Examining the relationships between body image, eating attitudes, BMI, and physical activity in rural and urban South African young adult females using structural equation modeling.

The persistence of food insecurity, malnutrition, increasing adiposity, and decreasing physical activity, heightens the need to understand relationships between body image satisfaction, eating attitudes, BMI and physical activity levels in South Africa. Females aged 18-23 years were recruited from rural (n = 509) and urban (n = 510) settings. Body image satisfaction was measured using Stunkard's silhouettes, and the 26-item Eating Attitudes questionnaire (EAT-26) was used to evaluate participants' risk of disordered eating. Minutes per week of moderate to vigorous physical activity (MVPA) was assessed using the Global Physical Activity Questionnaire (GPAQ). Significant linear correlates were included in a series of regressions run separately for urban and rural participants. Structural equation modeling (SEM) was used to test the relationships between variables. Urban females were more likely to be overweight and obese than rural females (p = 0.02), and had a greater desire to be thinner (p = 0.02). In both groups, being overweight or obese was positively associated with a desire to be thinner (p<0.01), and negatively associated with a desire to be fatter (p<0.01). Having a disordered eating attitude was associated with body image dissatisfaction in the urban group (β = 1.27, p<0.01, CI: 0.38; 2.16), but only with a desire to be fatter in the rural group (β = 0.63, p = 0.04, CI: 0.03; 1.23). In the SEM model, body image dissatisfaction was associated with disordered eating (β = 0.63), as well as higher MVPA participation (p<0.01). These factors were directly associated with a decreased risk of disordered eating attitude, and with a decreased desire to be thinner. Findings indicate a shift in both settings towards more Westernised ideals. Physical activity may provide a means to promote a healthy body image, while reducing the risk of disordered eating. Given the high prevalence of overweight and obesity in both rural and urban women, this study provides insights for future interventions aimed at decreasing adiposity in a healthy way

The Selection of a Hepatocyte Cell Line Susceptible to Plasmodium falciparum Sporozoite Invasion That Is Associated With Expression of Glypican-3

In vitro studies of liver stage (LS) development of the human malaria parasite Plasmodium falciparum are technically challenging; therefore, fundamental questions about hepatocyte receptors for invasion that can be targeted to prevent infection remain unanswered. To identify novel receptors and to further understand human hepatocyte susceptibility to P. falciparum sporozoite invasion, we created an optimized in vitro system by mimicking in vivo liver conditions and using the subcloned HC-04.J7 cell line that supports mean infection rates of 3–5% and early development of P. falciparum exoerythrocytic forms—a 3- to 5-fold improvement on current in vitro hepatocarcinoma models for P. falciparum invasion. We juxtaposed this invasion-susceptible cell line with an invasion-resistant cell line (HepG2) and performed comparative proteomics and RNA-seq analyses to identify host cell surface molecules and pathways important for sporozoite invasion of host cells. We identified and investigated a hepatocyte cell surface heparan sulfate proteoglycan, glypican-3, as a putative mediator of sporozoite invasion. We also noted the involvement of pathways that implicate the importance of the metabolic state of the hepatocyte in supporting LS development. Our study highlights important features of hepatocyte biology, and specifically the potential role of glypican-3, in mediating P. falciparum sporozoite invasion. Additionally, it establishes a simple in vitro system to study the LS with improved invasion efficiency. This work paves the way for the greater malaria and liver biology communities to explore fundamental questions of hepatocyte-pathogen interactions and extend the system to other human malaria parasite species, like P. vivax

A Mammalian Conserved Element Derived from SINE Displays Enhancer Properties Recapitulating Satb2 Expression in Early-Born Callosal Projection Neurons

Short interspersed repetitive elements (SINEs) are highly repeated sequences that account for a significant proportion of many eukaryotic genomes and are usually considered “junk DNA”. However, we previously discovered that many AmnSINE1 loci are evolutionarily conserved across mammalian genomes, suggesting that they may have acquired significant functions involved in controlling mammalian-specific traits. Notably, we identified the AS021 SINE locus, located 390 kbp upstream of Satb2. Using transgenic mice, we showed that this SINE displays specific enhancer activity in the developing cerebral cortex. The transcription factor Satb2 is expressed by cortical neurons extending axons through the corpus callosum and is a determinant of callosal versus subcortical projection. Mouse mutants reveal a crucial function for Sabt2 in corpus callosum formation. In this study, we compared the enhancer activity of the AS021 locus with Satb2 expression during telencephalic development in the mouse. First, we showed that the AS021 enhancer is specifically activated in early-born Satb2+ neurons. Second, we demonstrated that the activity of the AS021 enhancer recapitulates the expression of Satb2 at later embryonic and postnatal stages in deep-layer but not superficial-layer neurons, suggesting the possibility that the expression of Satb2 in these two subpopulations of cortical neurons is under genetically distinct transcriptional control. Third, we showed that the AS021 enhancer is activated in neurons projecting through the corpus callosum, as described for Satb2+ neurons. Notably, AS021 drives specific expression in axons crossing through the ventral (TAG1−/NPY+) portion of the corpus callosum, confirming that it is active in a subpopulation of callosal neurons. These data suggest that exaptation of the AS021 SINE locus might be involved in enhancement of Satb2 expression, leading to the establishment of interhemispheric communication via the corpus callosum, a eutherian-specific brain structure

Inhibition of alpha-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region

The interplay between dopamine and alpha-synuclein (AS) plays a central role in Parkinson's disease (PD). PD results primarily from a severe and selective devastation of dopaminergic neurons in substantia nigra pars compacta. The neuropathological hallmark of the disease is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies within the surviving neurons, enriched in filamentous AS. In vitro, dopamine inhibits AS fibril formation, but the molecular determinants of this inhibition remain obscure. Here we use molecular dynamic (MD) simulations to investigate the binding of dopamine and several of its derivatives onto conformers representative of an NMR ensemble of AS structures in aqueous solution. Within the limitations inherent to MD simulations of unstructured proteins, our calculations suggest that the ligands bind to the (125)YEMPS(129) region, consistent with experimental findings. The ligands are further stabilized by long-range electrostatic interactions with glutamate 83 (E83) in the NAC region. These results suggest that by forming these interactions with AS, dopamine may affect AS aggregation and fibrillization properties. To test this hypothesis, we investigated in vitro the effects of dopamine on the aggregation of mutants designed to alter or abolish these interactions. We found that point mutations in the (125)YEMPS(129) region do not affect AS aggregation, which is consistent with the fact that dopamine interacts non-specifically with this region. In contrast, and consistent with our modeling studies, the replacement of glutamate by alanine at position 83 (E83A) abolishes the ability of dopamine to inhibit AS fibrillization

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Evaluation of a text messaging intervention to promote preconception micronutrient supplement use: feasibility study nested in the Healthy Life Trajectories Initiative study in South Africa

