The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration.

The eIF4E family of translation initiation factors bind 5' methylated caps and act as the limiting step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c, for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting that Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

Autotaxin in encephalitogenic CD4 T cells as a therapeutic target for multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the CNS. A defining characteristic of MS is the ability of autoreactive T lymphocytes to cross the blood-brain barrier and mediate inflammation within the CNS. Previous work from our lab found the gene Enpp2 to be highly upregulated in murine encephalitogenic T cells. Enpp2 encodes for the protein autotaxin, a secreted glycoprotein that catalyzes the production of lysophosphatidic acid and promotes transendothelial migration of T cells from the bloodstream into the lymphatic system. The present study sought to characterize autotaxin expression in T cells during CNS autoimmune disease and determine its potential therapeutic value. Myelin-activated CD4 T cells upregulated expression of autotaxin in vitro, and ex vivo analysis of CNS-infiltrating CD4 T cells showed significantly higher autotaxin expression compared with cells from healthy mice. In addition, inhibiting autotaxin in myelin-specific T cells reduced their encephalitogenicity in adoptive transfer studies and decreased in vitro cell motility. Importantly, using two mouse models of MS, treatment with an autotaxin inhibitor ameliorated EAE severity, decreased the number of CNS infiltrating T and B cells, and suppressed relapses, suggesting autotaxin may be a promising therapeutic target in the treatment of MS.

Reproductive health service access and utilisation among migrant women in Dhaka's urban slums: a qualitative study.

This study explores the impact of migration on the access and utilisation of sexual and reproductive health services by women living in an informal settlement in Dhaka, Bangladesh. A total of 16 in-depth interviews were conducted in March and April of 2019 with women (18-49 years old) who had migrated from rural areas to Dhaka. They reported continued economic insecurity while receiving minimal support from the state. All women reported financial and infrastructural barriers to accessing formal sexual and reproductive health services and tended to seek resources and support through social networks within the slum and from informal health services. Compared with more recent migrants, women who had migrated and resided in the slums for longer found it easier to utilise social networks and resources for sexual and reproductive health. Women had more agency in experimenting with contraceptives but had less power in making decisions during pregnancy and when seeking health care. Menstrual health was a neglected aspect of public health. The study indicates that public health policy targeting the urban poor needs to address the unique challenges faced by migrant women in informal settlements to rectify inequities in health services that leave significant portions of the urban poor population behind.

Loss of growth hormone signaling in the mouse germline or in adulthood reduces islet mass and alters islet function with notable sex differences.

In the endocrine pancreas, growth hormone (GH) is known to promote pancreatic islet growth and insulin secretion. In this study, we show that GH receptor (GHR) loss in the germline and in adulthood impacts islet mass in general but more profoundly in male mice. GHR knockout (GHRKO) mice have enhanced insulin sensitivity and low circulating insulin. We show that the total cross-sectional area of isolated islets (estimated islet mass) was reduced by 72% in male but by only 29% in female GHRKO mice compared with wild-type controls. Also, islets from GHRKO mice secreted ∼50% less glucose-stimulated insulin compared with size-matched islets from wild-type mice. We next used mice with a floxed Ghr gene to knock down the GHR in adult mice at 6 mo of age (6mGHRKO) and examined the impact on glucose and islet metabolism. By 12 mo of age, female 6mGHRKO mice had increased body fat and reduced islet mass but had no change in glucose tolerance or insulin sensitivity. However, male 6mGHRKO mice had nearly twice as much body fat, substantially reduced islet mass, and enhanced insulin sensitivity, but no change in glucose tolerance. Despite large losses in islet mass, glucose-stimulated insulin secretion from isolated islets was not significantly different between male 6mGHRKO and controls, whereas isolated islets from female 6mGHRKO mice showed increased glucose-stimulated insulin release. Our findings demonstrate the importance of GH to islet mass throughout life and that unique sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose metabolism.NEW & NOTEWORTHY Growth hormone (GH) is important for more than just growth. GH helps to maintain pancreatic islet mass and insulin secretion throughout life. Sex-specific adaptations to the loss of GH signaling allow mice to maintain normal glucose regulation despite losing islet mass.

Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth.

