Exopolysaccharide protects Vibrio cholerae from exogenous attacks by the type 6 secretion system

The type 6 secretion system (T6SS) is a nanomachine used by many Gram-negative bacteria, including Vibrio cholerae, to deliver toxic effector proteins into adjacent eukaryotic and bacterial cells. Because the activity of the T6SS is dependent on direct contact between cells, its activity is limited to bacteria growing on solid surfaces or in biofilms. V. cholerae can produce an exopolysaccharide (EPS) matrix that plays a role in adhesion and biofilm formation. In this work, we investigated the effect of EPS production on T6SS activity between cells. We found that EPS produced by V. cholerae cells functions as a unidirectional protective armor that blocks exogenous T6SS attacks without interfering with its own T6SS functionality. This EPS armor is effective against both samespecies and heterologous attackers. Mutations modulating the level of EPS biosynthesis gene expression result in corresponding modulation in V. cholerae resistance to exogenous T6SS attack. These results provide insight into the potential role of extracellular biopolymers, including polysaccharides, capsules, and S-layers in protecting bacterial cells from attacks involving cell-associated macromolecular protein machines that cannot readily diffuse through these mechanical defenses

Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants, K132N and V215E, with different phenotypic association with acute intermittent porphyria

The autosomal dominantly inherited disease AIP (acute intermittent porphyria) is caused by mutations in HMBS [hydroxymethylbilane synthase; also known as PBG (porphobilinogen) deaminase], the third enzyme in the haem biosynthesis pathway. Enzyme-intermediates with increasing number of PBG molecules are formed during the catalysis of HMBS. In this work, we studied the two uncharacterized mutants K132N and V215E comparative with wt (wild- type) HMBS and to the previously reported AIP-associated mutants R116W, R167W and R173W. These mainly present defects in conformational stability (R116W), enzyme kinetics (R167W) or both (R173W). A combination of native PAGE, CD, DSF (differential scanning fluorimetry) and ion-exchange chromatography was used to study conformational stability and activity of the recombinant enzymes. We also investigated the distribution of intermediates corresponding to specific elongation stages. It is well known that the thermostability of HMBS increases when the DPM (dipyrromethane) cofactor binds to the apoenzyme and the holoenzyme is formed. Interestingly, a decrease in thermal stability was measured concomitant to elongation of the pyrrole chain, indicating a loosening of the structure prior to product release. No conformational or kinetic defect was observed for the K132N mutant, whereas V215E presented lower conformational stability and probably a perturbed elongation process. This is in accordance with the high association of V215E with AIP. Our results contribute to interpret the molecular mechanisms for dysfunction of HMBS mutants and to establish genotype–phenotype relations for AIP.publishedVersio

Predictors and consequences of HIV status disclosure to adolescents living with HIV in Eastern Cape, South Africa: a prospective cohort study

Introduction The World Health Organization recommends full disclosure of HIV-positive status to adolescents who acquired HIV perinatally (APHIV) by age 12. However, even among adolescents (aged 10–19) already on antiretroviral therapy (ART), disclosure rates are low. Caregivers often report the child being too young and fear of disclosure worsening adolescents’ mental health as reasons for non-disclosure. We aimed to identify the predictors of disclosure and the association of disclosure with adherence, viral suppression and mental health outcomes among adolescents in sub-Saharan Africa. Methods Analyses included three rounds (2014–2018) of data collected among a closed cohort of adolescents living with HIV in Eastern Cape, South Africa. We used logistic regression with respondent random-effects to identify factors associated with disclosure, and assess differences in ART adherence, viral suppression and mental health symptoms between adolescents by disclosure status. We also explored differences in the change in mental health symptoms and adherence between study rounds and disclosure groups with logistic regression. Results Eight hundred and thirteen APHIV were interviewed at baseline, of whom 769 (94.6%) and 729 (89.7%) were interviewed at the second and third rounds, respectively. The proportion aware of their HIV-positive status increased from 63.1% at the first round to 85.5% by the third round. Older age (adjusted odds ratio [aOR]: 1.27; 1.08–1.48) and living in an urban location (aOR: 2.85; 1.72–4.73) were associated with disclosure between interviews. There was no association between awareness of HIV-positive status and ART adherence, viral suppression or mental health symptoms among all APHIV interviewed. However, among APHIV not aware of their status at baseline, adherence decreased at the second round among those who were disclosed to (N = 131) and increased among those not disclosed to (N = 151) (interaction aOR: 0.39; 0.19–0.80). There was no significant difference in the change in mental health symptoms between study rounds and disclosure groups. Conclusions Awareness of HIV-positive status was not associated with higher rates of mental health symptoms, or lower rates of viral suppression among adolescents. Disclosure was not associated with worse mental health. These findings support the recommendation for timely disclosure to APHIV; however, adherence support post-disclosure is important

