Host adaptive mutations in the influenza A virus (IAV) PB2 protein are critical for human infection, but their molecular action is not well understood. We observe that when IAV containing avian PB2 infects mammalian cells, viral ribonucleoprotein (vRNP) aggregates that localize to the microtubule-organizing center (MTOC) are formed. These vRNP aggregates resemble LC3B-associated autophagosome structures, with aggresome-like properties, in that they cause the re-distribution of vimentin. However, electron microscopy reveals that these aggregates represent an accumulation of autophagic vacuoles. Compared to mammalian-PB2 virus, avian-PB2 virus induces higher autophagic flux in infected cells, indicating an increased rate of autophagosomes containing avian vRNPs fusing with lysosomes. We found that p62 is essential for the formation of vRNP aggregates and that the Raptor-interacting region of p62 is required for interaction with vRNPs through the PB2 polymerase subunit. Selective autophagic sequestration during late-stage virus replication is thus an additional strategy for host restriction of avian-PB2 IAV.The introduction of rest intervals interspersed with practice strengthens wakeful consolidation of skill. The mechanisms by which the brain binds discrete action representations into consolidated, highly temporally resolved skill sequences during waking rest are not known. To address this question, we recorded magnetoencephalography (MEG) during acquisition and rapid consolidation of a sequential motor skill. We report the presence of prominent, fast waking neural replay during the same rest periods in which rapid consolidation occurs. The observed replay is temporally compressed by approximately 20-fold relative to the acquired skill, is selective for the trained sequence, and predicts the magnitude of skill consolidation. Replay representations extend beyond the hippocampus and entorhinal cortex to the contralateral sensorimotor cortex. These results document the presence of robust hippocampo-neocortical replay supporting rapid wakeful consolidation of skill.The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD.Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells-the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. this website Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence.Drug development is hampered by poor target selection. Phenotypic screens using neurons differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature of amyotrophic lateral sclerosis (ALS), we design a multi-step screening funnel using patient-derived motor neurons. High-content live cell imaging is used to evaluate neuronal excitability, and from a screen against a chemogenomic library of 2,899 target-annotated compounds, 67 reduce the hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation, without cytotoxicity. Bioinformatic deconvolution identifies 13 targets that modulate motor neuron excitability, including two known ALS excitability modulators, AMPA receptors and Kv7.2/3 ion channels, constituting target validation. We also identify D2 dopamine receptors as modulators of ALS motor neuron excitability. This screen demonstrates the power of human disease cell-based phenotypic screens for identifying clinically relevant targets for neurological disorders.Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.