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Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival 1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A 1 R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

Risk variants for schizophrenia affect more than 100 genomic loci, yet cell- and tissue-specific roles underlying disease liability remain poorly characterized. We have generated for two cortical areas implicated in psychosis, the dorsolateral prefrontal cortex and anterior cingulate cortex, 157 reference maps from neuronal, neuron-depleted and bulk tissue chromatin for two histone marks associated with active promoters and enhancers, H3-trimethyl-Lys4 (H3K4me3) and H3-acetyl-Lys27 (H3K27ac). Differences between neuronal and neuron-depleted chromatin states were the major axis of variation in histone modification profiles, followed by substantial variability across subjects and cortical areas. Thousands of significant histone quantitative trait loci were identified in neuronal and neuron-depleted samples. Risk variants for schizophrenia, depressive symptoms and neuroticism were significantly over-represented in neuronal H3K4me3 and H3K27ac landscapes. Our Resource, sponsored by PsychENCODE and CommonMind, highlights the critical role of cell-type-specific signatures at regulatory and disease-associated noncoding sequences in the human frontal lobe.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org.

Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development. Human embryo development involves extensive transcriptional remodeling. In this study, the authors apply long- and short-read RNA-Seq to profile the transcriptomes of 73 human preimplantation embryos spanning zygotic to blastocyst stages, identifying tens of thousands of additional isoforms transcribed from both known and unannotated gene loci.

Human immunodeficiency virus (HIV) infection depletes CD4 T-cells, and long-term persistence of latent virus prevents full clearance of HIV even in the presence of effective antiretroviral therapy (ART), Here we present the HIV-1-induced lineage tracing (HILT) system, a model that irreversibly marks infected cells within a humanized mouse model, which detects rare latently infected cells. Immunodeficient mice transplanted with genetically modified hematopoietic stem cells develop a human immune system, in which CD4 T-cells contain a genetic switch that permanently labels cells infected by HIV-1 expressing cre-recombinase. Through single-cell RNA sequencing of HILT-marked cells during acute infection and post-ART treatment, we identify distinct CD4+ T-cell transcriptional lineages enriched in either active or latent infections. Comparative gene expression analysis highlights common pathways modulated in both states, including EIF2, Sirtuin, and protein ubiquitination. Critical regulators of these pathways, including JUN , BCL2 , and MDM2 , change to opposite directions in the two states, highlighting gene expression programs that may support HIV persistence across T-cell lineages and states. Characterization of HIV infection at the cellular level is important to understand the molecular forces maintaining the latent reservoir and productive infection in T cells. Here authors describe the pathways that are governing these T cell states across the T lineage via a humanized mouse model allowing precise labeling of the HIV-infected cells coupled to single cell RNA sequencing.

The removal of carbonyl sulfide (COS), a byproduct gas in the steel industry, is crucial due to its environmental impact, including acid rain formation and corrosion of chemical equipment. This study explores enhancing the catalytic performance for COS hydrolysis at low temperatures by loading potassium hydroxide (KOH) onto boehmite catalysts. The modified catalysts demonstrated significantly improved COS conversion rates and hydrogen sulfide (H 2 S) yields compared to untreated counterparts. At 40 °C, K/Boehmite catalysts achieved approximately 80% COS conversion. As the temperature increased to 50, 60, and 70 °C, COS conversion efficiencies neared 100%, with H 2 S yields reaching up to 98% for K/Boehmite-3 (A method involving the loading of KOH onto boehmite catalysts.) Characterization results confirmed that KOH increased the number of active sites on the catalyst surface, enhancing COS adsorption and reaction. The KOH modification increases alkalinity and promotes the formation of surface hydroxyl groups, which play a key role in the hydrolysis reaction. These hydroxyl groups facilitate water adsorption and the breakdown of COS into H 2 S and CO 2 . This study presents a straightforward method for KOH impregnation on boehmite, marking the first use of boehmite as a COS hydrolysis catalyst, significantly boosting its efficiency and offering a viable solution for industrial COS removal while effectively generating H 2 S.

Clinical measurement. Manual dexterity is an important aspect of motor function across the age span. To identify a single measure of manual dexterity for inclusion in the National Institutes of Health (NIH) Toolbox Assessment of Neurological and Behavioral Function. A total of 340 subjects participated in our study. Two alternatives, Rolyan ® 9-Hole Peg Test (9-HPT) and Grooved Pegboard test, were compared by assessing their score range across age groups (3–85 yr) and their test–retest reliability, concurrent, and known groups validity. The 9-HPT was a simple, efficient, and low-cost measure of manual dexterity appropriate for administration across the age range. Test–retest reliability coefficients were 0.95 and 0.92 for right and left hands, respectively. The 9-HPT correlated with Bruininks-Oseretsky Test (BOT) of Motor Proficiency, dexterity subscale, at −0.87 to −0.89 and with Purdue Pegboard at −0.74 to −0.75. The Grooved Pegboard had good test–retest reliability (0.91 and 0.85 for right and left hands, respectively). The Grooved Pegboard correlated with BOT at −0.50 to −0.63 and with Purdue Pegboard at −0.73 to −0.78. However, the Grooved Pegboard required longer administration time and was challenging for the youngest children and oldest adults. Based on its feasibility and measurement properties, the 9-HPT was recommended for inclusion in the motor battery of the NIH Toolbox. NA.

Cross-sectional observational, clinical measurement. Manual dexterity is an important aspect of motor function across the age span. To present the norms for the 9-Hole Peg Test (9-HPT) across the age span (3–85 years) and compare the 9-HPT performance by age group, gender, dominance, handedness, ethnicity, race, and language preference. A population-based sample of 4319 subjects contributed data to this study which was part of the NIH Toolbox Norming Project. The 16–39 age groups demonstrated the shortest completion time (dominant hand, males completed a trial in 19–20 s, and females 18–19 s), and the youngest children 3–5 age groups showed the longest completion time with largest variation (males 32–51 s and females 32–45 s). Across all age groups, females performed slightly better as compared to males (22.5 versus 24.2 s). Dominant hands completed the test more quickly than the non-dominant hands (23.3 versus 25.4 s). Individuals who are not Hispanic or Latino performed slightly better than individuals who are Hispanic or Latino (22.2 versus 25.6 s). The completion time for English speakers was shorter than Spanish speakers (22.3 versus 27.8 s). There were no statistical differences by handedness (P = 0.6) or race (White versus Black or African American, P = 0.4). We present norms of the 9-HPT established by the NIH Toolbox. The norms can be used to determine the presence of impairments in dexterity across the age span. NA

Minimal clinically important improvement (MCII) is the smallest outcome measure change important to patients. Research suggests that MCII is dependent on patients' baseline functional status measures. The purposes of this study were: (1) to confirm whether MCII is dependent on patients' admission scores and (2) to test whether MCII is dependent on selected demographic characteristics. This was a prospective, longitudinal, observational cohort study of 6,651 patients with orthopedic knee impairments treated in 332 outpatient rehabilitation clinics in 27 states in the United States. Patient self-reports of functional status (FS) from the Lower Extremity Functional Scale were assessed using a computerized adaptive testing application (0-100 scale). An anchored-based longitudinal method, with a 15-point Likert-type scale (-7 to +7), was used to provide a global rating of change (GROC). The MCII threshold for the GROC was defined at a cut-score of +3 or greater and was determined using nonparametric receiver operating characteristic curve analysis for each of the following variables: sex, symptom acuity, age group, and quartile of baseline FS scores. The results showed that MCII was dependent on patient baseline and demographic characteristics. Patients who were male, were younger, had more-acute symptoms, or had lower FS scores at admission required more FS change to report meaningful change. As this study was a secondary analysis, how the length of treatment mediated the relationship between the independent and dependent variables was unclear. Although a single MCII index may provide a standard cut-score defining the smallest FS change that is meaningful to patients, researchers and clinicians should be aware that MCII is context specific and not a fixed attribute. Current results may help researchers, clinicians, and policy makers to interpret FS change related to the importance of the change to the patient.

Numerous reports document the spread of SARS-CoV-2, but there is limited information on its introduction before the identification of a local case. This may lead to incorrect assumptions when modeling viral origins and transmission. Here, we utilize a sample pooling strategy to screen for previously undetected SARS-CoV-2 in de-identified, respiratory pathogen-negative nasopharyngeal specimens from 3,040 patients across the Mount Sinai Health System in New York. The patients had been previously evaluated for respiratory symptoms or influenza-like illness during the first 10 weeks of 2020. We identify SARS-CoV-2 RNA from specimens collected as early as 25 January 2020, and complete SARS-CoV-2 genome sequences from multiple pools of samples collected between late February and early March, documenting an increase prior to the later surge. Our results provide evidence of sporadic SARS-CoV-2 infections a full month before both the first officially documented case and emergence of New York as a COVID-19 epicenter in March 2020. Matthew M. Hernandez and Ana S. Gonzalez-Reiche and colleagues report evidence of SARSCoV-2 infections in respiratory pathogen-negative nasopharyngeal specimens collected in New York, which date back to over one month before the first officially documented case in the state. The findings provide insights in to the origins of the virus in New York.