Threshold Level Research Articles

A targeted review on occurrence, remediation, and risk assessments of bisphenol A in Africa.

Bisphenol A (BPA) is a vital raw material used to manufacture various household and commercial goods. However, BPA is a contaminant of emerging concern (CEC) and an endocrine-disrupting chemical (EDC) capable of migrating and bio-accumulating in environmental and biological compartments. At threshold levels, they become toxic causing adverse health and environmental issues. BPA's occurrence in food, food contact materials (FCMs), beverages, water, cosmetics, consumer goods, soil, sediments, and human/biological fluids across Africa was outlined. Unlike most reviews, it further collated data on BPA remediation techniques, including the human and ecological risk assessment studies conducted across Africa. A systematic scrutiny of the major indexing databases was employed extracting relevant data for this study. Results reveal that only 10 out of 54 countries have researched BPA in Africa. BPA levels in water were the most investigated, whereas levels in cosmetics and consumer goods were the least studied. Maximum BPA concentrations found in Africa were 3,590,000ng/g (cosmetic and consumer goods), 154,820,000ng/g (soils), 189ng/mL (water), 1139ng/g (food), and 208.55ng/mL (biological fluids). The optimum percentage removal/degradation of BPA was within 70-100%. The potential health and ecological risk levels were assessed by comparing them with recommended limits and were found to fall within safe/low risks to unsafe/high risks. In conclusion, this study revealed that there is still little research on BPA in Africa. Levels detected in some matrices call for increased research, stricter health and environmental regulations, and surveillance.

Evaluation of the Domino Effect Caused by Pool Fires in a Tank Farm

Major hazard installations (MHIs), such as oil refineries, petrochemical plants, and terminals, use large-capacity storage tanks for storing crude oil and by-products. Pool fire is one of the most common types of storage tank fire incidents. This technical article aims to investigate the domino effect resulting from a pool fire in a tank farm consisting of eight large floating-roof storage tanks, with a focus on four specific tanks. A crude oil storage tank was selected as the primary tank (source tank). Point source and plume solid models were used to estimate the thermal radiation. It has been noted that the thermal radiation from the source tank to the adjacent tank in the same dike exceeds the threshold heat radiation level and might result in a domino effect; however, the thermal radiation from the source tank alone does not reach the threshold level for the tanks in the other dike. Additionally, it was found that the thermal radiation from both the primary and secondary tanks just reaches the threshold level for the farther-away tank in the other dike. The domino effect occurs provided that the firefighting system is not activated and the emergency response team does not intervene within ten minutes.

Rubella antibody levels in the healthy Chinese population: a meta-analysis

ObjectivesTo gain a comprehensive understanding of rubella seroprevalence in the healthy population in China and to offer data-driven support for the goal of rubella elimination.MethodsCNKI, Wanfang database, VIP database, CBM, PubMed, web of Science, and Embase databases were searched to collect studies reporting the positive rate of rubella antibody among the Chinese healthy populations between 2001 and 2022. We conducted a meta-analysis using R language, and data were combined using random effects model.ResultsA total of 97 studies were included, encompassing a sample size of 103,018. Meta-analysis showed that the overall prevalence of rubella antibody positivity in the Chinese healthy population was 77.29% (95% CI: 75.26-79.33). The prevalence of rubella antibody varied significantly based on age and vaccination status. Among the age groups studied, the <1-year-old group exhibited the lowest positivity rate for rubella antibody at 47.87% (95% CI: 41.53-54.21),while the ≥50 years old group showed the highest positivity rate at 85.43% (95% CI: 81.01-89.85); individuals with a history of vaccination demonstrated a higher antibody positivity rate compared to those without vaccination history.ConclusionsThe prevalence of rubella antibody in healthy Chinese population is relatively low. In order to establish a solid immunity threshold levels, it requires conducting timely immunization programs on key groups such as middle school students and the women of childbearing age on the basis of ensuring a high level of rubella-containing-vaccines (RCV) coverage, so as to achieve the goal of eliminating rubella.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024607949.