BACKGROUND: It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants' length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group). RESULTS: Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, -0.93±1.05; prenatal 4200, -1.11±1.12; prenatal 16,800, -0.97±0.97; prenatal 28,000, -1.06±1.07; and prenatal and postpartum 28,000, -0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose. CONCLUSIONS: In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013 .).

Determinants of household food security and dietary diversity during the COVID-19 pandemic in Bangladesh.

OBJECTIVES: The study aimed to determine the associated factors of household food security (HFS) and household dietary diversity (HDD) during the COVID-19 pandemic in Bangladesh. DESIGN: Both online survey and face-to-face interviews were employed in this cross-sectional study. The Household Food Security Scale and Household Dietary Diversity Score were used to access HFS and HDD, respectively. The HDD scores were derived from a 24-h recall of food intake from 12 groups. SETTING: Bangladesh. PARTICIPANTS: A total sample of 1876 households were recruited. RESULTS: The overall mean scores of HFS and HDD were 31·86 (sd 2·52) and 6·22 (sd 5·49), respectively. Being a rural resident, having no formal education, occupation of household head other than government job and low monthly income were potential determinants of lower HFS and HDD. Approximately 45 % and 61 % of Bangladeshi households did not get the same quantity and same type of food, respectively, as they got before the pandemic. Over 10 % of respondents reported that they lost their job or had to close their businesses, and income reduction was reported by over 70 % of household income earners during the COVID-19 pandemic, which in turn was negatively associated with HFS and HDD. CONCLUSION: Household socio-economic variables and COVID-19 effects on occupation and income are potential predictors of lower HFS and HDD scores. HFS and HDD deserve more attention during this pandemic particularly with reference to low-earning households and the households whose earning persons' occupation has been negatively impacted during the COVID-19 pandemic.

Antibiotic practices among household members and their domestic animals within rural communities in Cumilla district, Bangladesh: a cross-sectional survey.

BACKGROUND: Antibiotic resistance is a global threat to human health, and inappropriate use of antibiotics in humans and animals is widely considered to be a key driver of antibiotic resistant infections. Antibiotic use in humans and animals is growing rapidly in low- and, particularly, middle-income countries. However, there is little detailed understanding about practices related to the use of antibiotics in humans and animals within community settings in such countries. Here we aimed to understand the antibiotic practices of rural households across Cumilla district, Bangladesh, in relation to household members and their domestic animals. METHODS: In 2018 we conducted a cross-sectional survey using representative cluster sampling methods. We collected self-reported information from 682 female and 620 male household heads, with women also asked about their children's antibiotic practices. RESULTS: Only 48% (95% CI: 40, 56%) of women and men had heard of antibiotics, and among those women and men who were aware of antibiotics and the children of those women 70% (95% CI: 64, 76%) reported having previously taken antibiotics, while among these individuals who reported previously taking antibiotics 21% (95% CI: 18, 25%) said they had done so most recently within the last month. Risky/inappropriate antibiotic practices in humans and animals were often reported. For example, among women and men who were aware of antibiotics and the children of those women 52% (95% CI: 40, 63%) reported previously taking antibiotics for a "cough/cold", despite antibiotics being typically inappropriate for use against viral upper respiratory tract infections. Among poultry-owning respondents who were aware of antibiotics 11% (95% CI: 8, 15%) reported previously giving healthy poultry antibiotics, mainly for growth/prophylaxis, while among cattle-owning respondents who were aware of antibiotics and reported previously giving their cattle feed 20% (95% CI: 9, 37%) said the feed had contained antibiotics at least sometimes. CONCLUSIONS: Our results highlight the need for context-adapted interventions at both the community level and the health systems level to reduce inappropriate antibiotic use among humans and domestic animals in rural Bangladesh. Successfully reducing inappropriate use of antibiotics among humans and animals is a required and critical step in tackling antimicrobial resistance.

Effect of Osmolytes on Conformational Behavior of Intrinsically Disordered Protein α-Synuclein.

