Chromatin status and transcription factor binding to gonadotropin promoters in gonadotrope cell lines.

BackgroundProper expression of key reproductive hormones from gonadotrope cells of the pituitary is required for pubertal onset and reproduction. To further our understanding of the molecular events taking place during embryonic development, leading to expression of the glycoproteins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), we characterized chromatin structure changes, imparted mainly by histone modifications, in model gonadotrope cell lines.MethodsWe evaluated chromatin status and gene expression profiles by chromatin immunoprecipitation assays, DNase sensitivity assay, and RNA sequencing in three developmentally staged gonadotrope cell lines, αT1-1 (progenitor, expressing Cga), αT3-1 (immature, expressing Cga and Gnrhr), and LβT2 (mature, expressing Cga, Gnrhr, Lhb, and Fshb), to assess changes in chromatin status and transcription factor access of gonadotrope-specific genes.ResultsWe found the common mRNA α-subunit of LH and FSH, called Cga, to have an open chromatin conformation in all three cell lines. In contrast, chromatin status of Gnrhr is open only in αT3-1 and LβT2 cells. Lhb begins to open in LβT2 cells and was further opened by activin treatment. Histone H3 modifications associated with active chromatin were high on Gnrhr in αT3-1 and LβT2, and Lhb in LβT2 cells, while H3 modifications associated with repressed chromatin were low on Gnrhr, Lhb, and Fshb in LβT2 cells. Finally, chromatin status correlates with the progressive access of LHX3 to Cga and Gnrhr, followed by PITX1 binding to the Lhb promoter.ConclusionOur data show the gonadotrope-specific genes Cga, Gnrhr, Lhb, and Fshb are not only controlled by developmental transcription factors, but also by epigenetic mechanisms that include the modulation of chromatin structure, and histone modifications

KELT-16b: A Highly Irradiated, Ultra-short Period Hot Jupiter Nearing Tidal Disruption

We announce the discovery of KELT-16b, a highly irradiated, ultra-short period hot Jupiter transiting the relatively bright (V = 11.7) star TYC 2688-1839-1/KELT-16. A global analysis of the system shows KELT-16 to be an F7V star with K and . The planet is a relatively high-mass inflated gas giant with density g cm-3, surface gravity , and K. The best-fitting linear ephemeris is and day. KELT-16b joins WASP-18b, -19b, -43b, -103b, and HATS-18b as the only giant transiting planets with P \u3c 1 day. Its ultra-short period and high irradiation make it a benchmark target for atmospheric studies by the Hubble Space Telescope, Spitzer, and eventually the James Webb Space Telescope. For example, as a hotter, higher-mass analog of WASP-43b, KELT-16b may feature an atmospheric temperature-pressure inversion and day-to-night temperature swing extreme enough for TiO to rain out at the terminator. KELT-16b could also join WASP-43b in extending tests of the observed mass-metallicity relation of the solar system gas giants to higher masses. KELT-16b currently orbits at a mere ∼1.7 Roche radii from its host star, and could be tidally disrupted in as little as a few ×105 years (for a stellar tidal quality factor of ). Finally, the likely existence of a widely separated bound stellar companion in the KELT-16 system makes it possible that Kozai-Lidov (KL) oscillations played a role in driving KELT-16b inward to its current precarious orbit

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen

Does economic development contribute to sex differences in ischaemic heart disease mortality? Hong Kong as a natural experiment using a case-control study

<p>Abstract</p> <p>Background</p> <p>The male excess risk of premature ischemic heart disease (IHD) mortality may be partially due to an unknown macro-environmental influence associated with economic development. We examined whether excess male risk of IHD mortality was higher with birth in an economically developed environment.</p> <p>Methods</p> <p>We used multivariable logistic regression in a population-based case-control study of all adult deaths in Hong Kong Chinese in 1998 to compare sex differences in IHD mortality (1,189 deaths in men, 1,035 deaths in women and 20,842 controls) between Hong Kong residents born in economically developed Hong Kong or in contemporaneously undeveloped Guangdong province in China.</p> <p>Results</p> <p>Younger (35–64 years) native-born Hong Kong men had a higher risk of IHD death than such women (odds ratio 2.91, 95% confidence interval 1.66 to 5.13), adjusted for age, socio-economic status and lifestyle. There was no such sex difference in Hong Kong residents who had migrated from Guangdong. There were no sex differences in pneumonia deaths by birth place.</p> <p>Conclusion</p> <p>Most of these people migrated as young adults; we speculate that environmentally mediated differences in pubertal maturation (when the male disadvantage in lipids and fat patterning emerges) may contribute to excess male premature IHD mortality in developed environments.</p

A prospective cohort study of dietary patterns of non-western migrants in the Netherlands in relation to risk factors for cardiovascular diseases: HELIUS-Dietary Patterns

<p>Abstract</p> <p>Background</p> <p>In Western countries the prevalence of cardiovascular disease (CVD) is often higher in non-Western migrants as compared to the host population. Diet is an important modifiable determinant of CVD. Increasingly, dietary patterns rather than single nutrients are the focus of research in an attempt to account for the complexity of nutrient interactions in foods. Research on dietary patterns in non-Western migrants is limited and may be hampered by a lack of validated instruments that can be used to assess the habitual diet of non-western migrants in large scale epidemiological studies. The ultimate aims of this study are to (1) understand whether differences in dietary patterns explain differences in CVD risk between ethnic groups, by developing and validating ethnic-specific Food Frequency Questionnaires (FFQs), and (2) to investigate the determinants of these dietary patterns. This paper outlines the design and methods used in the HELIUS-Dietary Patterns study and describes a systematic approach to overcome difficulties in the assessment and analysis of dietary intake data in ethnically diverse populations.</p> <p>Methods/Design</p> <p>The HELIUS-Dietary Patterns study is embedded in the HELIUS study, a Dutch multi-ethnic cohort study. After developing ethnic-specific FFQs, we will gather data on the habitual intake of 5000 participants (18-70 years old) of ethnic Dutch, Surinamese of African and of South Asian origin, Turkish or Moroccan origin. Dietary patterns will be derived using factor analysis, but we will also evaluate diet quality using hypothesis-driven approaches. The relation between dietary patterns and CVD risk factors will be analysed using multiple linear regression analysis. Potential underlying determinants of dietary patterns like migration history, acculturation, socio-economic factors and lifestyle, will be considered.</p> <p>Discussion</p> <p>This study will allow us to investigate the contribution of the dietary patterns on CVD risk factors in a multi-ethnic population. Inclusion of five ethnic groups residing in one setting makes this study highly innovative as confounding by local environment characteristics is limited. Heterogeneity in the study population will provide variance in dietary patterns which is a great advantage when studying the link between diet and disease.</p

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB