More than a third of FDA-approved drugs work by targeting a G protein-coupled receptor, or GPCR. The human body has more than 800 types of GPCRs that provide cells with information about the external environment to calibrate responses. Drugs that either block or activate GPCRs are used to treat a wide range of diseases including hypertension, pain, and inflammation. Most drugs bind to the outside of the receptor, but this can result in adverse side effects because receptors often resemble one another. In a new study published in Nature, Sivaraj Sivaramakrishnan, PhD, a Professor in the College of Biological Sciences, along with graduate student Fred Sadler and co-authors Michael Ritt and Yatharth Sharma, uncovered the role of the third intracellular loop in the GPCR’s signaling mechanism, suggesting the possibility of a more targeted approach to drug discovery and a paradigm shift for new therapeutics. The open-access article is titled Autoregulation of GPCR Signalling Through the Third Intracellular Loop.”
Losing Key Type of Pancreatic Cell May Contribute to Diabetes
Multiple types of beta cells produce insulin in the pancreas, helping to balance blood sugar levels. Losing a particularly productive type of beta cell may contribute to the development of diabetes, according to a new study by Weill Cornell Medicine investigators. In the study, published March 16, 2023 in Nature Cell Biology, Dr. James Lo, Associate Professor of Medicine at Weill Cornell Medicine, and colleagues measured gene expression in individual beta cells collected from mice to determine how many different types of beta cells exist in the pancreas. The team discovered four distinct beta cell types, including one that stood out. The cluster 1 group of beta cells produced more insulin than other beta cells and appeared better able to metabolize sugar. The study also showed that loss of this beta cell type might contribute to type 2 diabetes. The article is titled “A Beta Cell Subset with Enhanced Insulin Secretion and Glucose Metabolism Is Reduced In Type 2 Diabetes.”
Researchers Highlight Nucleolar DNA Damage Response in Fight Against Cancer
Cancer, which affects millions every year, requires proteins to spread through the body. In a new strategy to beat the wide-ranging disease, scientists are sabotaging its protein factories. In a new forum paper published on March 16, 2023 in Trends in Biology, researchers from the University of North Carolina at Charlotte encapsulated the young field of nucleolar DNA damage response (DDR) pathways. The review highlights six mechanisms by which cells repair DNA damage, including one which was published five months ago in Nucleic Acids Research by the same authors. By attacking these mechanisms, future applied researchers might be able to trip up cancer’s reproduction and growth. “The whole purpose of the Trends paper is to bring attention to scientists in the field and trigger their research,” says Shan Yan, PhD, the main author. “I did not realize the significance of this field, which is only fifteen years old, until a couple of years ago.” The review is titled “Molecular Mechanisms of Nucleolar DNA Damage Checkpoint Response.”
Senescence-Associated Exosomes Transfer Fibrosis to Neighboring Cells
“This shows that SA-EXOs can serve as potent SASP mediators that activate invasive characteristics in neighboring cells.”
A new research paper was published March 15, 2023 inAging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) Volume 15, Issue 5, entitled, “Senescence-Associated Exosomes Transfer miRNA-Induced Fibrosis to Neighboring Cells.”
Extra X Chromosome-Linked Gene May Explain Decreased Viral Infection Severity in Females
It has long been known that viral infections can be more severe in males than females, but the question as to why has remained a mystery – until possibly now. The key may lie in an epigenetic regulator that boosts the activity of specialized anti-viral immune cells known as natural killer (NK) cells. In a study published March 16, 2023 in Nature Immunology, a collaborative team of UCLA researchers has found that female mouse and human NK cells have an extra copy of an X chromosome-linked gene called UTX. UTX acts as an epigenetic regulator to boost NK cell anti-viral function, while repressing NK cell numbers.
Genetic Causes of Three Previously Unexplained Rare Diseases Identified; Computational Approach Developed By Mount Sinai Researchers Helps Identify Previously Unknown Genetic Causes of Primary Lymphedema, Thoracic Aortic Aneurysm Disease, and Congenital Deafness
Using a new computational approach they developed to analyze large genetic datasets from rare disease cohorts, researchers at the Icahn School of Medicine at Mount Sinai and colleagues have discovered previously unknown genetic causes of three rare conditions: primary lymphedema (characterized by tissue swelling), thoracic aortic aneurysm disease, and congenital deafness. The work was done in collaboration with colleagues at the University of Bristol, UK; KU Leuven, Belgium; the University of Tokyo; the University of Maryland; Imperial College London, and others from around the world.
Study Offers Potential Strategy to Improve T Cell Therapy in Solid Tumors; Simultaneous Knockout of Two Inflammatory Regulators Boosts T Cell Expansion in Models
A new approach that delivers a “one-two punch” to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine at the University of Pennsylvania. The findings, published on March 15, 2023 in PNAS, showed that targeting two regulators that control gene functions related to inflammation led to at least 10 times greater T cell expansion in models, resulting in increased antitumor immune activity and durability. The open-access article is titled “Combined Disruption of T Cell Inflammatory Regulators Regnase-1 and Roquin-1 Enhances Antitumor Activity of Engineered Human T Cells.”
Immobilizing Mosquito Sperm by Inactivating Key Protein
New UC Riverside (UCR) research makes it likely that proteins responsible for activating mosquito sperm can be shut down, preventing them from swimming to or fertilizing eggs. The study could help control populations of Culex, the common house mosquito that transmits brain-swelling encephalitis and West Nile Virus. “During mating, mosquitoes couple tail to tail, and the males transfer sperm into the female reproductive tract. It can be stored there awhile, but it still has to get from point A to point B to complete fertilization,” said Cathy Thaler, PhD, UCR cell biologist and the study’s first author. Key to completing that journey are the specialized proteins secreted during ejaculation that activate the sperm flagella, or ‘tails,’ that power their movement.
Immune Cell Gives Possible Explanation for Sex Differences In Pancreatic Cancer
Immunotherapy is an effective form of therapy for different types of cancer. However, for pancreatic cancer, its effect is limited and differs between men and women. Researchers at Karolinska Institutet have now found a possible explanation for this sex difference. The study, which was published om March 15, 2023 in Cancer Research, reveals the presence of an immune cell in women with pancreatic cancer that obstructs the body’s immune response. The results can pave the way for a more sex-specific treatment. The article is titled “FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-Cell Exhaustion in a Sex-Dependent Manner.”
How Genome Doubling Helps Cancer Develop
A single cell contains 2-3 meters of DNA, meaning that the only way to store it is to package it into tight coils. The solution is chromatin: a complex of DNA wrapped around proteins called histones. In the 3D space, this complex is progressively folded into a multi-layered organization composed of loops, domains, and compartments, which makes up what we know as chromosomes. The organization of chromatin is closely linked to gene expression and the cell’s proper function, so any problems in chromatin structure can have detrimental effects, including the development of cancer. A common event in about 30% of all human cancers is “whole genome doubling” (WGD), whereby the entire set of chromosomes in a cell is duplicated. WGD leads to genomic instability inside the cell, which can result in chromosomal alterations and other mutations that contribute to the development of cancer.