Glassharrison5728

tes considering the birth weight and serum creatinine.Neonatal sepsis accounts for significant morbidity and mortality, particularly among premature infants in the Neonatal Intensive Care Unit. Abnormal vital sign patterns serve as physiomarkers of sepsis and provide early warning of illness before overt clinical decompensation. The systemic inflammatory response to pathogens signals the autonomic nervous system, leading to changes in temperature, respiratory rate, heart rate, and blood pressure. In infants with comorbidities of prematurity, vital sign abnormalities often occur in the absence of infection, which confounds sepsis diagnosis. This review will cover the mechanisms of vital sign changes in neonatal sepsis, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve, which is critical to the host response to infectious and inflammatory insults. We will also review the clinical implications of vital sign changes in neonatal sepsis, including their use in early warning scores and systems to direct clinicians to the bedside of infants with physiologic changes that might be due to sepsis. IMPACT This manuscript summarizes and reviews the relevant literature on the physiological manifestations of neonatal sepsis and how we monitor and analyze these through vital signs and advanced analytics.Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis and electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after- hyperpolarization potentials, an action potential duration of ~3 ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at a frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, as well as those from isogenic induced GABAergic and glutamatergic neurons, were enriched in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder; however, each neuronal subtype demonstrated subtype-specific heritability enrichments in biologically relevant pathways, and iDANs alone were uniquely enriched in autism spectrum disorder risk loci. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.Long-read technologies hold the promise to obtain more complete genome assemblies and to make them easier. Coupled with long-range technologies, they can reveal the architecture of complex regions, like centromeres or rDNA clusters. These technologies also make it possible to know the complete organization of chromosomes, which remained complicated before even when using genetic maps. However, generating a gapless and telomere-to-telomere assembly is still not trivial, and requires a combination of several technologies and the choice of suitable software. Here, we report a chromosome-scale assembly of a banana genome (Musa acuminata) generated using Oxford Nanopore long-reads. We generated a genome coverage of 177X from a single PromethION flowcell with near 17X with reads longer than 75 kbp. From the 11 chromosomes, 5 were entirely reconstructed in a single contig from telomere to telomere, revealing for the first time the content of complex regions like centromeres or clusters of paralogous genes.Punishment involves learning the relationship between actions and their adverse consequences. Both the acquisition and expression of punishment learning depend on the basolateral amygdala (BLA), but how BLA supports punishment remains poorly understood. To address this, we measured calcium (Ca2+) transients in BLA principal neurons during punishment. Male rats were trained to press two individually presented levers for food; when one of these levers also yielded aversive footshock, responding on this punished lever decreased relative to the other, unpunished lever. CX-5461 nmr In rats with the Ca2+ indicator GCaMP6f targeted to BLA principal neurons, we observed excitatory activity transients to the footshock punisher and inhibitory transients to lever-presses earning a reward. Critically, as rats learned punishment, activity around the punished response transformed from inhibitory to excitatory and similarity analyses showed that these punished lever-press transients resembled BLA transients to the punisher itself. Systemically administered benzodiazepine (midazolam) selectively alleviated punishment. Moreover, the degree to which midazolam alleviated punishment was associated with how much punished response-related BLA transients reverted to their pre-punishment state. Together, these findings show that punishment learning is supported by aversion-coding of instrumental responses in the BLA and that the anti-punishment effects of benzodiazepines are associated with a reversion of this aversion coding.Memories of negative experiences exert important control of behavior in the face of actual or anticipated threat. Sometimes, however, this control extends to non-threatening situations, a phenomenon known as overgeneralization of negative memories. Overgeneralization is a reliable cognitive phenotype of major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder. We therefore sought to develop an animal model to study stress-induced generalization of negative memories (SIG) and determine its dependence on the episodic-like memory circuit. We found that male and female mice, which were trained to differentiate a threatening from neutral context, exhibited robust SIG in response to subsequent social stress. Using chemogenetic circuit manipulations during memory retrieval, we demonstrated that both excitatory afferents to the dorsal hippocampus (DH) from the ventral tegmental area (VTA), and excitatory efferents from the DH to the retrosplenial cortex (RSC) contribute to SIG. Based on the known roles of these projections, we suggest that (1) by targeting subcortical VTA circuits that provide valence signals to the DH, stress prioritizes the retrieval of negative over neutral memories, and (2) by forwarding such information to the RSC, stress engages cortical mechanisms that support the retrieval of general relative to specific memory features. Altogether, these results suggest that various components of the extended hippocampal circuit can serve as treatment targets for memory overgeneralization.Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.The current standard of care for many patients with HER2-positive breast cancer is neoadjuvant chemotherapy in combination with anti-HER2 agents, based on HER2 amplification as detected by in situ hybridization (ISH) or protein immunohistochemistry (IHC). However, hematoxylin & eosin (H&E) tumor stains are more commonly available, and accurate prediction of HER2 status and anti-HER2 treatment response from H&E would reduce costs and increase the speed of treatment selection. Computational algorithms for H&E have been effective in predicting a variety of cancer features and clinical outcomes, including moderate success in predicting HER2 status. In this work, we present a novel convolutional neural network (CNN) approach able to predict HER2 status with increased accuracy over prior methods. We trained a CNN classifier on 188 H&E whole slide images (WSIs) manually annotated for tumor Regions of interest (ROIs) by our pathology team. Our classifier achieved an area under the curve (AUC) of 0.90 in cross-validation of slide-level HER2 status and 0.81 on an independent TCGA test set. Within slides, we observed strong agreement between pathologist annotated ROIs and blinded computational predictions of tumor regions / HER2 status. Moreover, we trained our classifier on pre-treatment samples from 187 HER2+ patients that subsequently received trastuzumab therapy. Our classifier achieved an AUC of 0.80 in a five-fold cross validation. Our work provides an H&E-based algorithm that can predict HER2 status and trastuzumab response in breast cancer at an accuracy that may benefit clinical evaluations.Metastatic tumors (MTs) may show different characteristics of the immune microenvironment from primary tumors (PTs) in non-small cell lung cancer (NSCLC). The heterogeneity of immune markers in metastatic NSCLC and its associated factors has not been well demonstrated. In this study, 64 surgically resected specimens of paired PTs and MTs were obtained from 28 patients with NSCLC. Multiplex immunofluorescence (mIF; panel including programmed death-ligand 1 (PD-L1), Cytokeratin, CD8, and CD68) was performed on whole sections. The heterogeneity of the immune contexture of PD-L1 expression, infiltrating lymphocytes, and immune-to-tumor cell distances was quantified via digital image analysis. In a quantitative comparison of MTs and corresponding PTs, MTs showed higher PD-L1 expression levels, lower density of CD8+ cytotoxic T lymphocytes (CTLs), and longer spatial distance between CTLs and tumor cells. Subgroup analysis, which associated clinical factors, revealed that the heterogeneity of immune markers was more obvious in extrapulmonary, metachronous, and treated MTs, while fewer differences were observed in intrapulmonary, synchronous, and untreated MTs.