Increased Burden of Suicidality Among Young Street-Involved Sex Workers who Use Drugs in Vancouver, Canada

Abstract: Background: The risks of suicidality among street-involved youth who use drugs and engage in sex work is not well described. This study sought to evaluate if street-involved youth who engage in sex work were at an elevated risk for attempting suicide. Methods: Data were derived from the At-Risk Youth Study, a prospective cohort of street-involved youth who use drugs in Vancouver, Canada. Multivariable generalized estimating equation analyses were employed to examine whether youth who engaged in sex work were at elevated risk of attempting suicide, controlling for possible confounders. Results: Between September 2005 and May 2015, 1210 youth were recruited into the cohort, of whom, 173 (14.3%) reported recently attempting suicide at some point during the study period. In multivariable analysis, youth who engaged in sex work were significantly more likely to report a recent suicide attempt (adjusted odds ratio=1.93; 95% confidence interval: 1.28-2.91). Conclusions: Street-involved youth who engage in sex work were observed to be at a significantly higher risk for suicidality. Systematic discrimination and unaddressed trauma may contribute to the observed increased burden of suicidality among this population. Interventions that support the mental health and well-being of street-involved youth who engage in sex work are urgently needed

Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages

© 2019 the American Physiological Society. previously showed that mice deficient in apo-ptosis signal-regulating kinase-1 (ASK1) were partially protected against ventilator-induced lung injury. Because ASK1 can promote both cell death and inflammation, we hypothesized that ASK1 activation regulates inflammasome-mediated inflammation. Mice deficient in ASK1 expression (ASK1 +/+ ) exhibited significantly less inflammation and lung injury (as measured by neutrophil infiltration, IL-6, and IL-1β) in response to treatment with inhaled lipopolysaccharide (LPS) compared with wild-type (WT) mice. To determine whether this proinflammatory response was mediated by ASK1, we investigated inflammasome-mediated responses to LPS in primary macrophages and bone marrow-derived macrophages (BMDMs) from WT and ASK1 +/+ mice, as well as the mouse alveolar macrophage cell line MH-S. Cells were treated with LPS alone for priming or LPS followed by ATP for activation. When macrophages were stimulated with LPS followed by ATP to activate the inflammasome, we found a significant increase in secreted IL-1β from WT cells compared with ASK1-deficient cells. LPS priming stimulated an increase in NOD-like receptor 3 (NLRP3) and pro-IL-1β in WT BMDMs, but expression of NLRP3 was significantly decreased in ASK1 +/+ BMDMs. Subsequent ATP treatment stimulated an increase in cleaved caspase-1 and IL-1β in WT BMDMs compared with ASK1 +/+ BMDMs. Similarly, treatment of MH-S cells with LPS + ATP caused an increase in both cleaved caspase-1 and IL-1β that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming

Chemosensory modulation of neural circuits for sodium appetite

Sodium is the main cation in the extracellular fluid and it regulates various physiological functions. Depletion of sodium in the body increases the hedonic value of sodium taste, which drives animals towards sodium consumption. By contrast, oral sodium detection rapidly quenches sodium appetite, suggesting that taste signals have a central role in sodium appetite and its satiation. Nevertheless, the neural mechanisms of chemosensory-based appetite regulation remain poorly understood. Here we identify genetically defined neural circuits in mice that control sodium intake by integrating chemosensory and internal depletion signals. We show that a subset of excitatory neurons in the pre-locus coeruleus express prodynorphin, and that these neurons are a critical neural substrate for sodium-intake behaviour. Acute stimulation of this population triggered robust ingestion of sodium even from rock salt, while evoking aversive signals. Inhibition of the same neurons reduced sodium consumption selectively. We further demonstrate that the oral detection of sodium rapidly suppresses these sodium-appetite neurons. Simultaneous in vivo optical recording and gastric infusion revealed that sodium taste—but not sodium ingestion per se—is required for the acute modulation of neurons in the pre-locus coeruleus that express prodynorphin, and for satiation of sodium appetite. Moreover, retrograde-virus tracing showed that sensory modulation is in part mediated by specific GABA (γ-aminobutyric acid)-producing neurons in the bed nucleus of the stria terminalis. This inhibitory neural population is activated by sodium ingestion, and sends rapid inhibitory signals to sodium-appetite neurons. Together, this study reveals a neural architecture that integrates chemosensory signals and the internal need to maintain sodium balance

3D-cultured blastoids model human embryogenesis from pre-implantation to early gastrulation stages

Naive human pluripotent stem cells have the remarkable ability to self-organize into blastocyst-like structures ( blastoids ) that model lineage segregation in the pre-implantation embryo. However, the extent to which blastoids can recapitulate the defining features of human post-implantation development remains unexplored. Here, we report that blastoids cultured on thick three-dimensional (3D) extracellular matrices capture hallmarks of early post-implantation development, including epiblast lumenogenesis, rapid expansion and diversification of trophoblast lineages, and robust invasion of extravillous trophoblast cells by day 14. Extended blastoid culture results in the localized activation of primitive streak marker TBXT and the emergence of embryonic germ layers by day 21. We also show that the modulation of WNT signaling alters the balance between epiblast and trophoblast fates in post-implantation blastoids. This work demonstrates that 3D-cultured blastoids offer a continuous and integrated in vitro model system of human embryonic and extraembryonic development from pre-implantation to early gastrulation stages

Interaction effects of polyfluoroalkyl substances and sex steroid hormones on asthma among children

To evaluate the interactions between polyfluoroalkyl substances (PFASs) and reproductive hormones and associated asthma, a total of 231 asthmatic and 225 non-asthmatic adolescents were selected from northern Taiwan in the Genetic and Biomarkers study for Childhood Asthma from 2009-2010. The interaction between PFASs and reproductive hormones on asthma was analyzed with a two-level binary logistic regression model. The results showed that, among asthmatics, PFASs were positively associated with estradiol levels and negatively associated with testosterone levels. However, only significant association was identified for PFNA and estradiol in control group. After controlling for hormone levels, associations between PFAS exposure and asthma were consistently stronger among children with higher than lower estradiol, with odds ratios (OR) for asthma ranging from 1.25 for PFOS (95% Confidence Interval [CI]: 0.90, 1.72) to 4.01 for PFDA (95% CI: 1.46, 11.06) among boys and 1.25 for PFOS (95% CI: 0.84, 1.86) to 4.16 for PFNA (95% CI: 1.36, 12.73) among girls. Notably, the interactions between estradiol and PFASs were significant for PFOS (p = 0.026) and PFNA (p = 0.043) among girls. However, testosterone significantly attenuated the association between PFOS and asthma across sex. In conclusions, our findings suggested that reproductive hormones amplify the association between PFASs and asthma among adolescents

Direct images and spectroscopy of a giant protoplanet driving spiral arms in MWC 758

Understanding the driving forces behind spiral arms in protoplanetary disks remains a challenge due to the faintness of young giant planets. MWC 758 hosts such a protoplanetary disk with a two-armed spiral pattern that is suggested to be driven by an external giant planet. We present new thermal infrared observations that are uniquely sensitive to redder (i.e., colder or more attenuated) planets than past observations at shorter wavelengths. We detect a giant protoplanet, MWC 758c, at a projected separation of ~100 au from the star. The spectrum of MWC 758c is distinct from the rest of the disk and consistent with emission from a planetary atmosphere with Teff = 500 +/- 100 K for a low level of extinction (AV<30), or a hotter object with a higher level of extinction. Both scenarios are commensurate with the predicted properties of the companion responsible for driving the spiral arms. MWC 758c provides evidence that spiral arms in protoplanetary disks can be caused by cold giant planets or by those whose optical emission is highly attenuated. MWC 758c stands out both as one of the youngest giant planets known, and also as one of the coldest and/or most attenuated. Furthermore, MWC 758c is among the first planets to be observed within a system hosting a protoplanetary disk.Comment: Published in Nature Astronom

Investigation of Testosterone, Androstenone, and Estradiol Metabolism in HepG2 Cells and Primary Culture Pig Hepatocytes and Their Effects on 17βHSD7 Gene Expression

Steroid metabolism is important in various species. The accumulation of androgen metabolite, androstenone, in pig adipose tissue is negatively associated with pork flavor, odour and makes the meat unfit for human consumption. The 17β-hydroxysteroid dehydrogenase type 7 (17βHSD7) expressed abundantly in porcine liver, and it was previously suggested to be associated with androstenone levels. Understanding the enzymes and metabolic pathways responsible for androstenone as well as other steroids metabolism is important for improving the meat quality. At the same time, metabolism of steroids is known to be species- and tissue-specific. Therefore it is important to investigate between-species variations in the hepatic steroid metabolism and to elucidate the role of 17βHSD7 in this process. Here we used an effective methodological approach, liquid chromatography coupled with mass spectrometry, to investigate species-specific metabolism of androstenone, testosterone and beta-estradiol in HepG2 cell line, and pig cultured hepatocytes. Species- and concentration-depended effect of steroids on 17βHSD7 gene expression was also investigated. It was demonstrated that the investigated steroids can regulate the 17βHSD7 gene expression in HepG2 and primary cultured porcine hepatocytes in a concentration-dependent and species-dependent pattern. Investigation of steroid metabolites demonstrated that androstenone formed a 3′-hydroxy compound 3β-hydroxy-5α-androst-16-ene. Testosterone was metabolized to 4-androstene-3,17-dione. Estrone was found as the metabolite for β-estradiol. Inhibition study with 17βHSD inhibitor apigenin showed that apigenin didn't affect androstenone metabolism. Apigenin at high concentration (50 μM) tends to inhibit testosterone metabolism but this inhibition effect was negligible. Beta-estradiol metabolism was notably inhibited with apigenin at high concentration. The study also established that the level of testosterone and β-estradiol metabolites was markedly increased after co-incubation with high concentration of apigenin. This study established that 17βHSD7 is not the key enzyme responsible for androstenone and testosterone metabolism in porcine liver cells. © 2012 Chen et al

Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs

Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD