The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify ...astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.
•We develop the first method to acutely purify fetal and adult human astrocytes•We obtain transcriptome profiles of human neurons, glia, and vascular cells•While similar, human and mouse astrocytes have unique genomic and functional traits•Human astrocytes exist in at least two distinct developmental stages
Zhang et al. developed a method to acutely purify healthy and diseased human astrocytes and to culture them in serum-free conditions. They obtained transcriptome profiles of purified human CNS cell types and discovered two distinct stages of human astrocyte development.
•SFD builds capacity via social interaction, skill building, and empowerment.•SFD may be less effective developing shared values and critical learning cultures.•There is a need for evidence of ...capacity building outcomes in North America.•Sport practitioners need grounding in developmental components of SFD programs.•Participatory action research may better promote capacity building through SFD.
Population health promotion and preventing disease remain important global policy goals. Because of the complex nature of health, and the recognition of the limits of individual-oriented health promotion strategies, recent decades have seen increased interest by public health researchers and practitioners in community-level approaches to health promotion. Increasingly, community-level approaches have been based upon the theoretical concept of community capacity. Community capacity is seen as a critical mechanism for supporting and promoting community-level health and through the sport for development (SFD) model, there is evidence of sport being an important practice for community development. However, little is known about the potential role of sport as a mechanism for building community capacity. Therefore, the purpose of this review is to examine the efficacy of sport to contribute to the process of community capacity building. Using seven established dimensions of community capacity, there is evidence that many SFD practices can effectively facilitate dimensions of community capacity when conducted in intentional, culturally relevant ways. Specifically, sport has demonstrated efficacy in building local skills, knowledge, and resources, increasing social cohesion, facilitating structures and mechanisms for community dialog, leadership development, and encouraging civic participation. More research is needed to understand sport's ability to promote capacity building through collective action, developing value systems that support democracy and inclusion, and encouraging critical reflection. To increase the usefulness of sport to support community health development, SFD principles should be included as part of sport management university curricula. Additionally, practitioners need grounding in community and human development research to support non-sport components of programs. Finally, participatory action research techniques should be used by researchers and practitioners. Sport-based development often generates high interest from residents, funders, and policy makers. By applying principles of community capacity building, sport may be uniquely positioned to enhance sustainable community health development initiatives.
Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug-target combinations exist, it would be useful ...to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H(4) receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (<100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available ...tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.
Chordomas are malignant neoplasms that typically arise in the axial spine and primarily affect adults. When chordomas arise in pediatric patients they are more likely to display unusual histological ...features and aggressive behavior. We noted the absence of SMARCB1/INI1 expression by immunohistochemistry in an index case of poorly differentiated chordoma of the sacrum, leading us to further examine SMARCB1/INI1 expression as well as that of brachyury, a highly specific marker of notochordal differentiation, in 3 additional poorly differentiated chordomas of the clivus, 10 typical chordomas, and 8 atypical teratoid/rhabdoid tumors (AT/RTs). All 4 poorly differentiated chordomas and all AT/RTs lacked nuclear expression of SMARCB1/INI1, while the 10 typical chordomas maintained strong nuclear SMARCB1/INI1 immunoreactivity. All 10 typical and 4 poorly differentiated chordomas expressed brachyury; all 8 AT/RTs were brachyury immunonegative. Cytogenetic evaluation utilizing FISH probes near the SMARCB1/INI1 locus on chromosome 22q was also performed in all of the poorly differentiated chordomas in this series. Three of the four poorly differentiated chordomas had evidence for deletion of this region by FISH. Analysis of the SMARCB1/INI1 gene sequence was performed using formalin-fixed paraffin-embedded tissue in all cases and no point mutations were observed. In summary, all poorly differentiated chordomas in this series showed the absence of SMARCB1/INI1 expression, and were reliably distinguished from AT/RTs, clinically by their characteristic primary sites of origin and pathologically by strong nuclear brachyury expression. Our findings reveal a likely role for SMARCB1/INI1 in a subset of chordomas with aggressive features.
