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The Coronavirus Disease 2019 (COVID-19) pandemic and associated mitigation policies created a global economic and health crisis of unprecedented depth and scale, raising the estimated prevalence of depression by more than a quarter in high-income countries. Low- and middle-income countries (LMICs) suffered the negative effects on living standards the most severely. However, the consequences of the pandemic for mental health in LMICs have received less attention. Therefore, this study assesses the association between the COVID-19 crisis and mental health in 8 LMICs. We conducted a prospective cohort study to examine the correlation between the COVID-19 pandemic and mental health in 10 populations from 8 LMICs in Asia, Africa, and South America. The analysis included 21,162 individuals (mean age 38.01 years, 64% female) who were interviewed at least once pre- as well as post-pandemic. The total number of survey waves ranged from 2 to 17 (mean 7.1). Our individual-level primary outcome measure was based on validated screening tools for depression and a weighted index of depression questions, dependent on the sample. Sample-specific estimates and 95% confidence intervals (CIs) for the association between COVID-19 periods and mental health were estimated using linear regressions with individual fixed effects, controlling for independent time trends and seasonal variation in mental health where possible. In addition, a regression discontinuity design was used for the samples with multiple surveys conducted just before and after the onset of the pandemic. We aggregated sample-specific coefficients using a random-effects model, distinguishing between estimates for the short (0 to 4 months) and longer term (4+ months). The random-effects aggregation showed that depression symptoms are associated with a increase by 0.29 standard deviations (SDs) (95% CI [−.47, −.11], p -value = 0.002) in the 4 months following the onset of the pandemic. This change was equivalent to moving from the 50th to the 63rd percentile in our median sample. Although aggregate depression is correlated with a decline to 0.21 SD (95% CI [−0.07, −.34], p -value = 0.003) in the period thereafter, the average recovery of 0.07 SD (95% CI [−0.09, .22], p -value = 0.41) was not statistically significant. The observed trends were consistent across countries and robust to alternative specifications. Two limitations of our study are that not all samples are representative of the national population, and the mental health measures differ across samples. Controlling for seasonality, we documented a large, significant, negative association of the pandemic on mental health, especially during the early months of lockdown. The magnitude is comparable (but opposite) to the effects of cash transfers and multifaceted antipoverty programs on mental health in LMICs. Absent policy interventions, the pandemic could be associated with a lasting legacy of depression, particularly in settings with limited mental health support services, such as in many LMICs. We also demonstrated that mental health fluctuates with agricultural crop cycles, deteriorating during “lean”, pre-harvest periods and recovering thereafter. Ignoring such seasonal variations in mental health may lead to unreliable inferences about the association between the pandemic and mental health.

Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.

Macrophage function is determined by microenvironment and origin. Brain and retinal microglia are both derived from yolk sac progenitors, yet their microenvironments differ. Utilizing single-cell RNA sequencing (scRNA-seq) data from mice, we tested the hypothesis that retinal and brain microglia exhibit distinct transcriptional profiles due to their unique microenvironments. Eyes and brains from 2-4 month wildtype mice were combined (20 eyes; 3 brains) to yield one biologically diverse sample per organ. Each tissue was digested into single cell suspensions, enriched for immune cells, and sorted for scRNA-seq. Analysis was performed in Seurat v3 including clustering, integration, and differential expression. Multi-parameter flow cytometry was used for validation of scRNA-seq results. Lymphocytic choriomeningitis virus (LCMV) Clone 13, which produces a systemic, chronic, and neurotropic infection, was used to validate scRNA-seq and flow cytometry results . Cluster analysis of integrated gene expression data from eye and brain identified 6 microglial clusters. Differential expression analysis revealed that eye microglia were enriched for more pro-inflammatory processes including antigen processing via MHC class I (14.0-fold, and ) and positive regulation of T-cell immunity (8.4-fold) compared to brain microglia. Multi-parameter flow cytometry confirmed that retinal microglia expressed 3.2-fold greater H2-Db and 263.3-fold more H2-Kb than brain microglia. On Day 13 and 29 after LCMV infection, CD8 T-cell density was greater in the retina than the brain. Our data demonstrate that the microenvironment of retina and brain differs, resulting in microglia-specific gene expression changes. Specifically, retinal microglia express greater MHC class I by scRNA-seq and multi-parameter flow cytometry, resulting in a possibly enhanced capability to stimulate CD8 T-cell inflammation during LCMV infection. These results may explain tissue-specific differences between retina and brain during systemic viral infections and CD8 T-cell driven autoimmune disease.