α-Synuclein is an intrinsically disordered protein whose function in a healthy brain is poorly understood. It is genetically and neuropathologically linked to Parkinson's disease (PD). PD is manifested after the accumulation of plaques of α-synuclein aggregates in the brain cells. Aggregates of α-synuclein are very toxic and lead to the disruption of cellular homeostasis and neuronal death. α-Synuclein can also contribute to disease propagation as it may exert noxious effects on neighboring cells. Understanding the mechanism of α-synuclein aggregation will facilitate the problem of dealing with neurodegenerative diseases in general and that of PD in particular. Here, we have used molecular dynamics simulations to investigate the behavior of α-synuclein at various temperatures and in different concentrations of urea and trimethyl amine oxide. The residue region from 61 to 95 of α-synuclein is experimentally known as amyloidogenic. In our study, we have identified some other regions, which also have the propensity to form an aggregate besides this known sequence. Urea being a denaturant interacts more with these regions of α-synuclein through hydrogen bond formation and inhibits the ß-sheet formation, whereas trimethyl amine oxide itself does not interact much with the protein and stabilizes the protein by preferentially distributing water molecules on the surface of the protein.

Genetic characterization of human metapneumovirus identified through community and facility-based surveillance of infants in Dhaka, Bangladesh.

BACKGROUND: Acute respiratory infection (ARI) is a leading cause of morbidity and mortality in children in low and middle-income countries. Human metapneumovirus (hMPV) is one of the most common viral etiological agents for ARIs in children. OBJECTIVES: In this study, we explored the genotypic diversity and the epidemiology of hMPV among infants in Dhaka, Bangladesh. STUDY DESIGN: Between December 2014 and August 2016, a total of 3810 mid-turbinate nasal swab samples were collected from infants (0 to 6 months of age) who met clinical ARI criteria, as a part of a prospective ARI cohort study. hMPV was detected using polymerase chain reaction, and genotyped by sequencing and phylogenetic analysis. RESULTS: hMPV was identified in 206 (5.4%) nasal swab specimens. One-tenth of the hMPV-positive swabs (n = 19) were also positive for other respiratory viruses. hMPV activity peaked in January and September in 2015; however, no seasonal pattern of hMPV infection was detected. Phylogenetic analyses of the N and F gene-fragments revealed that the hMPV strains circulating in Dhaka, Bangladesh, belonged to three genotypes: A2b, A2c, and B1. Genotype A (57%) was the predominant hMPV genotype circulating in Bangladesh during the study period. CONCLUSION: This study describes both the epidemiology of hMPV infection and its genotypic strain diversity in Dhaka, Bangladesh.

Maternal BMI and nutritional status in early pregnancy and its impact on neonatal outcomes at birth in Bangladesh.

BACKGROUND: To assess the maternal characteristics and nutritional status according to body mass index (BMI) at 6-14 weeks of gestation and to examine the relationship between maternal nutritional status in early pregnancy and its impact on neonatal birth weight. METHODS: The investigation was conducted from April 2011 to June 2012 in Dhaka, Bangladesh. A total of 498 primigravida pregnant women participated in the study; women with known diabetes or previous gestational diabetes (GDM) were excluded. Maternal demographic details, pregnancy history and anthropometric measurements were obtained from the mother at the recruitment (6-14 weeks), 2nd visit between 24 and 28 week of gestation and 3rd visit at delivery. Cord venous blood samples of newborns (n = 138) were collected immediately after delivery for blood glucose, insulin, lipid profile, leptin and micronutrients including serum folate, ferritin, homocysteine, vitamin D, and vitamin B12. RESULTS: The prevalence at 6-14 weeks of pregnancy of anemia (Hb, < 11 g/dl), vitamin D deficiency (< 30 nmol/l), vitamin B12 deficiency (< 200 pg/ml), high homocysteine level (> 15 µmol/l), folate deficiency (< 3 ng/ml) and iron deficiency (ferritin < 13 ng/ml) were 19.5, 46.4, 15.1, 1.2, 0.4, and 12.7% respectively. GDM was found in 18.4% women. The prevalence of GDM was higher in overweight women (28.1%) than underweight (16.7%) and normal weight women (16.0%: p <  0.05). The incidence of low birth weight (LBW) and preterm delivery were 11.6 and 5.8% respectively and was not related to maternal BMI at 6-14 weeks of pregnancy. Maternal height was positively (p = 0.02), and homocysteine was negatively associated with neonatal birth weight (p = 0.02). In addition, the newborn's cord serum folate was positively (p = 0.03) and cord triglyceride was negatively (p = 0.03) associated with neonatal birth weight. CONCLUSION: Multiple maternal micronutrient deficiencies were present in early pregnancy. Maternal BMI in early pregnancy was not related to preterm deliveries or LBW. LBW was associated with lower folate, elevated cord triglyceride concentrations of the neonates and mother's height and increase in maternal homocysteine levels. The data has important implications for pregnancy care in Bangladesh and other similar communities.

