undruggable” Cancer Protein (BRAT1) Involved in Many Different Cancers

A chemist from Purdue University has found a way to synthesize a compound to fight a previously "undruggable" cancer protein with potential benefits across a myriad of cancer types. Inspired by a rare compound found in a shrub native to North America, Mingji Dai, PhD, Professor of Chemistry and a scientist at the Purdue University Center for Cancer Research, together with colleagues, studied the compound and discovered a cost-effective and efficient way to synthesize it in the lab. The synthesis is described in an article published online on March 11, 2021 in the Journal of the American Chemical Society. The article is titled “Total Synthesis and Target Identification of the Curcusone Diterpenes” (https://pubs.acs.org/doi/10.1021/jacs.1c00557). The compound--curcusone D--has the potential to help combat a protein found in many cancers, including some forms of breast, brain, colorectal, prostate, lung, and liver cancers, among others. The protein, dubbed BRAT1, had previously been deemed "undruggable" for its chemical properties. In collaboration with Dr. Alexander Adibekian's group at the Scripps Research Institute, the researchers linked curcusone D to BRAT1 and validated curcusone D as the first BRAT1 inhibitor. Curcusones are compounds that come from a shrub named Jatropha curcas (photo), also called the purging nut. Native to the Americas, it has spread to other continents, including Africa and Asia. The plant has long been used for medicinal properties, including the treatment of cancer, as well as being a proposed inexpensive source of biodiesel. Dr. Dai was interested in this family of compounds: curcusone A, B, C, and D.

Inhibition of Meprin β Enzyme, Linked to Development of Alzheimer's Disease, Is Analyzed; Crystal Structure of Meprin β / Fetuin-B Complex Determined by X-Ray Crystallography; Findings Could Lead to Creation of New Drugs

Researchers at Johannes Gutenberg University Mainz (JGU) in Germany and the Institute of Molecular Biology of Barcelona in Spain have discovered how the blood plasma protein fetuin-B binds to the enzyme meprin β and used a computer model to visualize their findings. These results could lead to the development of new drugs to treat serious diseases such as Alzheimer's and cancer. Meprin β releases proteins from cell membranes, thus controlling important physiological functions in the human body. However, a dysregulation of this process can trigger the development of Alzheimer's and cancer. Meprin β is regulated by fetuin-B binding to the enzyme when required, thereby preventing the release of other proteins. Presenting their findings in an online article published on April 6, 2021 in PNAS, the researchers are now the first to describe this binding in detail. The PNAS article is titled “The Crystal Structure of a 250-kDa Heterotetrameric Particle Explains Inhibition of Sheddase Meprin β by Endogenous Fetuin-B” (https://www.pnas.org/search/K%25C3%25B6rschgen%20content_type%3Ajournal). The team at Mainz University produced both meprin β and fetuin-B in insect cells and then allowed the molecules to react with one other in a test tube. By means of measurement of enzyme kinetics and biophysical analyses, the researchers determined that this reaction resulted in an exceptionally stable, high-molecular-mass complex. Their colleagues in Barcelona subsequently managed to crystallize the complex and determine its three-dimensional structure using X-ray crystallography. This involved X-rays being fired at the protein crystals, which allowed the atomic structure of the crystals to be calculated from the diffraction of the X-rays. A computer model of the structure was then generated.

POT1 Gene Mutation Predisposes to Glioma and Affects Survival in a Sex-Specific Manner

Researchers at Baylor College of Medicine and collaborators at other institutions have discovered that POT1 (protection of telomeres 1), a gene known to be associated with risk of glioma, the most common type of malignant brain tumor, mediates its effects in a sex-specific manner. The researchers found that female mice with glioma that lacked the gene survived less than males. This led them to investigate human glioma cells, where they found that low POT1 expression correlated with reduced survival in females. Published online on March 29, 2021 in Cancer Research, the study also shows that, compared to males, female tumors had reduced expression of immune signatures and increased expression of cell replication markers, suggesting that the immune response and tumor cell proliferation seemed to be involved in favoring tumor growth. The article is titled “POT1 Regulates Proliferation and Confers Sexual Dimorphism in Glioma” (https://cancerres.aacrjournals.org/content/early/2021/03/29/0008-5472.CA...). This study began as a collaboration between Dr. Benjamin Deneen's lab at Baylor and Dr. Melissa Bondy's lab, previously at Baylor and now at Stanford University. Dr. Bondy and her group study familial or inherited forms of glioma from the epidemiologic standpoint. Their studies have linked mutations in the gene POT1 to the risk of glioma development. In the current study, the researchers looked to determine whether Pot1 mutations affected glioma development in a mouse model of the condition developed in the Deneen lab. "We began our study by knocking out the Pot1 gene in our mouse model and examining whether this affected the development and growth of glioma tumors," said first author Dr. Ali Jalali, Assistant Professor of Neurosurgery at Baylor. Dr.

