Hoppering0010

The mouse accessory olfactory system (AOS) supports social and reproductive behavior through the sensation of environmental chemosignals. A growing number of excreted steroids have been shown to be potent AOS cues, including bile acids (BAs) found in feces. As is still the case with most AOS ligands, the specific receptors used by vomeronasal sensory neurons (VSNs) to detect BAs remain unknown. To identify VSN BA receptors, we first performed a deep analysis of VSN BA tuning using volumetric GCaMP6f/s Ca2+ imaging. These experiments revealed multiple populations of BA-receptive VSNs with submicromolar sensitivities. We then developed a new physiology-forward approach for identifying AOS ligand-receptor interactions, which we call Fluorescence Live Imaging for Cell Capture and RNA sequencing, or FLICCR-seq. FLICCR-seq analysis revealed five specific V1R family receptors enriched in BA-sensitive VSNs. These studies introduce a powerful new approach for ligand-receptor matching and reveal biological mechanisms underlying mammalian BA chemosensation.Global climate models (GCMs) disagree with other lines of evidence on the rapid adjustments of cloud cover and liquid water path to anthropogenic aerosols. Attempts to use observations to constrain the parameterizations of cloud processes in GCMs have failed to reduce the disagreement. We propose using observations sensitive to the relevant cloud processes rather than only to the atmospheric state and focusing on process realism in the absence of aerosol perturbations in addition to the process susceptibility to aerosols. We show that process-sensitive observations of precipitation can reduce the uncertainty on GCM estimates of rapid cloud adjustments to aerosols. The feasibility of an observational constraint depends on understanding the precipitation intensity spectrum in both observations and models and also on improving methods to compare the two.Neural organoids provide a powerful tool for investigating neural development, modeling neural diseases, screening drugs, and developing cell-based therapies. Somatic cells have previously been reprogrammed by transcription factors (TFs) into sensory ganglion (SG) neurons but not SG organoids. We identify a combination of triple TFs Ascl1, Brn3b/3a, and Isl1 (ABI) as an efficient means to reprogram mouse and human fibroblasts into self-organized and networked induced SG (iSG) organoids. The iSG neurons exhibit molecular features, subtype diversity, electrophysiological and calcium response properties, and innervation patterns characteristic of peripheral sensory neurons. Moreover, we have defined retinal ganglion cell (RGC)-specific identifiers to demonstrate the ability for ABI to reprogram induced RGCs (iRGCs) from fibroblasts. Unlike iSG neurons, iRGCs maintain a scattering distribution pattern characteristic of endogenous RGCs. iSG organoids may serve as a model to decipher the pathogenesis of sensorineural diseases and screen effective drugs and a source for cell replacement therapy.Starting from 12,000 years ago in the Middle East, the Neolithic lifestyle spread across Europe via separate continental and Mediterranean routes. Genomes from early European farmers have shown a clear Near Eastern/Anatolian genetic affinity with limited contribution from hunter-gatherers. However, no genomic data are available from modern-day France, where both routes converged, as evidenced by a mosaic cultural pattern. Here, we present genome-wide data from 101 individuals from 12 sites covering today's France and Germany from the Mesolithic (N = 3) to the Neolithic (N = 98) (7000-3000 BCE). Using the genetic substructure observed in European hunter-gatherers, we characterize diverse patterns of admixture in different regions, consistent with both routes of expansion. Early western European farmers show a higher proportion of distinctly western hunter-gatherer ancestry compared to central/southeastern farmers. Our data highlight the complexity of the biological interactions during the Neolithic expansion by revealing major regional variations.The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Mitomycin C cell line Activities responsible for this removal have, so far, not been identified. We show that Mre11 3' to 5' exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cells.Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (Teff) cells into regulatory T (Treg) cells, by restricting the expression of Teff cell-intrinsic Treg commitment programs. This was critical for stabilizing Teff cell functions and subverting immune-suppressive signals. T cell-specific deletion of Pcbp1 favored Treg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining Teff cell functions in cancer immunity.The ~180-km-diameter Chicxulub peak-ring crater and ~240-km multiring basin, produced by the impact that terminated the Cretaceous, is the largest remaining intact impact basin on Earth. International Ocean Discovery Program (IODP) and International Continental Scientific Drilling Program (ICDP) Expedition 364 drilled to a depth of 1335 m below the sea floor into the peak ring, providing a unique opportunity to study the thermal and chemical modification of Earth's crust caused by the impact. The recovered core shows the crater hosted a spatially extensive hydrothermal system that chemically and mineralogically modified ~1.4 × 105 km3 of Earth's crust, a volume more than nine times that of the Yellowstone Caldera system. Initially, high temperatures of 300° to 400°C and an independent geomagnetic polarity clock indicate the hydrothermal system was long lived, in excess of 106 years.