Knowledge, Awareness, and Perceived Threat Toward Alzheimer's Disease Among the Family Caregivers of Individuals with Chronic Physical Conditions in Bangladesh.

Background: Alzheimer's disease (AD) is a growing public health concern affecting millions of individuals worldwide. This disease burden is exacerbated in countries like Bangladesh, where public awareness and knowledge about the condition remains limited. Objective: This study aimed to assess the level of AD knowledge, awareness, and perceived threat among family caregivers of individuals with chronic physical conditions of Bangladesh. Methods: A descriptive cross-sectional study was conducted among the caregivers of patients selected via convenience sampling in six public hospitals between October 2022 and March 2023. The data was collected via face-to-face interviews employing a semi-structured questionnaire that contained information about socio-demographic characteristics, personal experiences with AD, knowledge of AD, level of awareness regarding AD, and perceived threat toward AD. Results: The findings revealed a poor knowledge of AD among the study participants. Regarding AD awareness, 52.5% considered memory loss in older individuals abnormal, 26.2% attributed AD to causes like black magic, psychological distress, or bad eyes. Regarding perceived threat, 60.2% wanted to assess their AD risk, while 68.2% disagreed with the likelihood of developing the disease. Multiple linear regression analysis revealed that age, place of residence, education, and employment status significantly contribute to AD knowledge scores. Conclusions: This study highlights the urgent need for public education and awareness campaigns to address the knowledge gap and reduce stigmatization associated with AD in Bangladesh. Targeted efforts, particularly among older age groups and rural communities, can enhance understanding and improve the quality of care and support for AD patients and their caregivers.

Prevalence of scabies and its associated environmental risk factors among the Forcibly Displaced Myanmar Nationals living in the Cox's Bazar district of Bangladesh.

Introduction: The Forcibly Displaced Myanmar Nationals (FDMNs) residing in refugee camps face various health challenges, including a rising prevalence of scabies, exacerbated by overcrowded conditions and limited healthcare access. This study aims to assess scabies prevalence, clinical features, and environmental factors among FDMNs, aiding interventions and recommendations for better health outcomes. Methodology: A cross-sectional study was conducted from April to May 2023 in six camps of Teknaf/Ukhia Cox's Bazar. Using a multistage sampling technique, 12 blocks were identified, and FDMNs seeking healthcare services from Primary Health Care posts were invited to participate in the study. Participants were adults, and children who volunteered to participate in this study. Scabies diagnosis was based on clinical examinations of exposed body areas by trained health professionals. Data on sociodemographic factors, environmental risk factors, and scabies symptoms were obtained through a semi-structured questionnaire administered by trained interviewers. Statistical analysis included descriptive statistics, Chi-square tests, and binary logistic regression models to explore associations between scabies infection and other explanatory factors. Result: A total of 679 FDMNs participated in the study, with a mean age of 29.13 years. Overall, 66.42 % of participants were diagnosed with scabies. Age, marital status, history of scabies infection, previous skin infection, family history of scabies and skin infection, floor type, pet animal, dust exposure, and seasonal exposure were significantly associated with the scabies infection. Binary logistic regression suggested that having history of scabies infection (OR 3.98, 95 % CI: 1.86 to 8.49, p < 0.001), skin infection (OR 2.46, 95 % CI: 1.32 to 4.58, p = 0.004), having family history of scabies infection (OR 3.06, 95 % CI: 1.29 to 7.23, p = 0.011), family history of skin infection (OR 27.41, 95% CI: 14.46 to 51.97, P < 0.001), having contact with street animal (OR 2.16, 95% CI: 1.27 to 3.66, P = 0.004), and winter season (OR 3.33, 95 % CI: 1.89 to 5.87, p < 0.001) were significantly associated with scabies infection. Conclusion: Tailored public health measures targeting hygiene, living conditions, and animal contact can mitigate the spread of scabies, particularly among vulnerable groups like Rohingya refugees, necessitating collaboration between stakeholders.