Background Availability of parks is associated with higher levels of physical activity among children and adolescents. Few studies examine actual park use and park-based physical activity in these ...populations. Purpose This study examined associations among individual, park, and neighborhood environmental characteristics and children's and adolescent's park-based physical activity. Methods Data were collected in 2007 on 2712 children in 20 randomly selected parks in Durham NC. The System for Observing Play and Recreation in Communities (SOPARC) provided measures of physical activity. Hierarchic regression analysis assessed associations among individual, park, and neighborhood environmental characteristics and children's park-based physical activity. Data were analyzed in 2010. Results Of the 2712 children observed, 34.2% and 13.2% were engaged in walking or vigorous physical activity. Environmental features of parks were associated with activity levels whereas neighborhood characteristics were not. Physical activity was negatively associated with gender (girls) ( p =0.003); presence of a parent ( p <0.0001); presence of nonparental adult ( p =0.006); and an interaction involving the 0–5 years age group and style of play ( p =0.017). Higher level of physical activity was associated with presence of other active children ( p <0.0001); courts (e.g., basketball); and an interaction between number of recreation facilities and formal activities ( p =0.004). Conclusions These social factors and design features should be considered in order to stimulate higher levels of park-based physical activity among children and adolescents.
Microbiomes confer beneficial physiological traits to their host, but microbial diversity is inherently variable, challenging the relationship between microbes and their contribution to host health. ...Here, we compare the diversity and architectural complexity of the epidermal microbiome from 74 individual whale sharks (Rhincodon typus) across five aggregations globally to determine if network properties may be more indicative of the microbiome-host relationship. On the premise that microbes are expected to exhibit biogeographic patterns globally and that distantly related microbial groups can perform similar functions, we hypothesized that microbiome co-occurrence patterns would occur independently of diversity trends and that keystone microbes would vary across locations. We found that whale shark aggregation was the most important factor in discriminating taxonomic diversity patterns. Further, microbiome network architecture was similar across all aggregations, with degree distributions matching Erdos-Renyi-type networks. The microbiome-derived networks, however, display modularity indicating a definitive microbiome structure on the epidermis of whale sharks. In addition, whale sharks hosted 35 high-quality metagenome assembled genomes (MAGs) of which 25 were present from all sample locations, termed the abundant 'core'. Two main MAG groups formed, defined here as Ecogroup 1 and 2, based on the number of genes present in metabolic pathways, suggesting there are at least two important metabolic niches within the whale shark microbiome. Therefore, while variability in microbiome diversity is high, network structure and core taxa are inherent characteristics of the epidermal microbiome in whale sharks. We suggest the host-microbiome and microbe-microbe interactions that drive the self-assembly of the microbiome help support a functionally redundant abundant core and that network characteristics should be considered when linking microbiomes with host health.
Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneous ...heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis after vaccination with the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson) have previously been described.
To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States.
Case series.
United States.
Case patients receiving a COVID-19 vaccine from 14 December 2020 through 31 August 2021 with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction) reported to the Vaccine Adverse Event Reporting System. If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for antiplatelet factor 4 antibodies or functional heparin-induced thrombocytopenia platelet test result was required.
Reporting rates (cases per million vaccine doses) and descriptive epidemiology.
A total of 57 TTS cases were confirmed after vaccination with Ad26.COV2.S (
= 54) or a messenger RNA (mRNA)-based COVID-19 vaccine (
= 3). Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). The median age of patients with TTS after Ad26.COV2.S vaccination was 44.5 years (range, 18 to 70 years), and 69% of patients were women. Of the TTS cases after mRNA-based COVID-19 vaccination, 2 occurred in men older than 50 years and 1 in a woman aged 50 to 59 years. All cases after Ad26.COV2.S vaccination involved hospitalization, including 36 (67%) with intensive care unit admission. Outcomes of hospitalizations after Ad26.COV2.S vaccination included death (15%), discharge to postacute care (17%), and discharge home (68%).
Underreporting and incomplete case follow-up.
Thrombosis with thrombocytopenia syndrome is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the 3 cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate.
Centers for Disease Control and Prevention.
Assigning behavioral functions to neural structures has long been a central goal in neuroscience and is a necessary first step toward a circuit-level understanding of how the brain generates ...behavior. Here, we map the neural substrates of locomotion and social behaviors for Drosophila melanogaster using automated machine-vision and machine-learning techniques. From videos of 400,000 flies, we quantified the behavioral effects of activating 2,204 genetically targeted populations of neurons. We combined a novel quantification of anatomy with our behavioral analysis to create brain-behavior correlation maps, which are shared as browsable web pages and interactive software. Based on these maps, we generated hypotheses of regions of the brain causally related to sensory processing, locomotor control, courtship, aggression, and sleep. Our maps directly specify genetic tools to target these regions, which we used to identify a small population of neurons with a role in the control of walking.
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•We developed machine-vision methods to broadly and precisely quantify fly behavior•We measured effects of activating 2,204 genetically targeted neuronal populations•We created whole-brain maps of neural substrates of locomotor and social behaviors•We created resources for exploring our results and enabling further investigation
Machine-vision analyses of large behavior and neuroanatomy data reveal whole-brain maps of regions associated with numerous complex behaviors.
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