Correlation Between Luteal Phase Serum Progesterone Levels and Pregnancy Outcome in Frozen Embryo Transfer Cycles: A Prospective Cohort Study

Objectives To study the correlation between luteal phase serum progesterone (P4) levels and pregnancy outcome in frozen embryo transfer (FET) cycles and to find out the cut-off level of luteal phase serum P4 which favours successful pregnancy outcome in FET cycles. Material and Methods This prospective cohort study included 100 women undergoing hormone replacement therapy (HRT)-FET cycle at Akanksha IVF Centre from December 2023 to June 2024, fulfilling the inclusion and exclusion criteria. Serum P4 levels were measured for all the patients in the luteal phase (days 21–23) after FET with intramuscular P4 as luteal phase support. Pregnancy outcome was assessed in terms of implantation rate, biochemical pregnancy rate, clinical pregnancy rate (CPR), first-trimester miscarriage rate and ongoing pregnancy rate. Results The most favourable pregnancy outcomes were observed at serum P4 levels 25.1-35 ng/mL. A statistically significant association was seen between the luteal phase serum P4 levels and implantation rate (36.08%), biochemical pregnancy rate (4%), CPR (52%) and ongoing pregnancy rate (42%). According to the receiver operating characteristic (ROC) curve analysis, the optimal cut-off value for favourable outcomes was determined to be 22.3 ng/mL. However, the analysis also indicated that the luteal phase serum P4 levels did not reliably predict clinical or ongoing pregnancy. Conclusion Larger studies are needed to establish a threshold level of serum P4 in the luteal phase that can differentiate between successful and unsuccessful implantation. However, it is still uncertain whether the issue of unsuccessful implantation can be resolved once it is detected on days 21–23 of the HRT-FET cycle.

International capital flows in the process of longevity catch-up

Abstract Using a polynomial cointegration technique, this paper shows that the bilateral US current account balance with China has a U-shaped relationship with the life expectancy gap between the US and China. A narrowing gap initially increases the US deficit with China, but eventually, this increased US deficit falls with the further catching-up of Chinese life expectancy. The life expectancy gap between the two countries has been below the threshold level since 2013, and this demographic trend has the potential to improve the US deficit with China. This U-shaped relationship can be theoretically reproduced. A two-country overlapping generations model indicates that the effect of life expectancy is decomposed into four components: retirement savings, social security burden, the number of elderly workers, and the productivity of elderly workers. The total effect of foreign life expectancy on the home current account balance exhibits a sign change in the catching-up of foreign life expectancy.

Sequestration of gene products by decoys enhances precision in the timing of intracellular events

Expressed gene products often interact ubiquitously with binding sites at nucleic acids and macromolecular complexes, known as decoys. The binding of transcription factors (TFs) to decoys can be crucial in controlling the stochastic dynamics of gene expression. Here, we explore the impact of decoys on the timing of intracellular events, as captured by the time taken for the levels of a given TF to reach a critical threshold level, known as the first passage time (FPT). Although nonlinearity introduced by binding makes exact mathematical analysis challenging, employing suitable approximations and reformulating FPT in terms of an alternative variable, we analytically assess the impact of decoys. The stability of the decoy-bound TFs against degradation impacts FPT statistics crucially. Decoys reduce noise in FPT, and stable decoy-bound TFs offer greater timing precision with less expression cost than their unstable counterparts. Interestingly, when both bound and free TFs decay at the same rate, decoy binding does not directly alter FPT noise. We verify these results by performing exact stochastic simulations. These results have important implications for the precise temporal scheduling of events involved in the functioning of biomolecular clocks, development processes, cell-cycle control, and cell-size homeostasis.