Myelin oligodendrocyte glycoprotein reactive Th17 cells drive Janus Kinase 1 dependent transcriptional reprogramming in astrocytes and alter cell surface cytokine receptor profiles during experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFß, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.

Exploring the barriers to feminine healthcare access among marginalized women in Bangladesh and facilitating access through a voice bot.

In today's digital age, ensuring high-quality healthcare services is paramount for both physical and mental well-being. This is particularly challenging in developing countries like Bangladesh, where marginalized individuals, especially women, face barriers to accessing essential healthcare. Financial constraints and limited awareness often hinder their ability to avail themselves of private or public healthcare services. Besides, women have distinct healthcare difficulties compared to men, and they are also more likely to catch certain illnesses and diseases. However, there is a noticeable gap in the existing literature, with insufficient research specifically dedicated to addressing the healthcare challenges faced by this underprivileged group of women in developing countries. In this study, we delve deeper into the healthcare challenges faced by underprivileged women in Bangladesh, including issues related to menstruation and gynecological disorders through a field study in a slum area. Drawing valuable insights from this field study, we propose leveraging voice bots in the telecommunications sector as an innovative solution to provide accessible and targeted healthcare support for marginalized women. We present the prototype of such a voice bot to be available 24/7 with detailed workflow and performance evaluation. We expect that our study will contribute to the ICTD scholarship by informing future interventions for economically disadvantaged communities as well as informing policymakers grappling with the healthcare challenges faced by underprivileged women.

Food craving, vitamin A, and menstrual disorders: A comprehensive study on university female students.

BACKGROUND: Menstrual disorders, influenced by dietary habits like high fat intake and low fruit and vegetable consumption, are a global public health issue. This study assessed the prevalence of dysmenorrhea, premenstrual syndrome (PMS), and irregular menstrual cycle (IMC) among female university students in Bangladesh, focusing on food cravings and low vitamin A intake as risk factors. METHODS: In this comprehensive study, data from randomly selected female university students were collected using a structured questionnaire. The associations were analyzed through chi-square tests and multivariable logistic regression, reported as adjusted odds ratios (AOR). RESULTS: The most prevalent menstrual disorder was dysmenorrhea (68.3%) followed by PMS (33.8%), and IMC (24.3%). Food cravers for high-fat and sweet foods were likely to experience dysmenorrhea (AOR: 2.4, 95% CI: 1.5-3.9, P<0.001), suffer from PMS (AOR: 3.9, 95% CI: 2.3-6.6, P<0.001), and have IMC (AOR: 3.0, 95% CI: 1.6-5.3, P<0.001) vs. subjects who didn't. Subjects consuming vitamin A-rich plant foods had 40% (AOR: 0.6, 95% CI: 0.4-0.9, P < 0.01) and 60% (AOR: 0.4, 95% CI: 0.2-0.6, P<0.001) less likely suffering from dysmenorrhea and IMC vs. who didn't. Both underweight and overweight/obese subjects experienced more than 2-fold dysmenorrhea vs. normal-weight peers. The chance of IMC was nearly 3-fold among overweight/obese subjects. However, lower physical activity was associated with PMS and IMC whereas family history was associated with dysmenorrhea and PMS. Among the socio-demographic factors, maternal education, place of residence, and earlier menarche (≤12 years) were associated with dysmenorrhea while marital status was associated with IMC. CONCLUSION: This study indicates that increasing the intake of vitamin A-rich plant foods and reducing high-fat, sweet foods can lower the risk of dysmenorrhea and IMC. Additionally, it highlights the need for regular exercise to mitigate the increased risk of PMS and IMC.

A randomised control trial of BIC/F/TAF vs DRV/c/F/TAF in context of HIV test-and-treat, BicTnT.

BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.

Protective effects of l-carnitine on isoprenaline -induced heart and kidney dysfunctions: Modulation of inflammation and oxidative stress-related gene expression in rats.