Regulatory T (Treg) cells are inevitable to prevent deleterious immune responses to self and commensal microorganisms. Treg function requires continuous expression of the transcription factor (TF) FOXP3 and is divided into two major subsets: resting (rTregs) and activated (aTregs). Continuous T cell receptor (TCR) signaling plays a vital role in the differentiation of aTregs from their resting state, and in their immune homeostasis. The process by which Tregs differentiate, adapt tissue specificity, and maintain stable phenotypic expression at the transcriptional level is still inconclusivei. In this work, the role of BATF is investigated, which is induced in response to TCR stimulation in naïve T cells and during aTreg differentiation. Mice lacking BATF in Tregs developed multiorgan autoimmune pathology. As a transcriptional regulator, BATF is required for Treg differentiation, homeostasis, and stabilization of FOXP3 expression in different lymphoid and non‐lymphoid tissues. Epigenetically, BATF showed direct regulation of Treg‐specific genes involved in differentiation, maturation, and tissue accumulation. Most importantly, FOXP3 expression and Treg stability require continuous BATF expression in Tregs, as it regulates demethylation and accessibility of the CNS2 region of the Foxp3 locus. Considering its role in Treg stability, BATF should be considered an important therapeutic target in autoimmune disease.

Background The Coronavirus Disease 2019 (COVID-19) pandemic and associated mitigation policies created a global economic and health crisis of unprecedented depth and scale, raising the estimated prevalence of depression by more than a quarter in high-income countries. Low- and middle-income countries (LMICs) suffered the negative effects on living standards the most severely. However, the consequences of the pandemic for mental health in LMICs have received less attention. Therefore, this study assesses the association between the COVID-19 crisis and mental health in 8 LMICs. Methods and findings We conducted a prospective cohort study to examine the correlation between the COVID-19 pandemic and mental health in 10 populations from 8 LMICs in Asia, Africa, and South America. The analysis included 21,162 individuals (mean age 38.01 years, 64% female) who were interviewed at least once pre- as well as post-pandemic. The total number of survey waves ranged from 2 to 17 (mean 7.1). Our individual-level primary outcome measure was based on validated screening tools for depression and a weighted index of depression questions, dependent on the sample. Sample-specific estimates and 95% confidence intervals (CIs) for the association between COVID-19 periods and mental health were estimated using linear regressions with individual fixed effects, controlling for independent time trends and seasonal variation in mental health where possible. In addition, a regression discontinuity design was used for the samples with multiple surveys conducted just before and after the onset of the pandemic. We aggregated sample-specific coefficients using a random-effects model, distinguishing between estimates for the short (0 to 4 months) and longer term (4+ months). The random-effects aggregation showed that depression symptoms are associated with a increase by 0.29 standard deviations (SDs) (95% CI [−.47, −.11], p-value = 0.002) in the 4 months following the onset of the pandemic. This change was equivalent to moving from the 50th to the 63rd percentile in our median sample. Although aggregate depression is correlated with a decline to 0.21 SD (95% CI [−0.07, −.34], p-value = 0.003) in the period thereafter, the average recovery of 0.07 SD (95% CI [−0.09, .22], p-value = 0.41) was not statistically significant. The observed trends were consistent across countries and robust to alternative specifications. Two limitations of our study are that not all samples are representative of the national population, and the mental health measures differ across samples. Conclusions Controlling for seasonality, we documented a large, significant, negative association of the pandemic on mental health, especially during the early months of lockdown. The magnitude is comparable (but opposite) to the effects of cash transfers and multifaceted antipoverty programs on mental health in LMICs. Absent policy interventions, the pandemic could be associated with a lasting legacy of depression, particularly in settings with limited mental health support services, such as in many LMICs. We also demonstrated that mental health fluctuates with agricultural crop cycles, deteriorating during “lean”, pre-harvest periods and recovering thereafter. Ignoring such seasonal variations in mental health may lead to unreliable inferences about the association between the pandemic and mental health. Nursena Aksunger and colleagues investigate the association between the COVID-19 pandemic and mental health in eight low- and middle-income countries. Author summary Why was this study done? The worldwide economic and health crises triggered by the Coronavirus Disease 2019 (COVID-19) pandemic have had a significant influence on mental health, with the estimated prevalence of depression having increased by more than 25% in high-income countries. Although the adverse consequences of the pandemic on living standards have been most severe in low- and middle-income countries (LMICs), the consequences of the pandemic for mental health in LMICs have received less attention. What did the researchers do and find? The purpose of this research is to investigate the association between the COVID-19 pandemic and mental health in 8 LMICs in Asia, Africa, and South America. Before and during the pandemic, the mental health of 21,162 individuals (mean age 38.01 years, 64.0% female) was measured using survey data. Our individual-level primary outcome measure was based on validated depression screening instruments and a sample-specific weighted index of depression questions. We found that depression symptoms were associated with a significant increase in the 4 months following the onset of the pandemic (0.29 standard deviations (SDs), 95% confidence interval (CI) [−.47, −.11], p-value = 0.002) and that the average recovery of 0.07 SD was not statistically significant in the subsequent period (95% CI [−0.09, .22], p-value = 0.41). What do these findings mean? We showed a substantial negative correlation between the COVID-19 pandemic and mental health after adjusting for seasonality, suggesting that the pandemic might induce long-term depression, especially in LMICs with poor mental health support facilities. We also provided evidence for seasonal changes in mental health depending on agricultural crop cycle. This seasonality should be considered when examining changes in mental health over time in order to prevent drawing inaccurate conclusions. The observed trends were consistent across countries and robust to alternative analyses, although the study was limited by the fact that not all samples were representative of the national population and the mental health indicators differed among samples.

Nepali women are often barred from going abroad through discriminatory state policies, and the women engaging in foreign employment are generally perceived as “loose” women in Nepalese society. The female migrant workers are also represented as lacking “agency” and “victims” of sex trafficking in the Nepalese media. Despite the unfavorable socio-political contexts, a substantial number of Nepali women have engaged in transnational labor migration in the last two decades, often “illegally” by using the open Nepal-India border to reach the destination countries. The study investigates the impact of women’s migration on the dominant discourse relating to female workers’ sexuality and agency by analyzing the experiences of female workers from Chitwan, Nepal, who have returned after working as housemaids in the Persian Gulf. The study finds that the dominant discourse is both contested and reproduced during the emigration process and after the return of female workers. However, the dominant discourse is overall restructured in the emigrant communities due to women’s participation in foreign employment and return with diverse experiences. As women’s varied migration experiences are hardly reported in the national media, the discursive change in the local communities does not necessarily bring a (similar) change in the national discourse. While violence highly prevailed against female workers in the Gulf, most acts of violence were indirect and non-physical. The extreme forms of violence, such as physical and sexual abuses, which are usually reported in the media, were somewhat uncommon. The major complaints of the respondents were low wages, withholding and non-payment of wages, withholding of passport, extremely long hours of work, constant criticism, lack of adequate rest, and the feeling of confinement. The violence against the housemaids was largely facilitated by the sponsorship-based labor recruitment system in the Gulf that bound the migrant workers with their employers. At the micro level, the living arrangement (having to live with the employers) was also a contributing factor to violence against the female workers. The female workers who were employed in a household with multiple housemaids were less likely to experience violence than those who were the only maid in the employer’s house.

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition characterized by hepatic steatosis in the absence of significant alcohol consumption and is increasingly recognized as the hepatic manifestation of metabolic syndrome (MetS). This review aims to explore the molecular mechanisms underlying the interaction between NAFLD, insulin resistance (IR), and MetS, with a focus on identifying therapeutic targets. A comprehensive review of existing literature on NAFLD, IR, and MetS was conducted. The review indicates that IR contributes to hepatic lipid accumulation through increased lipolysis, elevated free fatty acid flux, and impaired fatty acid oxidation, while MetS exacerbates the condition by promoting visceral adiposity, chronic inflammation, and impaired lipid metabolism. Additionally, dysbiosis and increased intestinal permeability in the gut-liver axis worsen IR, leading to a vicious cycle of metabolic dysfunction. In conclusion, addressing these interconnected pathways could enhance therapeutic strategies and reduce the burden of NAFLD-related complications.