HBsAg trajectories and key thresholds toward functional cure of hepatitis B

Chronic hepatitis B virus (HBV) infection remains a pivotal global health challenge. The pursuit of a functional cure for hepatitis B remains an ardent and intricate issue in clinical settings, as the current arsenal of nucleos(t)ide analogues (NAs) primarily achieves sustained suppression of HBV DNA but falls short in fully addressing clinical needs. The standalone use of Peg-interferon (PEG-IFN) or its combination with NAs still fails to satisfy the pressing clinical demands for functional cure. However, groundbreaking advancements in hepatitis B treatment have emerged through the research and development of antiviral agents with novel mechanisms, notably small nucleic acid drugs, which have ushered in a new era for functional cure prospects. Leveraging longitudinal data spanning multiple time points of HBsAg levels, we can now delineate the trajectory leading towards HBV functional cure and devise predictive models that refine clinical treatment protocols. Two pivotal thresholds of HBsAg levels emerge as crucial milestones, facilitating the selection of eligible participants for clinical trials. This refinement in screening enhances the personalized management of hepatitis B, tailoring interventions to individual patient needs and maximizing outcomes.

Optimizing residue return with soil moisture and nutrient stoichiometry reduced greenhouse gas fluxes in Alfisols

Optimum soil moisture and high crop residue return (RR) can increase the active pool of soil organic carbon and nitrogen, thus modulating the magnitude of greenhouse gas (GHG) fluxes. To determine the effect of soil moisture on the threshold level of RR for the wheat production system, we analyzed the relationship between GHG fluxes and RR at four levels, namely 0, 5, 10, and 15 Mg ha−1 (R0, R5, R10, and R15) under two soil moisture content (80% FC and 100% FC) and three levels of nutrient management (NS0: no nutrient; NS1, NS2= 3x NS1). Nutrient input (N and P) in NS1 balanced the residue C/nutrient stoichiometry to achieve 30% stabilization of the residue C input in RR (R5). All RR treatments (cf. R0) were found to significantly reduce N2O emission in moderate soil moisture content (80% FC) by 22–56% across nutrient management due to enhanced soil C mineralization, microbial biomass carbon, and N immobilization. However, averaged across nutrient management, a linear increase in N2O emission was observed with increasing RR under 100% FC soil moisture. A significant decrease in CH4 emission by ca. 46% in most RR treatments was observed in 100% FC compared with the R0. The N2O emission was negatively correlated (p = <0.001) with nutrient stoichiometry. Partial least square (PLS) regression indicated that GHG emissions were more responsive (values > 0.8) to management variables (RR rate, nitrogen (N) input rate, soil moisture, and nutrient stoichiometry of C: N) and post-incubation soil properties (SMBC and NO3-N) in Alfisols. This study demonstrated that the mechanisms responsible for RR effects on soil N2O, CH4 fluxes, and carbon mineralization depend on soil moisture and nutrient management, shifting the nutrient stoichiometry of residue C: N: P.

Hypothesis testing for detecting outlier evaluators.

In epidemiological studies, the measurements of disease outcomes are carried out by different evaluators. In this paper, we propose a two-stage procedure for detecting outlier evaluators. In the first stage, a regression model is fitted to obtain the evaluators' effects. Outlier evaluators have different effects than normal evaluators. In the second stage, stepwise hypothesis tests are performed to detect outlier evaluators. The true positive rate and true negative rate of the proposed procedure are assessed in a simulation study. We apply the proposed method to detect potential outlier audiologists among the audiologists who measured hearing threshold levels of the participants in the Audiology Assessment Arm of the Conservation of Hearing Study, which is an epidemiological study for examining risk factors of hearing loss.

Natural immunity and protection against variants in South African children through five COVID-19 waves: A prospective study.

Children have been largely spared from serious disease through the COVID-19 pandemic despite high exposure to SARS-CoV-2. Antibody responses to exposure and their role in protecting children from subsequent variant infection remains poorly understood. A prospective cohort study of children in a South African community through ancestral/Beta/Delta/Omicron BA.1/BA.2 and BA.4/BA.5 SARS-CoV-2 waves (March 2020-October 2022). Health seeking behaviour/illness was recorded and post-wave serum samples measured for IgG to Spike (CoV2-S-IgG) by ECLIA. To estimate protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter. Despite little disease 125/366 (34·2%) children (median age 6·7y (IQR 5.9·9 7·4y) were seropositive following wave 1, rising to 53·6%, 76·0%, 96·2% and 99·2% after waves 2 (Beta), 3 (Delta), 4 and 5 (Omicron variants) respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for Beta and least for Omicron. Levels of IgG specific for ancestral spike (S) antigen that provided a 50% protective threshold for the subsequent wave were lowest for the Beta and highest for the Omicron BA.1/BA.2 wave. In multivariate analysis, maternal seropositivity (aOR=2·57 (95% CI: 1·72; 3·82) was strongly associated with child seropositivity. Children responded robustly to successive waves of SARS-CoV-2 mounting IgG responses to spike antigen that were protective against subsequent waves. In the absence of vaccination almost all children were seropositive after the 5th wave but none were hospitalised suggesting natural immunity alone may be sufficient to protect children in a pandemic setting. UK NIH GECO award (GEC111), Wellcome Biomedical resources grant (221372/Z/20/Z), Wellcome Trust Centre for Infectious Disease Research in Africa (CIDRI), Bill & Melinda Gates Foundation, USA (OPP1017641, OPP1017579) and NIH H3 Africa (U54HG009824, U01AI110466]. HZ is supported by the SA-MRC. MPN is supported by an Australian National Health and Medical Research Council Investigator Grant (APP1174455). BJQ is supported by a grant from the Bill and Melinda Gates Foundation (OPP1139859). Stefan Flasche is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number 208812/Z/17/Z).

Introducing a Novel Pacemaker‐Mediated Arrhythmia: The Pseudo‐RNRVAS Arising From Atrial Capture Challenges

ABSTRACTBackgroundThis study aimed to define and explain a novel form of pacemaker‐mediated arrhythmia which is initiated and sustained by atrial capture loss coinciding with ventriculoatrial (VA) conduction within the postventricular atrial refractory period (PVARP). Unlike repetitive nonreentrant VA synchrony (RNRVAS), in the pseudo‐RNRVAS, the atrium is not stimulated due to pacing below the threshold level, rather than because of refractory atrial myocardium.ObjectiveThe objective was to elucidate the mechanisms of this pseudo‐RNRVAS, identify predisposing factors, and propose preventive strategies.MethodsTwenty‐one patients with dual‐chamber cardiac implantable electronic devices (CIEDs) exhibiting stable VA conduction within the PVARP were included. Pseudo‐RNRVAS were induced by altering atrial amplitude and lower rate interval while keeping other CIED parameters constant.ResultsPseudo‐RNRVAS developed after atrial capture loss in 20 out of 21 patients. Notably, 11 patients experienced pseudo‐RNRVAS at heart rates ≤ 70 bpm, and 7 patients at AV delay ≤ 150 ms. The condition initiated immediately following the first ventricular pace beat after atrial capture loss in 18 patients. In six cases, pseudo‐RNRVAS terminated intermittently and then restarted; in 14 cases, it did not resolve.ConclusionPseudo‐RNRVAS can occur even at low heart rates and without specific predisposing factors seen in RNRVAS. Conditions that increase atrial pacing probability and threshold raise the likelihood of pseudo‐RNRVAS. Early postimplantation may pose a heightened risk, correlating with pacemaker syndrome and susceptibility to heart failure.