The aim of this study was to evaluate the effect of l-carnitine (L-CAR) treatment on isoprenaline (ISO) administered kidney and heart impairment in male Long Evans rats. Four groups of rats were engaged in this study such as control, ISO, control + L-CAR, and ISO + L-CAR, where n = 6 in each group. The rats were also provided with chow food and water ad libitum. At the end of the study, all rats were sacrificed, and blood and tissue samples were collected for bio-chemical analysis. Oxidative stress parameters and antioxidant enzyme activities were determined in plasma and tissues. Antioxidant and inflammatory genes expression were analyzed in the kidney cortex, and histopathological studies of kidney tissues were performed. This study showed that creatinine and uric acid in plasma were significantly increased in ISO-administered rats. l-carnitine treatment lowered the uric acid and creatinine level. ISO-administered rats showed increased lipid peroxidation and declined levels of antioxidant enzymes activities in kidneys and heart. l-carnitine treatment restored antioxidant enzymes activities and protect against oxidative stress in kidney and heart. This effect is correlated with the restoration of Nrf-2-HO-1 genes expression followed by increased SOD and catalase genes expression in the kidney. l-carnitine treatment also prevented the TNF-α, IL-6, and NF-кB expression in kidneys of ISO administered rats. Histopathology staining showed that l-carnitine treatment prevented kidney damage and collagen deposition in ISO administered rats. The result of this study exhibited that l-carnitine treatment reduced oxidative stress and increased antioxidant enzyme activities by enhancing antioxidant genes expression in ISO administered rats.

Evaluation of the modulating effect of epidermal growth factor receptor inhibitor cetuximab in carbon-tetrachloride induce hepatic fibrosis in rats.

Liver fibrosis, developed in almost all chronic liver injuries. Epidermal growth factor receptors (EGFR) have been thought to contribute to cirrhosis and liver fibrosis. Therefore, using a rat model of carbon tetrachloride (CCl4)-induced liver fibrogenesis, we investigated the preventive effects of cetuximab, an inhibitor of the EGF receptor (EGFR). Ameliorative effects of cetuximab were examined in rats, brought on by biweekly doses of 50 mg/kg of carbon tetrachloride (CCl4). There were a total of 24 male Long Evans rats split up into four distinct groups such as control, CCl4, control+cetuximab and CCl4+cetuximab. After two weeks of treatment with cetuximab (100 µg/kg), samples of tissue and blood were taken after all the rats had been sacrificed. Plasma samples were examined for the biochemical indicators of inflammation and oxidative stress. Histological staining on liver sections was performed for morphologic pathologies, and related genes expressions analysis were done with RT-PCR in liver tissue. The findings showed that cetuximab could raise the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and considerably lower the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), and nitric oxide (NO). Sirius red staining and hematoxylin-eosin (H&E) displayed that cetuximab therapy reduced the inflammatory cells infiltration and enhanced fibrotic lesions. In the meantime, cetuximab therapy also dramatically reduces the expression of genes linked to inflammation in the liver tissue, including NF-кB, iNOS, IL-6, TNF-α, and TGF-ß. To sum up, the anti-inflammatory, antifibrotic, and antioxidant properties of cetuximab confer curative efficacy against liver fibrosis.

A pro-inflammatory gut mucosal cytokine response is associated with mild COVID-19 disease and superior induction of serum antibodies.

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.

Effect of flavonoids on the destabilization of α-synuclein fibrils and their conversion to amorphous aggregate: A molecular dynamics simulation and experimental study.

The second most prevalent neurodegenerative disease, Parkinson's disease (PD), is caused by the accumulation and deposition of fibrillar aggregates of the α-Syn into the Lewy bodies. To create a potent pharmacological candidate to destabilize the preformed α-Syn fibril, it is important to understand the precise molecular mechanism underlying the destabilization of the α-Syn fibril. Through molecular dynamics simulations and experiments, we have examined the molecular mechanisms causing the destabilization and suppression of a newly discovered α-Syn fibril with a Greek-key-like shape and an aggregation prone state (APS) of α-Syn in the presence and absence of various Flvs. According to MD simulation and experimental evidence, morin, quercetin, and myricetin are the Flvs, most capable of destabilizing the fibrils and converting them into amorphous aggregates. Compared to galangin and kaempferol, they have more hydroxyl groups and form more hydrogen bonds with fibrils.The processes by which morin and myricetin prevent new fibril production from APS and destabilize the fibrils are different. According to linear interaction energy analysis, van der Waals interaction predominates with morin, and electrostatic interaction dominates with myricetin. Our MD simulation and experimental findings provide mechanistic insights into how Flvs destabilize α-Syn fibrils and change their morphology, opening the door to developing structure-based drugs for treating Parkinson's disease.