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The neural mechanisms through which the state of anesthesia arises and dissipates remain unknown. One common belief is that emergence from anesthesia is the inverse process of induction, brought about by elimination of anesthetic drugs from their CNS site(s) of action. Anesthetic-induced unconsciousness may result from specific interactions of anesthetics with the neural circuits regulating sleep and wakefulness. Orexinergic agonists and antagonists have the potential to alter the stability of the anesthetized state. In this report, we refine the role of the endogenous orexin system in impacting emergence from, but not entry into the anesthetized state, and in doing so, we distinguish mechanisms of induction from those of emergence. We demonstrate that isoflurane and sevoflurane, two commonly used general anesthetics, inhibit c-Fos expression in orexinergic but not adjacent melanin-concentrating hormone (MCH) neurons; suggesting that wake-active orexinergic neurons are inhibited by these anesthetics. Genetic ablation of orexinergic neurons, which causes acquired murine narcolepsy, delays emergence from anesthesia, without changing anesthetic induction. Pharmacologic studies with a selective orexin-1 receptor antagonist confirm a specific orexin effect on anesthetic emergence without an associated change in induction. We conclude that there are important differences in the neural substrates mediating induction and emergence. These findings support the concept that emergence depends, in part, on recruitment and stabilization of wake-active regions of brain.

One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.

Veterans with disabilities can experience poor quality of life following military service due to the associated negative physical and psychological ramifications. However, participation in physical activities has shown to induce both physical and mental benefits and improve the quality of life of this population. Adaptive sports, an innovative approach to address the unique physical and psychosocial needs of veterans with disabilities, are becoming more widely used as a rehabilitation tool to improve the quality of life for these veterans. This study aimed to determine the acute influence of participation in a single-day, veteran-based, adaptive kayaking and sailing event on the perceived overall health, quality of life, and quality of social life of veterans with varying disabilities. It was hypothesized that all three categories and the sum score of quality of life would reflect a positive acute response after participation in the community-based physical activity event. Veterans responded to three quality of life-related questions using a 5-point Likert scale before and directly after participating in the event. Findings indicated that an adaptive sporting event can have an acute positive influence on the quality of life of veteran participants, with improvements observed in all three categories of perceived quality of life. Therefore, it is advantageous for the whole-health rehabilitation of veterans with disabilities for the Department of Veterans Affairs to continue to provide opportunities for veterans to participate in non-traditional, community-based activities.

Ever since the first documented use of an anesthetic nearly 166 years ago, the mechanisms by which general anesthetics produce unconsciousness have remained elusive. Recently, the endogenous neural circuitry that underlies transitions between sleep and wakefulness has emerged as an intriguing possible mediator for the hypnotic properties of general anesthetics. Increasing amounts of evidence suggest that the \"flip-flop\" switch model for sleep—reciprocal inhibitory connections between wake-active centers such as the orexinergic neurons in the hypothalamus and sleep-active centers such as the ventrolateral preoptic nucleus (VLPO) ensure quick, stable transitions between wakefulness and sleep—could also contribute to anesthetic-induced hypnosis (Chapter 1). In Chapter 2 we demonstrate that the forward and reverse paths through which anesthetic-induced hypnosis arises and dissipates are not identical. The hysteresis that separates induction from emergence is not a pharmacokinetic side-effect, and can be manipulated with single gene mutations that are known to affect sleep and wakefulness. The processes of induction and emergence are further distinguished in Chapter 3, where we demonstrate that genetic ablation of the wake-active (and anesthetic-inhibited) orexinergic neurons in the hypothalamus delays emergence but does not affect induction. Finally, in Chapter 4, we show that the sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) play a role in induction: the sleep-active neurons—but not the neighboring state-indifferent neurons—are directly depolarized by isoflurane, and VLPO lesions produce an acute resistance to induction. Together, this work supports the emerging hypothesis that at least some general anesthetics promote unconsciousness by acting on sleep/wake circuits. We identify the orexinergic neurons of the hypothalamus as a critical component of emergence from anesthesia and the sleep-active neurons in the VLPO as a similarly key mediator of induction.

Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.

Conservation machine learning conserves models across runs, users, and experiments—and puts them to good use. We have previously shown the merit of this idea through a small-scale preliminary experiment, involving a single dataset source, 10 datasets, and a single so-called cultivation method—used to produce the final ensemble. In this paper, focusing on classification tasks, we perform extensive experimentation with conservation random forests, involving 5 cultivation methods (including a novel one introduced herein— lexigarden ), 6 dataset sources, and 31 datasets. We show that significant improvement can be attained by making use of models we are already in possession of anyway, and envisage the possibility of repositories of models (not merely datasets, solutions, or code), which could be made available to everyone, thus having conservation live up to its name, furthering the cause of data and computational science.

The rapid pace of innovation in biological imaging and the diversity of its applications have prevented the establishment of a community-agreed standardized data format. We propose that complementing established open formats such as OME-TIFF and HDF5 with a next-generation file format such as Zarr will satisfy the majority of use cases in bioimaging. Critically, a common metadata format used in all these vessels can deliver truly findable, accessible, interoperable and reusable bioimaging data.OME’s next-generation file format (OME-NGFF) provides a cloud-native complement to OME-TIFF and HDF5 for storing and accessing bioimaging data at scale and works toward the goal of findable, accessible, interoperable and reusable bioimaging data.

In the flowering of Red-Green Thought over the past two decades, metabolic rift thinking is surely one of its most colorful varieties. The metabolic rift has captured the imagination of critical environmental scholars, becoming a shorthand for capitalism's troubled relations in the web of life. This article pursues an entwined critique and reconstruction: of metabolic rift thinking and the possibilities for a post-Cartesian perspective on historical change, the world-ecology conversation. Far from dismissing metabolic rift thinking, my intention is to affirm its dialectical core. At stake is not merely the mode of explanation within environmental sociology. The impasse of metabolic rift thinking is suggestive of wider problems across the environmental social sciences, now confronted by a double challenge. One of course is the widespread—and reasonable—sense of urgency to evolve modes of thought appropriate to an era of deepening biospheric instability. The second is the widely recognized—but inadequately internalized—understanding that humans are part of nature.

Mathieu Lupien, Jason Moore and colleagues show that breast cancer risk–associated SNPs commonly disrupt the binding of FOXA1 to chromatin, thereby directly affecting gene expression. Genome-wide association studies (GWAS) have identified thousands of SNPs that are associated with human traits and diseases. But, because the vast majority of these SNPs are located in non-coding regions of the genome, the mechanisms by which they promote disease risk have remained elusive. Employing a new methodology that combines cistromics, epigenomics and genotype imputation, we annotate the non-coding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results show that breast cancer risk–associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of histone H3 lysine 4 monomethylation (H3K4me1) in a cancer- and cell type–specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus.

Accurate prediction of disease risk based on the genetic make-up of an individual is essential for effective prevention and personalized treatment. Nevertheless, to date, individual genetic variants from genome-wide association studies have achieved only moderate prediction of disease risk. The aggregation of genetic variants under a polygenic model shows promising improvements in prediction accuracies. Increasingly, electronic health records (EHRs) are being linked to patient genetic data in biobanks, which provides new opportunities for developing and applying polygenic risk scores in the clinic, to systematically examine and evaluate patient susceptibilities to disease. However, the heterogeneous nature of EHR data brings forth many practical challenges along every step of designing and implementing risk prediction strategies. In this Review, we present the unique considerations for using genotype and phenotype data from biobank-linked EHRs for polygenic risk prediction.Electronic health records (EHRs) linked to biobanks provide new opportunities for developing and applying polygenic risk scores in the clinic. The authors review the opportunities and challenges that arise when using EHR data for the systematic evaluation of patient disease susceptibilities.