FX resilience around the world: Fighting volatile cross-border capital flows

The volatility of cross-border capital flow (CF) has become higher in the last two decades. We use a sample of advanced and emerging market economies in the last two decades, with a focus on portfolio fund flows (equities and bonds). We find that the impact of portfolio CF volatility on exchange rate (FX) volatility is diminished in the short-term if specific economic fundamentals of the country are stronger, especially when these fundamentals pass certain threshold levels. The finding is controlled for different exchange rate regimes and the level of capital control. We further introduce an intuitive FX resilience measure that can be used to assess the stability of exchange rates in the context of heightened CF volatility. The decomposed FX resilience measure shows that the major contributing fundamentals to FX resilience are from the finance channel, including short-term interest rate, fiscal surplus, and financial development.

Research on the prognosis and efficacy criteria of sudden sensorineural hearing loss

Sudden sensorineural hearing loss is a common and frequently-occurring disease. Looking at the efficacy evaluation of the diagnosis and treatment of sudden sensorineural hearing loss at home and abroad, each country has its own characteristics in the indicators and criteria of the treatment efficacy evaluation, and the common indicators of efficacy evaluation include: average pure-tone hearing threshold, the absolute value of hearing improvement of impaired frequency, the percentage of average pure-tone hearing threshold increase, speech discrimination score, speech recognition threshold, etc. The evaluation criteria mostly take the efficacy grade or the improvement level of average hearing threshold as the criterion of effective treatment, and the lack of unified standards is not conducive to the homogenization of global research related to sudden sensorineural hearing loss. In order to provide reference for the clinical evaluation of sudden sensorineural hearing loss in China, this study systematically reviewed the clinical practice guidelines and the evaluation indexes and criteria of clinical efficacy in high quality clinical multicenter studies of the disease in many countries.

CSF Parvalbumin Levels at Multiple Sclerosis Diagnosis Predict Future Worse Cognition, Physical Disability, Fatigue, and Gray Matter Damage.

Cognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the time of diagnosis, may have a prognostic role in patients with MS. In this cohort study, CSF analysis of PVALB and Nf-L levels was performed on all patients at diagnosis (T0) and combined with physical, cognitive, and MRI assessment after an average of 4 years of follow-up (T4) from diagnosis. Cognitive performance was evaluated with a comprehensive neuropsychologic battery: both global (cognitively normal, CN, mildly CI, mCI, and severely CI, sCI) and domain cognitive status (normal/impaired in memory, attention/information processing speed, and executive functions) were considered. Cortical thickness and gray matter volume data were acquired using 3T MRI scanner. A total of 72 patients with MS were included. At diagnosis, PVALB levels were higher in those patients who showed a worsening physical disability after 4 years of follow-up (p = 0.011). CSF PVALB levels were higher in sCI patients than in CN (p = 0.033). Moreover, higher PVALB levels significantly correlated with worse global cognitive (p = 0.024) and memory functioning (p = 0.044). A preliminary clinical threshold for PVALB levels at diagnosis was proposed (2.57 ng/mL), which maximizes the risk of showing CI (in particular, sCI) at follow-up, with a sensitivity of 91% (specificity 30%). No significant results were found for these associations with Nf-L. In addition, patients with higher levels of PVALB at diagnosis showed higher cognitive (p = 0.024) and global fatigue (p = 0.043) at follow-up. Finally, higher PVALB levels also correlated significantly with more pronounced CTh/volume at T4 in the inferior frontal gyrus (p = 0.044), postcentral gyrus (p = 0.025), frontal pole (p = 0.042), transverse temporal gyrus (p = 0.008), and cerebellar cortex (p = 0.041) and higher atrophy (change T0-T4) in the right thalamus (p = 0.038), pericalcarine cortex (p = 0.009), lingual gyrus (p = 0.045), and medial frontal gyrus (p = 0.028). The significant association found between parvalbumin levels in the CSF at diagnosis and cognitive, clinical, and neuroradiologic worsening after 4 years of follow-up support the idea that parvalbumin, in addition to Nf-L, might represent a new potential prognostic biomarker, reflecting MS neurodegenerative processes occurring since early disease stages.

Cancer and Autoimmune Diseases as Two Sides of Chronic Inflammation - and the Method of Therapy.

Chronic inflammation is associated with a prolonged increase in various inflammatory factors. According to clinical data, it can be linked with both cancer and autoimmune diseases in the same patients. This raises the critical question of how chronic inflammation relates to seemingly opposing diseases - tumors, in which there is immunosuppression, and autoimmune diseases, in which there is over-activation of the immune system. In this review, we consider chronic inflammation as a prerequisite for both immune suppression and an increased likelihood of autoimmune damage. We also discuss potential disease-modifying therapies targeting chronic inflammation, which can be helpful for both cancer and autoimmunity. On the one hand, pro-inflammatory factors persisting in the areas of chronic inflammation stimulate the production of anti-inflammatory factors due to a negative feedback loop, eliciting immune suppression. On the other hand, chronic inflammation can bring the baseline immunity closer to the threshold level required for triggering an autoimmune response using the bystander activation of immune cells. Focusing on the role of chronic inflammation in cancer and autoimmune diseases may open prospects for more intensive drug discovery for chronic inflammation.

Insurance market development and economic growth in Africa: Contingencies and thresholds of structural transformation

Despite insurance contributions to economic growth, the intervening role of structural transformation on the insurance-growth nexus remains scarce, leaving a gap in the literature. Motivated by the 2030 Sustainable Development Agenda, which envisages higher structural transformation, financial development and economic progress, this study examines the threshold effects and the joint impact of insurance and structural transformation on economic growth in Africa. The study employed the generalised method of moments and dynamic panel threshold estimations on 38 countries covering 2008 to 2020. The following findings emerge: First, insurance and structural transformation promote economic growth. Second, the results indicate that structural transformation enhances the impact of insurance on economic growth. This suggests that structural transformation matters in driving insurance market development, ultimately promoting economic growth. Third, the empirical evidence further reveals nonlinearities in the relationship and presents that a high level of insurance penetration stimulates growth and vice versa. More so, the synergistic effect of insurance and structural transformation on economic growth is more substantial at higher threshold levels. This implies that though insurance spurs economic growth, its impact is more effective through the intervening role of a strong structural transformation. Therefore, this study calls for government intervention and policies to improve structural transformations and form insurance synergies to promote growth.

Association between magnesium intake and chronic kidney diseases and kidney stones in adults aged 50 years and older: dose-response analysis of a nationally representative population-based study.

Higher serum magnesium concentrations have been linked to reduced risk of chronic kidney diseases (CKD). However, the dose-response relationships between magnesium intake and CKD and kidney stones in the general population remain unknown. This study aimed to quantitatively assess the dose-response relationships between magnesium intake and CKD and kidney stones. Adult participants (≥50 years) from the 2007-2018 National Health and Nutrition Examination Survey were included. Magnesium intake from diet and supplements were determined with structured dietary recalls. Patients with kidney stones were identified using a standard questionnaire. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2. The non-linear relationships were explored with restricted cubic splines. Stratified analyses by sex were conducted. The weighted prevalence of CKD and kidney stones was 12.16% and 13.13%, respectively. A non-linear relationship between magnesium intake and CKD (Pfor non-linearity<0.01) and kidney stones (Pfor non-linearity=0.02) was found. There was an initial steep decrease in odds of CKD and kidney stones with increasing intakes of magnesium, and then a platform or weaker decrease in odds of CKD and kidney stones was observed beyond 350 mg/day of magnesium intake[odds ratio (95% confidence interval) for CKD: 0.60 (0.46-0.78), 0.77 (0.61-0.98) for kidney stones]. Higher magnesium intake was inversely associated with odds of CKD in both males and females, while the inverse association between higher magnesium intake and odds of kidney stones was only statistically significant in females. Higher magnesium intake was non-linearly associated with lower odds of kidney stones and CKD, and a threshold level of 350 mg/day of magnesium intake was observed in adults aged 50 years and older. These findings deserve to be confirmed by prospective cohort studies.

NEUROTROPIC EFFECTS OF ENDOGENOUS COMPOUNDS – TYRONOME COMPONENTS IN THE CENTRAL NERVOUS SYSTEM

Background. During the last decades, data on potential cytoprotective effects of decarboxylated and deiodinated endogenous compounds – metabolites of thyroid hormones, constituting the thyronome, have been accumulated. The aim of this review is to systematize the biological effects of thyronome components in the central nervous system from the position of their possible role as potential neuroprotectants. Material and methods. English- and Russian-language full-text articles from PubMed, Mendeley, and e-library electronic databases were selected for analysis using query «(thyroid OR thyroid hormone metabolite OR *-iodo-thyronamine OR thyronamine OR TAAR OR thyronome OR T0AM OR T1AM OR thyroacetic acid) AND (brain OR central nervous system OR CNS OR stroke OR neurodegenerat*)». The search depth amounted to 10 years. Results. The review systematizes the most important neurotropic properties of 3-T1AM and other thyronome components, including their influence on behavioral effects, memory, pain threshold level, apoptosis, autophagy, and excitotoxic neuronal death, and describes the role of individual receptors and intracellular signal transduction pathways in the realization of these properties. Conclusion. The components of thyronome, in particular 3-T1AM, demonstrate a wide range of potential neuroprotective properties, and for its potential use in the clinic, it is relevant to find ways to increase local concentration in the brain or permeability to the BBB, as well as the development of more effective synthetic analogues.

Associations between T-cell traits and narcolepsy type 1: new insights from a Mendelian randomization study.

Narcolepsy type 1 (NT1) is primarily caused by a malfunctioning immune system in which T-cells damage the hypothalamus. To elucidate the causal relationships between biomarkers in T-cells and NT1, we employed Mendelian randomization (MR) analysis. We conducted a two-sample MR analysis utilizing genetically predicted T-cell traits to examine their effects on NT1. Genome-wide association study summary data were extracted from studies by Valeria (3,757 participants) for 211 T-cell traits, Ollila (6,073 cases and 84,856 controls) for NT1. The MR analysis was executed at two threshold levels. Inverse variance weighted, Wald ratio, weighted median, and MR-Egger regression methods were used for the MR analysis. Odds ratios (ORs) were calculated, and heterogeneity tests, as well as pleiotropy tests, were conducted. After Bonferroni correction at the significant level (p < 1.18 × 10-4), a higher ratio of naive CD4- CD8- T-cells was identified as a risk factor for NT1 (OR = 10.50; 95% CI: 6.98, 15.90, p = 3.89 ×10-29). Conversely, CD4 on HLA DR+ CD4+ T cells (mean fluorescence intensity, MFI) exhibited a negative correlation with NT1. At nominally significant levels (p < 0.05) for both threshold levels, HVEM (herpesvirus entry mediator) on naive CD8+ T cells (MFI) was suggested as a protective factor for NT1. Additionally, a higher ratio of CD25++ CD45RA- CD4 not regulatory T cells, CD127 on CD45RA- CD4 not regulatory T cells (MFI), CD127 on CD28+ CD4+ T cells (MFI), CD3 on HLA DR+ T cells (MFI), and CD3 on HLA DR+ CD4+ T cells (MFI) were suggested as risk factors for NT1. This study confirmed the causal effects of CD4+ and CD8+ T-cells on NT1 and found several novel T-cell-related characteristics.

Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programmes and repeats in pluripotent cells.

H3K9me3 heterochromatin, established by lysine methyltransferases (KMTs) and compacted by heterochromatin protein 1 (HP1) isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3 heterochromatin stability is presently limited to individual domains and DNA repeats. Here we engineered Suv39h2-knockout mouse embryonic stem cells to degrade remaining two H3K9me3 KMTs within 1 hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12-24 hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A 'binary switch' governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMT depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening and exit from pluripotency within 12 h. Unexpectedly, receding H3K9me3 domains unearth residual HP1β peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3 heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency.