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In this issue of Neuron, Park et al. (2020) show that the brain forms unified cognitive maps of relational knowledge. The hippocampal-entorhinal region and medial prefrontal cortices spontaneously combine multiple, distinct rank orders to two-dimensional cognitive maps enabling flexible inference.In this issue, Laukoter et al., 2020 report that parent-of-origin-dependent expression is homogeneous across distinct cortical cell types and within individual populations. Conversely, they observe preferential sensitivity of astrocytes to altered doses of imprinted loci.Opioids are commonly used as analgesics for severe pain, but their addictive potential has sparked a misuse epidemic. In this issue of Neuron, Keyes et al. (2020) examine the contributions of distinct paraventricular thalamus (PVT) outputs to contextual opioid memories. They identify a PVT→NAc→LH circuit essential for recall of opioid experiences.Dysfunctions of cortico-hippocampal circuits represent a hallmark of Alzheimer's disease. In this issue of Neuron, Jun et al. illuminate the spatial coding failures by familial Alzheimer's disease mutations that may underlie the progressive decline in spatial mnemonic processing.Artificial neural networks (ANNs) are essential tools in machine learning that have drawn increasing attention in neuroscience. Besides offering powerful techniques for data analysis, ANNs provide a new approach for neuroscientists to build models for complex behaviors, heterogeneous neural activity, and circuit connectivity, as well as to explore optimization in neural systems, in ways that traditional models are not designed for. In this pedagogical Primer, we introduce ANNs and demonstrate how they have been fruitfully deployed to study neuroscientific questions. We first discuss basic concepts and methods of ANNs. Then, with a focus on bringing this mathematical framework closer to neurobiology, we detail how to customize the analysis, structure, and learning of ANNs to better address a wide range of challenges in brain research. To help readers garner hands-on experience, this Primer is accompanied with tutorial-style code in PyTorch and Jupyter Notebook, covering major topics.The recent advent of human pluripotent stem cell (PSC)-derived 3D brain organoids has opened a window into aspects of human brain development that were not accessible before, allowing tractable monitoring and assessment of early developmental processes. However, their broad and effective use for modeling later stages of human brain development and disease is hampered by the lack of a stereotypic anatomical organization, which limits maturation processes dependent upon formation of unique cellular interactions and short- and long-range network connectivity. Emerging methods and technologies aimed at tighter regulatory control through bioengineering approaches, along with newer unbiased organoid analysis readouts, should resolve several of the current limitations. Here, we review recent advances in brain organoid generation and characterization with a focus on highlighting future directions utilizing interdisciplinary strategies that will be important for improving the physiological relevance of this model system.Human organoid models of the central nervous system, including the neural retina, are providing unprecedented opportunities to explore human neurodevelopment and neurodegeneration in controlled culture environments. In this Perspective, we discuss how the single-cell multi-omic toolkit has been used to identify features and limitations of brain and retina organoids and how these tools can be deployed to study congenital brain malformations and vision disorders in organoids. We also address how to improve brain and retina organoid protocols to revolutionize in vitro disease modeling.To determine whether double-strand break (DSB) mobility enhances the physical search for an ectopic template during homology-directed repair (HDR), we tested the effects of factors that control chromatin dynamics, including cohesin loading and kinetochore anchoring. The former but not the latter is altered in response to DSBs. Loss of the nonhistone high-mobility group protein Nhp6 reduces histone occupancy and increases chromatin movement, decompaction, and ectopic HDR. selleck products The loss of nucleosome remodeler INO80-C did the opposite. To see whether enhanced HDR depends on DSB mobility or the global chromatin response, we tested the ubiquitin ligase mutant uls1Δ, which selectively impairs local but not global movement in response to a DSB. Strand invasion occurs in uls1Δ cells with wild-type kinetics, arguing that global histone depletion rather than DSB movement is rate limiting for HDR. Impaired break movement in uls1Δ correlates with elevated MRX and cohesin loading, despite normal resection and checkpoint activation.Existing antibiotics are inadequate to defeat tuberculosis (TB), a leading cause of death worldwide. We sought potential targets for host-directed therapies (HDTs) by investigating the host immune response to mycobacterial infection. We used high-throughput CRISPR knockout and CRISPR interference (CRISPRi) screens to identify perturbations that improve the survival of human phagocytic cells infected with Mycobacterium bovis BCG (Bacillus Calmette-Guérin), as a proxy for Mycobacterium tuberculosis (Mtb). Many of these perturbations constrained the growth of intracellular mycobacteria. We identified over 100 genes associated with diverse biological pathways as potential HDT targets. We validated key components of the type I interferon and aryl hydrocarbon receptor signaling pathways that respond to the small-molecule inhibitors cerdulatinib and CH223191, respectively; these inhibitors enhanced human macrophage survival and limited the intracellular growth of Mtb. Thus, high-throughput functional genomic screens, by elucidating highly complex host-pathogen interactions, can serve to identify HDTs to potentially improve TB treatment.Glia are typically considered as supporting cells for neural development and synaptic transmission. Here, we report an active role of a glia in olfactory transduction. As a polymodal sensory neuron in C. elegans, the ASH neuron is previously known to detect multiple aversive odorants. We reveal that the AMsh glia, a sheath for multiple sensory neurons including ASH, cell-autonomously respond to aversive odorants via G-protein-coupled receptors (GPCRs) distinct from those in ASH. Upon activation, the AMsh glia suppress aversive odorant-triggered avoidance and promote olfactory adaptation by inhibiting the ASH neuron via GABA signaling. Thus, we propose a novel two-receptor model where the glia and sensory neuron jointly mediate adaptive olfaction. Our study reveals a non-canonical function of glial cells in olfactory transduction, which may provide new insights into the glia-like supporting cells in mammalian sensory procession.selleck products