BACKGROUND: Social messaging strategies such as SMS text messaging and radio are promising avenues for health promotion and behavior change in low- to middle-income settings. However, evidence of their acceptability, feasibility, and impact in the context of young women’s health and micronutrient deficiencies is lacking. OBJECTIVE: This study aimed to evaluate the feasibility of an automated 2-way text messaging intervention nested in an ongoing preconception health trial, the Healthy Life Trajectories Initiative (HeLTI; HeLTI Bukhali) in Soweto, South Africa. Second, we aimed to evaluate the acceptability of a health promotion radio serial, which aired concurrently in the region. METHODS: In this feasibility study, 120 participants enrolled in HeLTI Bukhali between November 2020 and February 2021 received the 6-month 2-way text messaging intervention. Quantitative and qualitative data on intervention acceptability, usability, interaction, perceived benefit, and fidelity were collected during 5 focus group discussions (FGDs) and from study data logs. During the FGDs, data were collected on the acceptability of the radio serial. Following the text messaging intervention, capillary hemoglobin levels were assessed, and a participant questionnaire provided information on adherence and attitudes toward supplements. The text messaging control group comprised the first 120 women recruited from November 2019 to February 2020, who received the Bukhali intervention but not the text messages. Statistical significance testing and a linear mixed model were used for indicative effect comparisons between the text message–receiving and control groups. RESULTS: The text messaging intervention was found to be acceptable and to have perceived benefits, including being reminded to take supplements, gaining knowledge, and feeling supported by the study team. The use of the 2-way text messaging reply function was limited, with only a 10.8% (13/120) response rate by week 24. Barriers to replying included a lack of interest or phone credit and technical issues. Regarding the indicative effect, participants receiving the text messages had higher self-reported adherence at follow-up than the text messaging control group (42/63, 67% vs 33/85, 39% taking supplements every time; P=.02), and altitude-adjusted hemoglobin increased more between baseline and follow-up in the SMS text message–receiving group than in the text messaging control group (1.03, 95% CI 0.49-1.57; P<.001). The radio serial content was acceptable, although few participants reported exposure before the FGD. CONCLUSIONS: Women reported that the text messaging intervention was useful and described the benefits of receiving the messages. Examination of hemoglobin status indicated a promising beneficial effect of text messaging support on adherence to micronutrient supplementation, requiring further exploration through randomized controlled studies. Health promotion through radio and text messages were both found to be acceptable, although more research into the radio serial reach among young women is needed. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR) PACTR201903750173871; https://tinyurl.com/4x6n32f

Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration

Abstract Successful muscle regeneration relies on the interplay of multiple cell populations. However, the signals required for this coordinated intercellular crosstalk remain largely unknown. Here, we describe how the Hedgehog (Hh) signaling pathway controls the fate of fibro/adipogenic progenitors (FAPs), the cellular origin of intramuscular fat (IMAT) and fibrotic scar tissue. Using conditional mutagenesis and pharmacological Hh modulators in vivo and in vitro, we identify DHH as the key ligand that acts as a potent adipogenic brake by preventing the adipogenic differentiation of FAPs. Hh signaling also impacts muscle regeneration, albeit indirectly through induction of myogenic factors in FAPs. Our results also indicate that ectopic and sustained Hh activation forces FAPs to adopt a fibrogenic fate resulting in widespread fibrosis. In this work, we reveal crucial post-developmental functions of Hh signaling in balancing tissue regeneration and fatty fibrosis. Moreover, they provide the exciting possibility that mis-regulation of the Hh pathway with age and disease could be a major driver of pathological IMAT formation

Building knowledge, optimising physical and mental health and setting up healthier life trajectories in South African women ( Bukhali): A preconception randomised control trial part of the Healthy Life Trajectories Initiative (HeLTI)

Introduction: South Africa\u27s evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs.Methods and analysis: Bukhali is the first individual randomised controlled trial in Africa to test the efficacy of a complex continuum of care intervention and forms part of the Healthy Life Trajectories Initiative (HeLTI) consortium implementing harmonised trials in Canada, China, India and SA. Starting preconception and continuing through pregnancy, infancy and childhood, the intervention is designed to improve nutrition, physical and mental health and health behaviours of South African women to offset obesity-risk (adiposity) in their offspring. Women aged 18-28 years (n=6800) will be recruited from Soweto, an urban-poor area of Johannesburg. The primary outcome is dual-energy X-ray absorptiometry derived fat mass index (fat mass divided by height2) in the offspring at age 5 years. Community health workers will deliver the intervention randomly to half the cohort by providing health literacy material, dispensing a multimicronutrient supplement, providing health services and feedback, and facilitating behaviour change support sessions to optimise: (1) nutrition, (2) physical and mental health and (3) lay the foundations for healthier pregnancies and early child development.Ethics and dissemination: Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent.Trial registration: This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871).Protocol version: 20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries