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Hedegaard Fink posted an update 6 months, 3 weeks ago
Our results showed that gradual replacement of individuals with naive immigrants greatly increased the probability that a more efficient behavior invaded a population’s cultural repertoire and outcompeted an established inefficient behavior. Fine-scale, automated behavioral tracking revealed that turnover did not increase innovation rates, but instead acted on adoption rates, as immigrants disproportionately sampled novel, efficient behaviors relative to available social information. These results provide strong evidence for cultural selection for efficiency in animals, and highlight the mechanism that links population turnover to this process.The bacterium Bdellovibrio bacteriovorus attaches to the exterior of a Gram-negative prey cell, enters the periplasm, and harvests resources to replicate before lysing the host to find new prey.1-7 Predatory bacteria such as this are common in many natural environments,8-13 as are groups of matrix-bound prey cell clusters, termed biofilms.14-16 Despite the ubiquity of both predatory bacteria and biofilm-dwelling prey, the interaction between B. bacteriovorus and prey inside biofilms has received little attention and has not yet been studied at the micrometer scale. Filling this knowledge gap is critical to understanding bacterial predator-prey interaction in nature. Here we show that B. bacteriovorus is able to attack biofilms of the pathogen Vibrio cholerae, but only up until a critical maturation threshold past which the prey biofilms are protected from their predators. Using high-resolution microscopy and detailed spatial analysis, we determine the relative contributions of matrix secretion and cell-cell packing of the prey biofilm toward this protection mechanism. Our results demonstrate that B. bacteriovorus predation in the context of this protection threshold fundamentally transforms the sub-millimeter-scale landscape of biofilm growth, as well as the process of community assembly as new potential biofilm residents enter the system. We conclude that bacterial predation can be a key factor influencing the spatial community ecology of microbial biofilms.Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Momelotinib Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.Mutations in the gene encoding the chromatin remodeler chromodomain helicase DNA-binding protein 8 (CHD8) are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have long been thought to be related to ASD pathogenesis, it has remained largely unknown whether dysfunction of CHD8 in the cerebellum contributes to ASD phenotypes. We here show that cerebellar granule neuron progenitor (GNP)-specific deletion of Chd8 in mice impairs the proliferation and differentiation of these cells as well as gives rise to cerebellar hypoplasia and a motor coordination defect, but not to ASD-like behavioral abnormalities. CHD8 is found to regulate the expression of neuronal genes in GNPs. It also binds preferentially to promoter regions and modulates local chromatin accessibility of transcriptionally active genes in these cells. Our results have thus uncovered a key role for CHD8 in cerebellar development, with important implications for understanding the contribution of this brain region to ASD pathogenesis.Most mitochondrial proteins are synthesized as precursors in the cytosol and post-translationally transported into mitochondria. The mitochondrial surface protein Tom70 acts at the interface of the cytosol and mitochondria. In vitro import experiments identified Tom70 as targeting receptor, particularly for hydrophobic carriers. Using in vivo methods and high-content screens, we revisit the question of Tom70 function and considerably expand the set of Tom70-dependent mitochondrial proteins. We demonstrate that the crucial activity of Tom70 is its ability to recruit cytosolic chaperones to the outer membrane. Indeed, tethering an unrelated chaperone-binding domain onto the mitochondrial surface complements most of the defects caused by Tom70 deletion. Tom70-mediated chaperone recruitment reduces the proteotoxicity of mitochondrial precursor proteins, particularly of hydrophobic inner membrane proteins. Thus, our work suggests that the predominant function of Tom70 is to tether cytosolic chaperones to the outer mitochondrial membrane, rather than to serve as a mitochondrion-specifying targeting receptor.Fascin protein is the main actin-bundling protein in filopodia and invadopodia, which are critical for tumor cell migration, invasion, and metastasis. Small-molecule fascin inhibitors block tumor invasion and metastasis and increase the overall survival of tumor-bearing mice. Here, we report a finding that fascin blockade additionally reinvigorates anti-tumor immune response in syngeneic mouse models of various cancers. Fascin protein levels are increased in conventional dendritic cells (cDCs) in the tumor microenvironment. Mechanistically, fascin inhibitor NP-G2-044 increases the number of intratumoral-activated cDCs and enhances the antigen uptake by cDCs. Furthermore, together with PD-1 blocking antibody, NP-G2-044 markedly increases the number of activated CD8+ T cells in the otherwise anti-PD-1 refractory tumors. Reduction of fascin levels in cDCs, but not fascin gene knockout in tumor cells, mimics the anti-tumor immune effect of NP-G2-044. These data demonstrate that fascin inhibitor NP-G2-044 simultaneously limits tumor metastasis and reinvigorates anti-tumor immune responses.
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