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School is a key site for prevention and early intervention in public mental health, with sexual and gender minority students being a priority group for action. Context is important in understanding how school inclusion of sexual and gender minorities shapes mental health and well-being, with rapidly changing social and political forces necessitating ongoing research. This coproduced UK secondary school-based study aimed to understand (a) key components of mentally, socially and emotionally healthy school environments for LGBTQ+ students considerate of intersecting minoritised identities; (b) staff information, skills and capacity needs and (c) factors influencing uptake and implementation. Online interviews and focus groups were conducted with 63 participants (22 staff, 32 students (aged 13-19 years), and 9 training providers), diverse in relation to gender and sexual identity, ethnicity, religious and social context. Data were analysed thematically. One overarching theme captured the need for an intersectionality-informed, contextually adaptable, whole school approach which 'shifts the narrative' away from deficit thinking, challenging prevailing cis/heteronormative and White norms. This underpinned four themes: (1) 'Feeling safe, seen and celebrated: embedding intersectional signs, signals and symbols', (2) 'Everyone's business: the need for collaboration', (3) 'Embedding a culture of change', and (4) 'Re-locating the problem: challenging deficit thinking'. Contextually diverse research is needed which critically addresses ways in which social power enacted interpersonally and structurally serves to hinder schools from enacting LGBTQ+ inclusivity. Evidence to inform and develop implementation strategies for institutional changes and to advocate for wider socio-political support is also key to mitigate the potential for widening inequities linked to inequitable school environments.

Understanding how different Black and other racially minoritised communities thrive is an emerging priority area in mental health promotion. Literature demonstrates health benefits of social capital (social resources embedded within social networks). However, its effects are not always positive, particularly for certain subpopulations who are already disadvantaged.The CONtributions of social NEtworks to Community Thriving (CONNECT) study will use Participatory Action Research (PAR) to investigate social capital as a resource that benefits (or hinders) racially minoritised communities and their mental health. The CONNECT study was designed within a partnership with community organisations and responds to local policy in two South-East London Boroughs, thereby providing potential channels for the action component of PAR. Taking an anti-racism lens, we acknowledge the underpinning role of racism in creating health inequities. We apply an intersectional framework to be considerate of overlapping forms of oppression such as age, gender, socioeconomic status, and sexual orientation as an essential part of developing effective strategies to tackle health inequities. Key components of this mixed methods PAR study include (1) involving racialised minority community members as peer researchers in the team (2) collecting and analysing primary qualitative data via interviews, photovoice, and community mapping workshops, (3) developing relevant research questions guided by peer researchers and collaborating organisations and analysing secondary quantitative data accordingly, (4) integrating qualitative and quantitative phases, and (5) working closely with community and policy partners to act on our findings and use our research for social change.The PAR approach will allow us to engage community (voluntary sector and government) and academic partners in decision making and help address imbalances in power and resource allocation. Knowledge generated through this collaborative approach will contribute to existing community initiatives, policies, and council strategies. This will ensure the views and experiences of racially minoritised communities drive the changes we are collaboratively committed to achieving.

[This corrects the article DOI: 10.1371/journal.pone.0161345.].

