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Researchers at Mount Sinai, New York, have used a structure-based designing approach to develop a small-molecule chimera called MS67 that targets protein degradation mechanisms and selectively breaks down WDR5, a chromatin binding protein that contributes to tumorigenesis of a wide range of human cancers including both solid tumors and blood cancers.
A new study from the University of Barcelona shows dopaminergic and noradrenergic receptor complexes play a pivotal role in catecholaminergic signaling in the brain’s prefrontal cortex and are therefore more effective targets for ADHD and impulsivity, than the receptor monomers that are being targeted by existing drugs. The paper is the first to describe a new heteromer between GPCR receptors that could help redirect the focus of the design of new pharmacological treatments to treat neuropsychiatric disorders involving two members of the GPCR family: α2AR and D4R receptors.
A new study shows TAK-981, a potent and selective inhibitor of SUMOylation, induces IFN1 signaling and protects the IFN1 pathway from inactivation within tumors. The inhibitor activates T cells and dendritic cells that present antigens to the adaptive immune system, in both mouse models and in cell lines. The activity of the potential cancer drug depends on the IFN1 pathway and adaptive immunity to suppress tumor growth. Combined with anti-PD1 antibody TAK-981 demonstrates prolonged survival in tumor-bearing mice and increased activation of natural killer cells and CD8 expressing T cells.
Bispecific antibodies are a promising next-generation antidote against existing and emerging SARS-CoV-2 variants of concern. A research team, led by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), has developed bispecific antibodies that simultaneously bind to two different antigens, targeting multiple regions of the SARS-CoV-2 spike protein. The researchers showed that these bispecific antibodies can neutralize the original virus as well as the emerging variants of concern.
Scientists at Boston Children’s Hospital and Harvard Medical School have developed a self-assembling delivery system that releases a class of potent anesthetics called site-1 sodium channel blockers (S1SCBs) over a prolonged period locally, at the site of injection. S1SCBs that include tetrodotoxin and saxitoxin are an attractive alternative to opioids. The researchers modified two peptides in the sodium channel with hydrophobic domains to induce self-assembly into nanostructures that bind to S1SCBs and release the anesthetic when the nanofibers are in the proximity of the nerve, providing sustained local anesthesia.
A new convection-enhanced macroencapsulation device (ceMED) designed by bioengineers from Brigham and Women’s Hospital, Harvard University, and the University of Massachusetts Medical School offers the potential of faster and more effective treatment for people with type 1 diabetes. Whereas traditional MEDs rely on diffusion, the new MED uses convection to create a continuous flow of nutrients through the capsule improving the number of cells that can be accommodated in each cartridge and increasing their survival, glucose sensitivity and insulin secretion.
New research employs single-cell sequencing to analyze transcriptomes of regeneration competent and incompetent fragments of planaria (Schmidtea mediterranea) to identify transient regeneration-activated cell states (TRACS) in the muscle, epidermis and intestine and develop a comprehensive atlas of whole-body regeneration. The authors identify cell types and genes important for regeneration and show that regenerative ability can emerge from coordinated transcriptional plasticity across all three germ layers.
New research reveals the chromosome-level genome assembly of the bowfin that bears a combination of ancestral features and more recently derived features, and occupies a key position in the fish family tree between the more recent teleosts and ancient lineages such as sturgeons. The sequencing study identified hundreds of gene-regulatory loci conserved across vertebrates and provides new insight into vertebrate evolution, such as genes that were once thought to be indispensable in vertebrate development on account of being responsible for key components of the anatomy are not necessarily so.
Combining optogenetics, cre recombination mediated neuron-specific mutations, sciatic nerve-injury, and disease models of arthritis, with direct measurements of inflammation and neuropathic pain. Scientists at the Feinstein Institutes show that the release of the nociceptor protein HMGB1 is required to mediate neuropathic pain (allodynia) and inflammation. The preclinical study provides direct evidence that nociceptor-related pain can be prevented by targeting HMGB1 in new therapeutic approaches to treat neuroinflammatory diseases.
A collaborative study led by scientists at the University of Bonn, Germany, have identified a new genetic program in the fruit fly that is conserved through evolution and has a dual role in creating neuronal branches during developmental stages and preventing these branches from degenerating in the adult brain. The team has identified a new kinase, WNK, in the fruit fly and its mammalian homologs that support a neuroprotective factor called Nmnat and also inhibits at least two other axon-destabilizing proteins called Sarm and Axed. These findings create new lines of investigation to develop therapeutics against neurodegeneration.