Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice

The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis-associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety-like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner

Identification of A Novel Class of Benzofuran Oxoacetic Acid-Derived Ligands that Selectively Activate Cellular EPAC1

Cyclic AMP promotes EPAC1 and EPAC2 activation through direct binding to a specific cyclic nucleotide-binding domain (CNBD) within each protein, leading to activation of Rap GTPases, which control multiple cell responses, including cell proliferation, adhesion, morphology, exocytosis, and gene expression. As a result, it has become apparent that directed activation of EPAC1 and EPAC2 with synthetic agonists may also be useful for the future treatment of diabetes and cardiovascular diseases. To identify new EPAC agonists we have developed a fluorescent-based, ultra-high-throughput screening (uHTS) assay that measures the displacement of binding of the fluorescent cAMP analogue, 8-NBD-cAMP to the EPAC1 CNBD. Triage of the output of an approximately 350,000 compound screens using this assay identified a benzofuran oxaloacetic acid EPAC1 binder (SY000) that displayed moderate potency using orthogonal assays (competition binding and microscale thermophoresis). We next generated a limited library of 91 analogues of SY000 and identified SY009, with modifications to the benzofuran ring associated with a 10-fold increase in potency towards EPAC1 over SY000 in binding assays. In vitro EPAC1 activity assays confirmed the agonist potential of these molecules in comparison with the known EPAC1 non-cyclic nucleotide (NCN) partial agonist, I942. Rap1 GTPase activation assays further demonstrated that SY009 selectively activates EPAC1 over EPAC2 in cells. SY009 therefore represents a novel class of NCN EPAC1 activators that selectively activate EPAC1 in cellulae

Body composition and physical activity in New Zealand Maori, Pacific and European children aged 5-14 years

Body fatness and the components of energy expenditure in children aged 5-14 years were investigated. In a group of seventy-nine healthy children (thirty-nine female, forty male), mean age 10-0 (SD 2-8) years, comprising twenty-seven Maori, twenty-six Pacific Island and twenty-six European, total energy expenditure (TEE) was determined over 10d using the doubly-labelled water method. Resting metabolic rate (RMR) was measured by indirect calorimetry and physical activity level (PAL) was calculated as TEE:RMR. Fat-free mass (FFM), and hence fat mass, was derived from the O-18-dilution space using appropriate values for FFM hydration in children. Qualitative information on physical activity patterns was obtained by questionnaire. Maori and Pacific children had a higher BMI than European children (P< 0.003), but % body fat was similar for the three ethnic groups. The % body fat increased with age for girls (r 0-42, P=0008), but not for boys. Ethnicity was not a significant predictor of RMR adjusted for FFM and fat mass. TEE and PAL, adjusted for body weight and age, were higher in Maori than European children (

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists

Spatial and Functional Characterization of Microbial Residents in the Human Placenta

A healthy placenta is critical to a healthy pregnancy because it is the principal organ that nurtures and protects the fetus until delivery. Among its many functions, it governs fetal nutrition, waste disposal, gas exchange, and fetal tolerance. Notably, the placenta has both maternal and fetal compartments that serve as powerful structural and immunological barriers against pathogens — including bacteria and viruses. The maternal compartment comprises the basal plate, which harbors fetal-derived trophoblasts that are in direct contact with maternal endothelial and immune cells. The fetal compartment harbors the placental villi, which are bathed in maternal blood and serve as site of maternal-fetal exchange. Finally, the fetal membranes encapsulate the amniotic cavity.Historically, the placenta was considered sterile because relatively few pathogens have been shown to breach this robust barrier. Transplacental microbes often incite pathways that lead to local and systemic immune activation and result in adverse outcomes such as loss of fetal viability or preterm birth. Despite advances in maternal and neonatal healthcare, preterm birth remains a global health problem, accounting for the majority of neonatal deaths for children under 5 years old. Contrary to the conventional sterile-womb paradigm, histological, PCR-based, and sequencing analyses point to the presence of “characteristically” non-pathogenic bacteria in normal term placentas. However the localization, impact, and origins of these bacteria on pregnancy and neonatal physiology is not understood.To address spatial localization within the placenta, we profiled the bacteria within the basal plate, placental villi, and fetal membranes using a multi-variable region 16S ribosomal sequencing and described the taxonomic composition, absolute abundance, predominant species, and bacterial diversity within each region. Indeed, we found that placental microbes at term exhibit spatially variable profiles. Furthermore, we found that Ralstonia insidiosa, a waterborne bacterium, dominates the basal plate region in normal term placentas.We tested the cell-specific localization and impact of R. insidiosa within the basal plate using cultured explants derived from term placentas and a cell line that phenotypically resembles fetal trophoblasts within the basal plate. We showed that R. insidiosa resides in the placental BP by direct localization of R. insidiosa within human basal plate biopsies and a trophoblast cell line. Furthermore, R. insidiosa replicates within these models and does not exhibit typical signs of pathogenicity such as overt inflammatory responses or cell death.To address the origins of R. insidiosa within the placenta, we examined potential routes of R. insidiosa entry into the placenta and associated pregnancy outcomes using a pregnant mouse model. We found that R. insidiosa colonizes the placenta via the intrauterine route and does not cause preterm labor. Together, this data supports the hypothesis that R. insidiosa normally seeds the placenta via the intrauterine route. For the first time, we show that R. insidiosa crosses placental barriers without causing adverse responses. Future studies will address the functional relevance of R. insidiosa for placental and neonatal physiology

Seeing COVID-19 through an urban lens

COVID-19 has changed the face of cities and recast urban life globally. In turn, cities have become the major theatres of the crisis for a once-in-a-century test to global resilience. Global health governance has thus far struggled to face up to the urban character of the pandemic. The UN Secretary General recently called for a better appreciation of how COVID-19 is unfolding in “an urban world” if we are to rebuild more sustainably. We argue it is imperative do so by attending to urban inequalities that underpin the crisis, and by understanding the fundamental inclusive development opportunity at play here if we allow urban expertise, and cities, closer to the heart of the global response. Under the presumptive ‘new normal’ of COVID-19, multiple intersecting policy agendas have come to the fore not just in the shape of health concerns but also with regards to environmental sustainability and ‘green’ economic recovery. Much of this has had to do with recasting the ways we live in cities. The UN has already stressed that approximately 95% of COVID-19 cases have taken place in urban settlements, with over 1,500 cities affected worldwide. Many have made the case that post-pandemic planning discussion must transcend dualistic framings pitting ‘health’ versus ‘environmental’ concerns, whilst not giving in to simplistic economic growth approaches. By far and large that implies radical changes to our cities and urban livelihoods. Yet these are rarely at the centre of the multilateral debate. We urgently need to attend to the urban socio-economic crisis underpinning COVID-19 that unfolds amidst the most vulnerable in cities both at the inter- and intra-urban scale