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A small, orally bioavailable molecule targeting an enzyme in the endoplasmic reticulum (ER) blocks protein folding, induces ER stress and results in tumor cell death. This discovery provides new insights to develop targeted strategies for treating solid tumors, including breast, brain, pancreatic and ovarian tumors. The study shows, the candidate drug is effective against estrogen receptor-positive breast cancers, TNBC, and other solid tumor types with elevated ER stress, without any adverse effects on normal human or animal cells.
Time-resolved transcriptomic and proteomic data from rat fetal cells of the master circadian clock in the hypothalamus of the brain demonstrate widespread genetic rhythmicity before the SCN develops the ability to keep time. This reveals that during the development of the fetal suprachiasmatic nuclei, maternal stimuli may substitute for an inter-cellular web of synapses that is yet to develop and drive cell-population rhythms before the SCN clock matures.
Scientists have discovered a family of metallochaperones that transfer zinc onto proteins and plays a significant role in maintaining zinc homeostasis and cellular integrity. The study has identified the first family of evolutionarily conserved proteins, ZNG1 (Zn-regulated GTPase metalloprotein activator), that interacts with a client protein called METAP1 (Zn metalloprotease methionine aminopeptidase 1) to include zinc in the client protein’s native conformation. The researchers think, when the body is starved for zinc, ZNG1 ensures zinc gets delivered to the most important zinc-containing proteins.
Scientists have discovered a new outflow route for cerebrospinal fluid (CSF) from the meninges to the bone marrow of the skull in mice. This is significant because the skull bone marrow hosts blood stem cells that produce white blood cells which can then migrate to the central nervous system. The privileged sampling of brain-derived danger signals in CSF by local marrow may have broad implications for inflammatory neurological disorders, including dementia.
Tau-induced increase in RNA export leads to a deficit in nonsense-mediated mRNA decay (NMD), a new study on fruit flies finds. Tau-induced deficits in RNA quality control are a druggable driver of neurodegeneration, the authors claim, that occurs early in the disease process and connects nuclear envelope invagination and RNA to neurodegeneration in a fly model of tauopathy. The study offers mechanistic insight into how aberrant export of RNA from the nucleus and subsequent accumulation of RNA within nuclear invaginations drive neurodegeneration in Alzheimer's disease and related tauopathies.
In newborn mice, MRV infection of the thymus results in disruption a physiological mechanism by which the body controls the number of autoreactive T cells (central tolerance). This results in autoreactive T cells in the circulation and the emergence of autoimmunity later in adulthood. This autoimmunity is much broader than can be explained by cross-reactivity or molecular mimicry because the infection produces a broad array of autoantibodies, in addition to autoantibodies against proteins on stomach cells.
Scientists at Northwestern University have demonstrated that the loss of a gene called Tango10 affects daily behavior in fruit flies and disrupts their 24-hour sleep-wake cycles. The protein’s expression in pacemaker neurons regulates their neuronal activity, potentially through voltage-gated potassium channel currents, that in turn regulate circadian behavior in flies. Since Tango10 is a conserved protein, the study could help identify and treat analogous defects in humans with clock-related disorders.
New research shows a natural compound in basil called fenchol may protect against Alzheimer’s disease pathology. A University of South Florida Health-led team discovered that the aromatic compound fenchol has the same beneficial effect as gut-derived short chain fatty acid (SCFA) metabolites in reducing neurotoxic amyloid-beta in the brain. The authors reported that fenchol, like SCFAs, activates fatty acid receptor 2 (FFAR2) on neurons in the brain, increasing lysosomal and proteasomal activity and decreasing amyloid beta-induced neurotoxicity and neuronal cell death.
Researchers at the Cincinnati Children’s Hospital Medical Center have identified a novel pathway they call the RIPIL-33 pathway that assembles in many types of epithelial cells upon exposure to various unrelated environmental allergens and processes the cytokine IL-33 into an active form within the cell to aid cellular recognition of the allergens. The new rapid reaction system may hold the key to understanding and treating people suffering from a wide range of allergies.
Research from Genentech and the University of California has improved upon the sole animal model of shigella infection, providing an indispensable tool for vaccine development. The study identifies the mechanism Shigella adopts to prevent programmed cell death of the infected host intestinal cells and enable infection. IpaH7.8, a Shigella ubiquitin ligase, inhibits a host pore-forming protein (GSDMD) that induces cell death. Eliminating GSDMD in mice already primed for Shigella infection, increases bacterial replication and disease severity, generating an improved model for human Shigellosis.