BackgroundAntimicrobial resistance (AMR) is currently one of the global public health threats. Increased antibiotic consumption in humans, animals, and agriculture has contributed directly to the spread of AMR. Upper respiratory tract infections (URIs) are one of the most common conditions treated by antibiotics, even if unnecessary as in cases of viral infections and self-limited conditions which represent the most cases of URIs. Investigating physicians' knowledge, attitudes, and practice regarding antibiotic prescriptions in children with acute URIs may reflect the problem of antibiotic over prescription. This study aims to assess the problem in our community and provide information for further planning of appropriate interventions to optimize antibiotic prescriptions.MethodsThis is a cross-sectional study for all non-specialized physicians dealing with acute upper respiratory tract infections (URIs) in pediatrics sittings in Assiut district, Egypt. We used a self-administered questionnaire to assess physicians' knowledge, attitudes, and practice. In addition, four clinical vignettes addressing different URI scenarios were included in the questionnaire to assess the patterns of antibiotic prescriptions in common cases.ResultsOur study included 153 physicians whose mean age was 32.2 ± 8.7, most of whom were pediatric residents in different health institutes in Assiut district. They had good knowledge as out of the 17 knowledge questions,the mean number of correct answers was 12.4 ± 2.9. Regarding their attitudes, mean attitude scores for inappropriate antibiotic prescribing were low. However, of those scores, the responsibility of others had the highest score (3.8 ± 0.61). Prescribing practice in special conditions of URIs showed that 80% of participants prescribed antibiotics if fever continued for more than five days and 61.4% if the child had a yellowish or greenish nasal discharge. Among 612 clinical vignettes, 326 contained antibiotic prescriptions (53.3%), and appropriate antibiotic prescriptions represented only 8.3% overall.ConclusionsPhysicians dealing with acute URIs in outpatients' clinics in the Assiut district have good knowledge about antibiotic use and resistance and demonstrate a good attitude toward appropriate antibiotic use. Although the percentage of inappropriate prescriptions in clinical vignettes in high, more research is required to investigate the factors of antibiotic inappropriate prescribing practice and non-adherence to guidelines. Also, it is essential to set up a national antibiotic stewardship program to improve antibiotic prescribing and contain antimicrobial resistance problems.

BackgroundWe conducted an overview of systematic reviews (SRs) summarizing the best evidence regarding the effect of COVID-19 on maternal and child health following Cochrane methods and PRISMA statement for reporting (PROSPERO-CRD42020208783).MethodsWe searched literature databases and COVID-19 research websites from January to October 2020. We selected relevant SRs reporting adequate search strategy, data synthesis, risk of bias assessment, and/or individual description of included studies describing COVID-19 and pregnancy outcomes. Pair of reviewers independently selected studies through COVIDENCE web-software, performed the data extraction, and assessed its quality through the AMSTAR-2 tool. Discrepancies were resolved by consensus. Each SR's results were synthesized and for the most recent, relevant, comprehensive, and with the highest quality, by predefined criteria, we presented GRADE evidence tables.ResultsWe included 66 SRs of observational studies out of 608 references retrieved and most (61/66) had "critically low" overall quality. We found a relatively low degree of primary study overlap across SRs. The most frequent COVID-19 clinical findings during pregnancy were fever (28-100%), mild respiratory symptoms (20-79%), raised C-reactive protein (28-96%), lymphopenia (34-80%), and pneumonia signs in diagnostic imaging (7-99%). The most frequent maternal outcomes were C-section (23-96%) and preterm delivery (14-64%). Most of their babies were asymptomatic (16-93%) or presented fever (0-50%), low birth weight (5-43%) or preterm delivery (2-69%). The odds ratio (OR) of receiving invasive ventilation for COVID-19 versus non-COVID-19 pregnant women was 1.88 (95% Confidence Interval [CI] 1.36-2.60) and the OR that their babies were admitted to neonatal intensive care unit was 3.13 (95%CI 2.05-4.78). The risk of congenital transmission or via breast milk was estimated to be low, but close contacts may carry risks.ConclusionThis comprehensive overview supports that pregnant women with COVID-19 may be at increased risk of adverse pregnancy and birth outcomes and low risk of congenital transmission.

PurposeGender minority (GM) adolescents, who have a different gender identity than their sex assigned at birth, may use substances as a coping strategy in response to GM-related stressors. This study examined longitudinal effects of gender minority stressors on substance use in GM adolescents, and related risk factors (internalized transphobia, depressive symptoms, anxious symptoms) and protective factors (resilience, gender-related pride, family functioning, social support, gender-related community connectedness).MethodsParticipants were 30 GM adolescents, ages 13-17 years, from the U.S. community-based longitudinal Trans Teen and Family Narratives Project. Participants completed an online survey every 6 months across 2 years (5 waves; data collected 2015-2019).ResultsExposure to gender minority stressors was associated with higher odds of alcohol use. Across models, internalized transphobia (risk factor), resilience (protective factor), and gender-related pride (protective factor) were the most significant mediators of associations between gender minority stressors and substance use. Family functioning and social support (protective factors) significantly moderated the association between gender minority stressors and alcohol use, such that family functioning and social support were protective for alcohol use at lower levels of gender minority stress, but not at higher levels.ConclusionResults suggest that GM adolescents engage in substance use as a coping strategy in response to gender minority stressors. A number of hypothesized risk and protective factors mediated or moderated these associations. Future interventions with GM adolescents should focus efforts on addressing internalized transphobia as a risk factor and strengthening resilience, gender-related pride, and family functioning as protective factors for substance use.

It is well established that sex differences exist in the manifestation of vascular diseases. Arterial stiffness (AS) has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a decline on executive function (EF) tasks. Interestingly, the relationship between AS and CVR is more complex, where some studies show decreased CVR with increased AS, and others demonstrate preserved CVR despite higher AS. Here, we investigated the possible role of sex on these hemodynamic relationships. Acquisitions were completed in 48 older adults. Pseudo-continuous arterial spin labeling (pCASL) data were collected during a hypercapnia challenge. Aortic pulse wave velocity (PWV) data was acquired using cine phase contrast velocity series. Cognitive function was assessed with a comprehensive neuropsychological battery, and a composite score for EF was calculated using four cognitive tests from the neuropsychological battery. A moderation model test revealed that sex moderated the relationship between PWV and CVR and PWV and EF, but not between CVR and EF. Together, our results indicate that the relationships between central stiffness, cerebral hemodynamics and cognition are in part mediated by sex.

In utero Zika virus (ZIKV; family Flaviviridae) infection causes a distinct pattern of birth defects and disabilities in the developing fetus and neonate that has been termed congenital zika syndrome (CZS). Over 8,000 children were affected by the 2016 to 2017 ZIKV outbreak in the Americas, many of whom developed CZS as a result of in utero exposure. To date, there is no consensus about how ZIKV causes CZS; animal models, however, are providing mechanistic insights. Using nonhuman primates, immunocompromised mice, immunocompetent mice, and other animal models (e.g., pigs, sheep, guinea pigs, and hamsters), studies are showing that maternal immunological responses, placental infection and inflammation, as well as viral genetic factors play significant roles in predicting the downstream consequences of in utero ZIKV infection on the development of CZS in offspring. There are thousands of children suffering from adverse consequences of CZS. Therefore, the animal models developed to study ZIKV-induced adverse outcomes in offspring could provide mechanistic insights into how other viruses, including influenza and hepatitis C viruses, impact placental viability and fetal growth to cause long-term adverse outcomes in an effort to identify therapeutic treatments.

Circulating androgens can modulate immune cell activity, but the impact of androgens on viral pathogenesis remains unclear. Previous data demonstrate that testosterone reduces the severity of influenza A virus (IAV) infection in male mice by mitigating pulmonary inflammation rather than by affecting viral replication. To examine the immune responses mediated by testosterone to mitigate IAV-induced inflammation, adult male mice remained gonadally intact or were gonadectomized and treated with either placebo or androgen-filled (i.e., testosterone or dihydrotestosterone) capsules prior to sublethal IAV infection. Like intact males, treatment of gonadectomized males with androgens improved the outcome of IAV infection, which was not mediated by changes in the control of virus replication or pulmonary cytokine activity. Instead, androgens accelerated pulmonary leukocyte contraction to limit inflammation. To identify which immune cells were contracting in response to androgens, the composition of pulmonary cellular infiltrates was analyzed and revealed that androgens specifically accelerated the contraction of total pulmonary inflammatory monocytes during peak disease, as well as CD8+ T cells, IAV-specific CD8+ T numbers, cytokine production and degranulation by IAV-specific CD8+ T cells, and the influx of eosinophils into the lungs following clearance of IAV. Neither depletion of eosinophils nor adoptive transfer of CD8+ T cells could reverse the ability of testosterone to protect males against IAV suggesting these were secondary immunologic effects. The effects of testosterone on the contraction of immune cell numbers and activity were blocked by co-administration of the androgen receptor antagonist flutamide and mimicked by treatment with dihydrotestosterone, which was also able to reduce the severity of IAV in female mice. These data suggest that androgen receptor signaling creates a local pulmonary environment that promotes downregulation of detrimental inflammatory immune responses to protect against prolonged influenza disease.

Only a single drug against schistosomiasis is currently available and new drug development is urgently required but very few drug targets have been validated and characterised. However, regulatory systems including cyclic nucleotide metabolism are emerging as primary candidates for drug discovery. Here, we report the cloning of ten cyclic nucleotide phosphodiesterase (PDE) genes of S. mansoni, out of a total of 11 identified in its genome. We classify these PDEs by homology to human PDEs. Male worms displayed higher expression levels for all PDEs, in mature and juvenile worms, and schistosomula. Several functional complementation approaches were used to characterise these genes. We constructed a Trypanosoma brucei cell line in which expression of a cAMP-degrading PDE complements the deletion of TbrPDEB1/B2. Inhibitor screens of these cells expressing only either SmPDE4A, TbrPDEB1 or TbrPDEB2, identified highly potent inhibitors of the S. mansoni enzyme that elevated the cellular cAMP concentration. We further expressed most of the cloned SmPDEs in two pde1Δ/pde2Δ strains of Saccharomyces cerevisiae and some also in a specialised strain of Schizosacharomyces pombe. Five PDEs, SmPDE1, SmPDE4A, SmPDE8, SmPDE9A and SmPDE11 successfully complemented the S. cerevisiae strains, and SmPDE7var also complemented to a lesser degree, in liquid culture. SmPDE4A, SmPDE8 and SmPDE11 were further assessed in S. pombe for hydrolysis of cAMP and cGMP; SmPDE11 displayed considerable preferrence for cGMP over cAMP. These results and tools enable the pursuit of a rigorous drug discovery program based on inhibitors of S. mansoni PDEs.

The current novel coronavirus disease 2019 (COVID-19) pandemic is revealing profound differences between men and women in disease outcomes worldwide. In the United States, there has been inconsistent reporting and analyses of male-female differences in COVID-19 cases, hospitalizations, and deaths. We seek to raise awareness about the male-biased severe outcomes from COVID-19, highlighting the mechanistic differences including in the expression and activity of angiotensin-converting enzyme 2 (ACE2) as well as in antiviral immunity. We also highlight how sex differences in comorbidities, which can be associated with both age and race, impact male-biased outcomes from COVID-19.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.

BACKGROUND:Maternal smoking during pregnancy has repeatedly been associated with decreased sperm counts in sons. Nevertheless, our team recently detected a lower total sperm count in the sons of smoking fathers as compared to sons of non-smoking fathers. Since paternal and maternal tobacco smoking often coincide, it is difficult to discriminate whether effects are mediated paternally or maternally when using questionnaire- or register-based studies. Therefore, getting an objective measure of the maternal nicotine exposure level during pregnancy might help disentangling the impact of paternally and maternally derived exposure. OBJECTIVES:Our aim was to study how paternal smoking at the time of the pregnancy was associated with semen quality in the sons after adjusting for the maternal levels of nicotine exposure during pregnancy. METHODS:We recruited 104 men (17-20 years old) from the general Swedish population. The participants answered a questionnaire about paternal smoking. Associations between smoking and semen volume, total sperm count, sperm concentration, morphology and motility were adjusted for levels of the nicotine metabolite cotinine in stored maternal serum samples obtained from rubella screening between the 6th and 35th week of pregnancy. We additionally adjusted for the estimated socioeconomic status. RESULTS:After adjusting for the maternal cotinine, the men of smoking fathers had 41% lower sperm concentration and 51% lower total sperm count than the men of non-smoking fathers (p = 0.02 and 0.003, respectively). This was robust to the additional adjustment. CONCLUSIONS:Our results suggest a negative association between paternal smoking and sperm counts in the sons, independent of the level maternal nicotine exposure during the pregnancy.

Prenatal heavy metals exposure has shown a negative impact on birth weight. However, their influence on different clinical forms of fetal smallness was never assessed.To investigate whether there is a differential association between heavy metals exposure and fetal smallness subclassification into intrauterine growth restriction (IUGR) and small-for-gestational age (SGA).In this prospective case-control study, we included 178 mother-infant pairs; 96 of appropriate for gestational age (AGA) and 82 of small fetuses diagnosed in third trimester. The small ones were further subclassified into IUGR, n = 49 and SGA, n = 33. Cadmium (Cd), mercury (Hg), lead (Pb), arsenic (As) and zinc (Zn) levels were measured in the maternal and cord serum, and in the placentas of the three groups.Maternal serum level of Cd (p

Spinal cord injury (SCI) is associated with complex pathophysiological processes that follow the primary traumatic event and determine the extent of secondary damage and functional recovery. Numerous reports have used global and hypothesis-driven approaches to identify protein changes that contribute to the overall pathology of SCI in an effort to identify potential therapeutic interventions. In this study, we use a semi-automatic annotation approach to detect terms referring to genes or proteins dysregulated in the SCI literature and develop a curated SCI interactome. Network analysis of the SCI interactome revealed the presence of a rich-club organization corresponding to a "powerhouse" of highly interacting hub-proteins. Studying the modular organization of the network have shown that rich-club proteins cluster into modules that are specifically enriched for biological processes that fall under the categories of cell death, inflammation, injury recognition and systems development. Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI. In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy. Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates.

Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women's health.

Dictyostelium discoideum has been used largely as a model organism to study the organization and function of the endocytic pathway. Here we describe dense structures present in D. discoideum endocytic compartments, which we named pycnosomes. Pycnosomes are constitutively secreted in the extracellular medium, from which they can be recovered by differential centrifugation. We identified the most abundant protein present in secreted pycnosomes, that we designated SctA. SctA defines a new family of proteins with four members in D. discoideum, and homologous proteins in other protists and eumetazoa. We developed a monoclonal antibody specific for SctA and used it to further characterize secreted and intracellular pycnosomes. Within cells, immunofluorescence as well as electron microscopy identified pycnosomes as SctA-enriched dense structures in the lumen of endocytic compartments. Pycnosomes are occasionally seen in continuity with intra-endosomal membranes, particularly in U18666A-treated cells where intraluminal budding is highly enhanced. While the exact nature, origin and cellular function of pycnosomes remain to be established, this study provides a first description of these structures as well as a characterization of reagents that can be used for further studies.

INTRODUCTION:Globally, rotavirus (RV) is the leading cause of gastroenteritis (GE) in children. Longitudinal data about changes in RV genotype distribution and vaccine effectiveness (VE) are scarce. This study was conducted in Lebanon over 3 consecutive RV seasons to estimate the rate of RVGE hospitalization, identify RV genotypes, determine the seasonal and geographical variations, and calculate RV VE. MATERIALS AND METHODS:This prospective, multicenter, hospital-based surveillance study was conducted between 2011 and 2013 and enrolled children (

Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095 mg/cc, bone: 570-1415 mg/cc, cementum: 1240-1340 mg/cc, dentin: 1480-1590 mg/cc, cementum affected by periodontitis: 1100-1220 mg/cc, hypomineralized carious dentin: 345-1450 mg/cc, hypermineralized carious dentin: 1815-2740 mg/cc, and dental calculus: 1290-1770 mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.

INTRODUCTION:It has been reported that posttraumatic stress disorder (PTSD) is associated with secondary spouse/partner (S/P) emotional distress and relationship violence. OBJECTIVE:To investigate the relationships between PTSD, S/P emotional distress and relationship violence among police recruits using a prospective design. METHODS:Two hypotheses were tested in 71 S/Ps: (1) Police officer reports of greater PTSD symptoms after 12 months of police service will be associated with greater secondary trauma symptoms among S/Ps; (2) Greater secondary trauma symptoms among S/Ps at 12 months will be associated with S/P reports of greater relationship violence. METHODS:71 police recruits and their S/Ps were assessed at baseline and 12 months after the start of police officer duty. Using linear and logistic regression, we analyzed explanatory variables for 12 month S/P secondary traumatic stress symptoms and couple violence, including baseline S/P variables and couple violence, as well as exposure and PTSD reports from both S/P and officer. RESULTS:S/P perception of officer PTSD symptoms predicted S/P secondary traumatic stress. OS/P secondary trauma was significantly associated with both total couple violence (.34, p = .004) and S/P to officer violence (.35, p = .003). CONCLUSIONS:Although results from this relatively small study of young police officers and their S/Ps must be confirmed by larger studies in general populations, findings suggest that S/P perception of PTSD symptoms may play a key role in the spread of traumatic stress symptoms across intimate partner relationships and intimate partner violence in the context of PTSD.

Sleep-wake cycling is controlled by the complex interplay between two brain systems, one which controls vigilance state, regulating the transition between sleep and wake, and the other circadian, which communicates time-of-day. Together, they align sleep appropriately with energetic need and the day-night cycle. Neural circuits connect brain stem sites that regulate vigilance state with the suprachiasmatic nucleus (SCN), the master circadian clock, but the function of these connections has been unknown. Coupling discrete stimulation of pontine nuclei controlling vigilance state with analytical chemical measurements of intra-SCN microdialysates in mouse, we found significant neurotransmitter release at the SCN and, concomitantly, resetting of behavioral circadian rhythms. Depending upon stimulus conditions and time-of-day, SCN acetylcholine and/or glutamate levels were augmented and generated shifts of behavioral rhythms. These results establish modes of neurochemical communication from brain regions controlling vigilance state to the central circadian clock, with behavioral consequences. They suggest a basis for dynamic integration across brain systems that regulate vigilance states, and a potential vulnerability to altered communication in sleep disorders.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Interactions between the cell basal membrane domain and the basement membrane are involved in several cell functions including proliferation, migration and differentiation. Intestinal epithelial cells can interact with laminin, a major intestinal basement membrane glycoprotein, via several cell-surface laminin-binding proteins including integrin and non-integrin receptors. The 37/67kDa laminin receptor (37/67LR) is one of these but its role in normal epithelial cells is still unknown. The aim of this study was to characterise the expression pattern and determine the main function of 37/67LR in the normal human small intestinal epithelium. Immunolocalization studies revealed that 37/67LR was predominantly present in the undifferentiated/proliferative region of the human intestinal crypt in both the immature and adult intestine. Using a human intestinal epithelial crypt (HIEC) cell line as experimental model, we determined that 37/67LR was expressed in proliferative cells in both the cytoplasmic and membrane compartments. Small-interfering RNA-mediated reduction of 37/67LR expression led to HIEC cell-cycle reduction and loss of the ability to adhere to laminin-related peptides under conditions not altering ribosomal function. Taken together, these findings indicate that 37/67LR regulates proliferation and adhesion in normal intestinal epithelial cells independently of its known association with ribosomal function.

Functional loads on an organ induce tissue adaptations by converting mechanical energy into chemical energy at a cell-level. The transducing capacity of cells alters physico-chemical properties of tissues, developing a positive feedback commonly recognized as the form-function relationship. In this study, organ and tissue adaptations were mapped in the bone-tooth complex by identifying and correlating biomolecular expressions to physico-chemical properties in rats from 1.5 to 15 months. However, future research using hard and soft chow over relevant age groups would decouple the function related effects from aging affects. Progressive curvature in the distal root with increased root resorption was observed using micro X-ray computed tomography. Resorption was correlated to the increased activity of multinucleated osteoclasts on the distal side of the molars until 6 months using tartrate resistant acid phosphatase (TRAP). Interestingly, mononucleated TRAP positive cells within PDL vasculature were observed in older rats. Higher levels of glycosaminoglycans were identified at PDL-bone and PDL-cementum entheses using alcian blue stain. Decreasing biochemical gradients from coronal to apical zones, specifically biomolecules that can induce osteogenic (biglycan) and fibrogenic (fibromodulin, decorin) phenotypes, and PDL-specific negative regulator of mineralization (asporin) were observed using immunohistochemistry. Heterogeneous distribution of Ca and P in alveolar bone, and relatively lower contents at the entheses, were observed using energy dispersive X-ray analysis. No correlation between age and microhardness of alveolar bone (0.7 ± 0.1 to 0.9 ± 0.2 GPa) and cementum (0.6 ± 0.1 to 0.8 ± 0.3 GPa) was observed using a microindenter. However, hardness of cementum and alveolar bone at any given age were significantly different (P

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.

BackgroundThe nuclear receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an important coordinator of glucose homeostasis. We report, for the first time, a unique differential regulation of its expression by the nutritional status in the mouse hypothalamus compared to peripheral tissues.Methodology/principal findingsUsing hyperinsulinemic-euglycemic clamps and insulinopenic mice, we show that insulin upregulates its expression in the hypothalamus. Immunofluorescence studies demonstrate that COUP-TFII gene expression is restricted to a subpopulation of ventromedial hypothalamic neurons expressing the melanocortin receptor. In GT1-7 hypothalamic cells, the MC4-R agonist MTII leads to a dose dependant increase of COUP-TFII gene expression secondarily to a local increase in cAMP concentrations. Transfection experiments, using a COUP-TFII promoter containing a functional cAMP responsive element, suggest a direct transcriptional activation by cAMP. Finally, we show that the fed state or intracerebroventricular injections of MTII in mice induce an increased hypothalamic COUP-TFII expression associated with a decreased hepatic and pancreatic COUP-TFII expression.Conclusions/significanceThese observations strongly suggest that hypothalamic COUP-TFII gene expression could be a central integrator of insulin and melanocortin signaling pathway within the ventromedial hypothalamus. COUP-TFII could play a crucial role in brain integration of circulating signal of hunger and satiety involved in energy balance regulation.

BACKGROUND:Community interactions can produce complex dynamics with counterintuitive responses. Synanthropic community members are of increasing practical interest for their effects on biodiversity and public health. Most studies incorporating introduced species have been performed on islands where they may pose a risk to the native fauna. Few have examined their interactions in urban environments where they represent the majority of species. We characterized house cat (Felis catus) predation on wild Norway rats (Rattus norvegicus), and its population effects in an urban area as a model system. Three aspects of predation likely to influence population dynamics were examined; the stratum of the prey population killed by predators, the intensity of the predation, and the size of the predator population. METHODOLOGY/PRINCIPAL FINDINGS:Predation pressure was estimated from the sizes of the rat and cat populations, and the characteristics of rats killed in 20 alleys. Short and long term responses of rat population to perturbations were examined by removal trapping. Perturbations removed an average of 56% of the rats/alley but had no negative long-term impact on the size of the rat population (49.6+/-12.5 rats/alley and 123.8+/-42.2 rats/alley over two years). The sizes of the cat population during two years (3.5 animals/alley and 2.7 animals/alley) also were unaffected by rat population perturbations. Predation by cats occurred in 9/20 alleys. Predated rats were predominantly juveniles and significantly smaller (144.6 g+/-17.8 g) than the trapped rats (385.0 g+/-135.6 g). Cats rarely preyed on the larger, older portion of the rat population. CONCLUSIONS/SIGNIFICANCE:The rat population appears resilient to perturbation from even substantial population reduction using targeted removal. In this area there is a relatively low population density of cats and they only occasionally prey on the rat population. This occasional predation primarily removes the juvenile proportion of the rat population. The top predator in this urban ecosystem appears to have little impact on the size of the prey population, and similarly, reduction in rat populations doesn't impact the size of the cat population. However, the selected targeting of small rats may locally influence the size structure of the population which may have consequences for patterns of pathogen transmission.

Hantaviruses, similar to several emerging zoonotic viruses, persistently infect their natural reservoir hosts, without causing overt signs of disease. Spillover to incidental human hosts results in morbidity and mortality mediated by excessive proinflammatory and cellular immune responses. The mechanisms mediating the persistence of hantaviruses and the absence of clinical symptoms in rodent reservoirs are only starting to be uncovered. Recent studies indicate that during hantavirus infection, proinflammatory and antiviral responses are reduced and regulatory responses are elevated at sites of increased virus replication in rodents. The recent discovery of structural and non-structural proteins that suppress type I interferon responses in humans suggests that immune responses in rodent hosts could be mediated directly by the virus. Alternatively, several host factors, including sex steroids, glucocorticoids, and genetic factors, are reported to alter host susceptibility and may contribute to persistence of hantaviruses in rodents. Humans and reservoir hosts differ in infection outcomes and in immune responses to hantavirus infection; thus, understanding the mechanisms mediating viral persistence and the absence of disease in rodents may provide insight into the prevention and treatment of disease in humans. Consideration of the coevolutionary mechanisms mediating hantaviral persistence and rodent host survival is providing insight into the mechanisms by which zoonotic viruses have remained in the environment for millions of years and continue to be transmitted to humans.