Postnatal Developmental Trends in Membrane Excitability and BK Channel Function in the Rodent Hippocampus

This dissertation outlines the postnatal development of excitability as well as expression and function of BK potassium channels in hippocampal neurons. I used patch clamp electrophysiology to measure how neuronal action potential waveforms and action potential firing frequencies change in early development, and how pharmacological blockade of BK channels affects these properties in hippocampal neurons. I also describe how the protein expression of the BK channel pore-forming α subunit and mRNA expression of different variants of the pore forming α subunit and auxiliary beta-4 subunit changes with development. I demonstrate in both cultured rat hippocampal neurons across the first seven postnatal days and in putative mouse hippocampal pyramidal neurons from postnatal day four to fifteen in acutely prepared slices that maturation brings changes in action potential kinetics and large increases in the capacity for high frequency firing. In the cultured neurons I demonstrate that during the first postnatal week, the contribution of BK channels to action potential repolarization decreases but the channel’s role in maintaining high-frequency firing increases. This change in the timing of BK channel activity in the action potential waveform is accompanied by a slowing of BK current onset measured by a decreasing effect of BK current blockade on potassium current rise time. Additionally, I demonstrated in pyramidal neurons in mouse brain slices that there is a loss of BK channel contribution to action potential repolarization between postnatal day four and fifteen. These changes in the BK channel’s role in neuronal action potential firing are accompanied by large increases in the expression of α subunit protein measured by Western blot and by large increases in mRNA transcript expression, measured by RT-qPCR, of both the α and beta-4 subunits in the hippocampus. The rise in beta-4 subunit expression can explain the apparent slowing of BK channel activation through development. I investigated whether BK channel blockade in neonatal brain slices could attenuate hyperexcitability in a model of seizure activity as BK channels in immature neurons share properties of BK channel variants implicated in epilepsy but found no evidence to support this hypothesis

The Swift Ultra-Violet/Optical Telescope

The UV/Optical Telescope (UVOT) is one of three instruments flying aboard the Swift Gamma-ray Observatory. It is designed to capture the early (approximately 1 minute) UV and optical photons from the afterglow of gamma-ray bursts in the 170-600 nm band as well as long term observations of these afterglows. This is accomplished through the use of UV and optical broadband filters and grisms. The UVOT has a modified Ritchey-Chretien design with micro-channel plate intensified charged-coupled device detectors that record the arrival time of individual photons and provide sub-arcsecond positioning of sources. We discuss some of the science to be pursued by the UVOT and the overall design of the instrument.Comment: 55 Pages, 28 Figures, To be published in Space Science Review

Abnormalities of White Matter Microstructure in Unmedicated Obsessive-Compulsive Disorder and Changes after Medication

BACKGROUND: Abnormalities of myelin integrity have been reported in obsessive-compulsive disorder (OCD) using multi-parameter maps of diffusion tensor imaging (DTI). However, it was still unknown to what degree these abnormalities might be affected by pharmacological treatment. OBJECTIVE: To investigate whether the abnormalities of white matter microstructure including myelin integrity exist in OCD and whether they are affected by medication. METHODOLOGY AND PRINCIPAL FINDINGS: Parameter maps of DTI, including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD), were acquired from 27 unmedicated OCD patients (including 13 drug-naïve individuals) and 23 healthy controls. Voxel-based analysis was then performed to detect regions with significant group difference. We compared the DTI-derived parameters of 15 patients before and after 12-week Selective Serotonin Reuptake Inhibitor (SSRI) therapies. Significant differences of DTI-derived parameters were observed between OCD and healthy groups in multiple structures, mainly within the fronto-striato-thalamo-cortical loop. An increased RD in combination with no change in AD among OCD patients was found in the left medial superior frontal gyrus, temporo-parietal lobe, occipital lobe, striatum, insula and right midbrain. There was no statistical difference in DTI-derived parameters between drug-naive and previously medicated OCD patients. After being medicated, OCD patients showed a reduction in RD of the left striatum and right midbrain, and in MD of the right midbrain. CONCLUSION: Our preliminary findings suggest that abnormalities of white matter microstructure, particularly in terms of myelin integrity, are primarily located within the fronto-striato-thalamo-cortical circuit of individuals with OCD. Some abnormalities may be partly reversed by SSRI treatment

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Phase 1 trial to model primary, secondary, and tertiary dengue using a monovalent vaccine.

Acknowledgements: not applicable.Funder: National Institutes of Health (NIH)BACKGROUND: The four co-circulating and immunologically interactive dengue virus serotypes (DENV1-4) pose a unique challenge to vaccine design because sub-protective immunity can increase the risk of severe dengue disease. Existing dengue vaccines have lower efficacy in DENV seronegative individuals but higher efficacy in DENV exposed individuals. There is an urgent need to identify immunological measures that are strongly associated with protection against viral replication and disease following sequential exposure to distinct serotypes. METHODS/DESIGN: This is a phase 1 trial wherein healthy adults with neutralizing antibodies to zero (seronegative), one non-DENV3 (heterotypic), or more than one (polytypic) DENV serotype will be vaccinated with the live attenuated DENV3 monovalent vaccine rDEN3Δ30/31-7164. We will examine how pre-vaccine host immunity influences the safety and immunogenicity of DENV3 vaccination in a non-endemic population. We hypothesize that the vaccine will be safe and well tolerated, and all groups will have a significant increase in the DENV1-4 neutralizing antibody geometric mean titer between days 0 and 28. Compared to the seronegative group, the polytypic group will have lower mean peak vaccine viremia, due to protection conferred by prior DENV exposure, while the heterotypic group will have higher mean peak viremia, due to mild enhancement. Secondary and exploratory endpoints include characterizing serological, innate, and adaptive cell responses; evaluating proviral or antiviral contributions of DENV-infected cells; and immunologically profiling the transcriptome, surface proteins, and B and T cell receptor sequences and affinities of single cells in both peripheral blood and draining lymph nodes sampled via serial image-guided fine needle aspiration. DISCUSSION: This trial will compare the immune responses after primary, secondary, and tertiary DENV exposure in naturally infected humans living in non-endemic areas. By evaluating dengue vaccines in a new population and modeling the induction of cross-serotypic immunity, this work may inform vaccine evaluation and broaden potential target populations. TRIAL REGISTRATION: NCT05691530 registered on January 20, 2023

Phase 1 trial to model primary, secondary, and tertiary dengue using a monovalent vaccine

Abstract Background The four co-circulating and immunologically interactive dengue virus serotypes (DENV1-4) pose a unique challenge to vaccine design because sub-protective immunity can increase the risk of severe dengue disease. Existing dengue vaccines have lower efficacy in DENV seronegative individuals but higher efficacy in DENV exposed individuals. There is an urgent need to identify immunological measures that are strongly associated with protection against viral replication and disease following sequential exposure to distinct serotypes. Methods/Design This is a phase 1 trial wherein healthy adults with neutralizing antibodies to zero (seronegative), one non-DENV3 (heterotypic), or more than one (polytypic) DENV serotype will be vaccinated with the live attenuated DENV3 monovalent vaccine rDEN3Δ30/31-7164. We will examine how pre-vaccine host immunity influences the safety and immunogenicity of DENV3 vaccination in a non-endemic population. We hypothesize that the vaccine will be safe and well tolerated, and all groups will have a significant increase in the DENV1-4 neutralizing antibody geometric mean titer between days 0 and 28. Compared to the seronegative group, the polytypic group will have lower mean peak vaccine viremia, due to protection conferred by prior DENV exposure, while the heterotypic group will have higher mean peak viremia, due to mild enhancement. Secondary and exploratory endpoints include characterizing serological, innate, and adaptive cell responses; evaluating proviral or antiviral contributions of DENV-infected cells; and immunologically profiling the transcriptome, surface proteins, and B and T cell receptor sequences and affinities of single cells in both peripheral blood and draining lymph nodes sampled via serial image-guided fine needle aspiration. Discussion This trial will compare the immune responses after primary, secondary, and tertiary DENV exposure in naturally infected humans living in non-endemic areas. By evaluating dengue vaccines in a new population and modeling the induction of cross-serotypic immunity, this work may inform vaccine evaluation and broaden potential target populations. Trial Registration NCT05691530 registered on January 20, 2023

Associations between social vulnerabilities and psychosocial problems in European children. Results from the IDEFICS study.<br>On behalf of the IDEFICS consortium

The effect of socioeconomic inequalities on children's mental health remains unclear. This study aims to explore the cross-sectional and longitudinal associations between social vulnerabilities and psychosocial problems, and the association between accumulation of vulnerabilities and psychosocial problems. 5987 children aged 2-9 years from eight European countries were assessed at baseline and 2-year follow-up. Two different instruments were employed to assess children's psychosocial problems: the KINDL (Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents) was used to evaluate children's well-being and the Strengths and Difficulties Questionnaire (SDQ) was used to evaluate children's internalising problems. Vulnerable groups were defined as follows: children whose parents had minimal social networks, children from non-traditional families, children of migrant origin or children with unemployed parents. Logistic mixed-effects models were used to assess the associations between social vulnerabilities and psychosocial problems. After adjusting for classical socioeconomic and lifestyle indicators, children whose parents had minimal social networks were at greater risk of presenting internalising problems at baseline and follow-up (OR 1.53, 99% CI 1.11-2.11). The highest risk for psychosocial problems was found in children whose status changed from traditional families at T0 to non-traditional families at T1 (OR 1.60, 99% CI 1.07-2.39) and whose parents had minimal social networks at both time points (OR 1.97, 99% CI 1.26-3.08). Children with one or more vulnerabilities accumulated were at a higher risk of developing psychosocial problems at baseline and follow-up. Therefore, policy makers should implement measures to strengthen the social support for parents with a minimal social network