Study of "Exceptional Responders" Among Glioblastoma Patients Treated with Chemotherapy Leads to ID of New Drug Target (PI3Kγ) for Deadly Brain Cancer; In Animal Models, Treatment with PI3Kγ Inhibitors Resulted in Durable Responses to Chemotherapy

Despite access to some of the best possible medical care in the world, US Senators John McCain and Edward Kennedy both died within 18 months of their diagnosis of glioblastoma, an aggressive form of brain cancer. While this deadly outcome typifies the nature of this disease, some glioblastoma patients see exceptional benefits from chemotherapy and survive beyond expectations. Why this happens has been revealed by researchers at the University of Minnesota in a new study published online on April 20, 2021in PNAS. The article is titled “PI3Kγ Inhibition Suppresses Microglia/TAM Accumulation in Glioblastoma Microenvironment to Promote Exceptional Temozolomide Response” (https://www.pnas.org/content/118/16/e2009290118). "Deciphering the molecular underpinning of these exceptional responses may hold the key to transforming the hope for miracles into the reality of an expected cure for glioblastoma patients," said Clark C. Chen (https://med.umn.edu/bio/itn-leadership/clark-chen), MD, PhD, Lyle French Chair in Neurosurgery and Head of the Department of Neurosurgery at the University of Minnesota Medical School, who is senior author of the study. The study team looked at the gene expression profiles of glioblastoma specimens collected from approximately 900 glioblastoma patients from regions across the world to identify unique features associated with exceptional responders, defined as glioblastoma patients who survive more than two years after treatment. "We utilized different state-of-the-art analytics to study these samples, including methods innovated by Dr. Aaron Sarver, a member of the University of Minnesota (U of M) Institute of Health Informatics. Impressively, these analytics converged on a single observation, a paucity of microglia and macrophages," Dr. Chen said.

Russian Scientists Discover New Gene Regulation Mechanism Involving Regions of Double-Stranded RNA

A team of scientists from Russia studied the role of double-stranded fragments of maturing RNA and showed that the interaction between distant parts of the RNA can regulate gene expression. The research was published online on April 16, 2021 in Nature Communications. The open-access article is titled “Conserved Long-Range Base Pairings Are Associated with Pre-mRNA Processing of Human Genes” (https://www.nature.com/articles/S41467-021-22549-7). In school, students are typically taught that DNA is double-stranded and that RNA is single-stranded, but that is not entirely true. Scientists have encountered many cases of RNA forming a double-stranded (also known as “secondary”) structure (https://en.wikipedia.org/wiki/Nucleic_acid_secondary_structure) that plays an important role in the functioning of RNA molecules. These structures are involved in the regulation of gene expression, where the double-stranded regions typically carry out specific functions and, if lost, may cause severe disorders. A double-stranded structure is created by sticky complementary regions. For the RNA strands to stick to each other, U and G should appear opposite A and C, respectively. The majority of the sticking regions are located close to one another, but the role of those located far apart has not been well understood. Scientists from the Skoltech Center for Life Sciences (CLS) led by Professor Dmitri Pervouchine, PhD, and their colleagues from Russian and international laboratories used molecular and bioinformatics techniques to analyze the structure and roles of complementary RNA regions spaced far apart, but capable of forming secondary structures.

Research Sheds New Light on Pancreatic Cancer Metastasis; Zinc Transporter ZIP4 Plays Key Role in Transition of Pancreatic Tumor Cells from Epithelial to Mesenchymal Phenotype, Enhancing Metastasis

With an overall survival rate of just 9% for those diagnosed, pancreatic cancer remains exceedingly difficult to treat. However, the patient's primary tumor typically isn't what leads to death--it is the cancer's ability to evade detection and metastasize to other organs. A team of researchers at the Oklahoma University (OU) College of Medicine has published a new study in the April 1, 2021 issue of Gastroenterology, the world's leading publication on GI tract disease, that sheds new light on the ability of pancreatic cancer cells to spread throughout the body. The article is titled “Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer” (https://www.gastrojournal.org/article/S0016-5085(21)00025-1/fulltext). Understanding why metastasis occurs is crucial for developing a therapeutic strategy to stop the spread. The study, led by scientist Min Li, PhD, and physician-scientist Courtney Houchen (photo), MD, centers around ZIP4, a protein that transports zinc throughout the body. While zinc is important for good health, too much of the heavy metal causes problems. In the new study, researchers found that when ZIP4 is overexpressed in patients with pancreatic cancer, it essentially prompts the tumor cells to transform themselves in a manner that allows them to stealthily travel to the body's other organs. In scientific terms, the tumor cells transition from an epithelial to a mesenchymal phenotype. "That transition means the tumor cells are doing everything they can to avoid the surveillance of the body's immune system, as well as chemotherapy and other therapies," Dr. Li said. "They become more evasive and are able to penetrate the blood vessels, which permits them to go anywhere in the body."

Scientists View Bacterial Protein Channels with Cryo-EM to Elucidate Their Method of Function

Almost all bacteria rely on the same emergency valves--protein channels that pop open under pressure, releasing a deluge of cell contents. It is a last-ditch effort, a failsafe that prevents bacteria from exploding and dying when stretched to the limit. If we understood how these protein channels worked, antibiotic drugs could be designed to open them on demand, draining a bacterium of its nutrients by exploiting a floodgate common to many species. But these channels are tricky to operate in the lab. And how precisely they open and close, passing through a sub-conducting state and ending in a desensitized state under the influence of mechanical forces, remains poorly understood. Now, new research from the laboratory of Rockefeller University’s Thomas Walz, PhD, Professor of Biochemistry, Biophysics, Chemical Biology, and Structural Biology, introduces a novel method to activate and visualize these channels, making it possible to explain their function. The findings shed light on key membrane proteins in bacteria, and the same method can be used to improve our understanding of similar channels in humans. The results were published online on February 10, 2021 in Nature. The article is titled “Visualization of the Mechanosensitive Ion Channel MscS Under Membrane Tension” (https://www.nature.com/articles/s41586-021-03196-w). "We were actually able to see the entire cycle of the protein channel passing through a series of functional stages," Dr. Walz says.

Crohn’s Disease May Develop from Altered Immune Cell Signaling During Bile Acid Exposure; Study Published in Nature Reveals How T Cells in Small Intestine Respond to Bile Acids, Offering Localized Treatment Direction for a Cause of Chronic Illness

People with Crohn’s disease are typically treated with powerful anti-inflammatory medications that act throughout their body, not just in their digestive tract, creating the potential for unintended, and often serious, side effects. New research from the lab of Mark Sundrud, PhD, Associate Professor in the Department of Immunology and Microbiology at Scripps Research, Florida, suggests a more targeted treatment approach is possible. Crohn’s disease develops from chronic inflammation in the digestive tract, often the small intestine. More than half a million people in the United States live with the disease, which can be debilitating and require repetitive surgeries to remove irreversibly damaged intestinal tissue. Writing in an article published online on April 7, 2021 in Nature, Dr. Sundrud’s team finds that certain immune cells in the small intestine have evolved a molecular sensing mechanism to protect themselves from the toxic effects of high bile acid concentrations in the small intestine. This sensory mechanism can be manipulated with small drug-like molecules, they find, and the treatment reduced small bowel inflammation in mice. The Nature article is titled “CAR Directs T Cell Adaptation to Bile Acids in the Small Intestine” (https://www.nature.com/articles/s41586-021-03421-6). “It seems that these immune cells, called T effector cells, have learned how to protect themselves from bile acids,” Dr. Sundrud says. “These T cells utilize an entire network of genes to interact safely with bile acids in the small intestine. This pathway may malfunction in at least some individuals with Crohn’s disease.”

Study Suggests Common Drug (Dopamine) Could Be Used to Prevent Certain Squamous Cell Skin Cancers

New data published by researchers at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC--James) suggests that an oral drug currently used in the clinical setting to treat neuromuscular diseases could also help prevent a common form of skin cancer caused by damage from ultraviolet-B (UVB) radiation from the sun. While this data was gathered from preclinical studies, senior author Sujit Basu, MD, PhD, says preliminary results in animal models are very promising and worthy of immediate further investigation through phase I human studies. Dr. Basu and his colleagues reported their initial findings online on April 12, 2021 in Cancer Prevention Research a journal of the American Association for Cancer Research. The article is titled “Dopamine Prevents Ultraviolet B-Induced Development and Progression of Premalignant Cutaneous Lesions Through Its D2 Receptors” (https://cancerpreventionresearch.aacrjournals.org/content/early/2021/04/...). According to the American Cancer Society, more than 5.4 million basal and squamous cell skin cancers are diagnosed annually in the United States. The disease typically recurs throughout a person’s lifetime, and advanced disease can lead to physical disfiguration. These cancers are linked to the sun’s damaging rays, and despite increased public awareness on sun safety precautions, rates of the disease have been increasing for many years. Previous peer-reviewed, published studies have shown that dopamine receptors play a role in the development of cancerous tumors; however, their role in precancerous lesions is unknown.

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