Which factors affect postpartum educational enrollment of adolescent mothers in South Africa? A latent class analysis

Interrupted education of adolescent mothers remains a major concern, but limited evidence-based programming exists to support postpartum schooling of this group. This study aimed to better understand the factors that render some adolescent mothers vulnerable to school non-enrollment, and how to reduce these risks. Data from 1,046 adolescent and young mothers (10-24 years) from rural and urban communities in South Africa's Eastern Cape was obtained through a questionnaire containing validated and study-specific measures relating to sociodemographic characteristics, schooling, relationships, violence exposure, and health. Using latent class analysis, we explored emerging latent groups and their relationship to mothers' enrollment in school, college, or tertiary education. The analyses revealed three distinct groups of mothers: The 'most disadvantaged' subgroup (39%) experienced multiple risks, including food insecurity, living in informal housing, lacking positive relationships with their caregiver, and the highest distance to school; The 'disadvantaged' subgroup (44%) did not experience food insecurity whilst reporting better caregiver relationships and lower distance to school. However, this group still showed high probabilities of residing in informal housing and in communities that expose them to violence; A 'least disadvantaged' subgroup (17%) was largely unaffected by economic and community risks and experienced good caregiver relationships. Compared to the most disadvantaged mothers, the least disadvantaged mothers showed the highest probability of being enrolled in education (65% versus 45%). Adolescent motherhood can impede continued enrollment in education and individual-centered interventions alone might not be sufficient to mitigate the risks for non-enrollment. Services and provisions that address severe poverty and improve family relationships might provide an opportunity to positively influence schooling among adolescent mothers

Adolescent parenthood and HIV-infection in South Africa—Associations with child cognitive development

HIV, both directly and indirectly, impacts child development outcomes. The most severe impacts are for children infected with HIV, and those exposed but uninfected are also shown to have challenges-though less severe. However, little is known regarding the development of children born to adolescent mothers affected by HIV. This study aims to examine cognitive development for children born to adolescent mothers, comparing those children living with HIV, those HIV exposed and uninfected (HEU) and those HIV unexposed (HU). Analyses utilise cross-sectional data from 920 adolescent mother (10-19 years)-first born child dyads residing in the Eastern Cape Province, South Africa. Participants completed detailed study questionnaires inclusive of validated and study specific measures relating to sociodemographic characteristics, HIV, and maternal and child health. Trained assessors administered standardised child development assessments (using the Mullen Scales of Early Learning) with all children. Chi-square tests and ANOVA tests were used to explore maternal and child characteristics according to child HIV status (HIV, HEU, HU) on cognitive development. Linear regression models were used to explore the cross-sectional associations between child HIV status and child cognitive development. 1.2% of children were living with HIV, 20.5% were classified as being HEU and, 78.3% were classified as HU. Overall, children living with HIV were found to perform lower across developmental domains compared to both HEU and HU groups (composite score of early learning: 73.0 vs 91.2 vs. 94.1, respectively: F = 6.45, p = 0.001). HEU children on average scored lower on all developmental domains compared to HU children, reaching significance on the gross motor domain (p<0.05). Exploratory analyses identified maternal education interruption as a potential risk factor for lower child cognitive development scores and, higher maternal age to be protective of child cognitive development scores. These exploratory findings address a critical evidence gap regarding the cognitive development of children born to adolescent mothers affected by HIV in South Africa. Analyses identify stepwise differences in the average scoring on child cognitive development domains according to child HIV status among children born to adolescent mothers affected by HIV; with children living with HIV performing worse overall. Young mothers and their children may benefit from adapted interventions aimed at bolstering child development outcomes. Targeted programming particularly among younger adolescent mothers and those experiencing education interruption may identify those families, particularly in need. Attention to maternal continuity of education and age of conception may be interventions to consider

Stable Southern Hemisphere westerly winds throughout the Holocene until intensification in the last two millennia

The Southern Hemisphere westerly winds sustain the Southern Ocean’s role as one of Earth’s main carbon sinks, and have helped sequester nearly half the anthropogenic CO2 stored in the ocean. Observations show shifts in the vigor of this climate regulator, but models disagree how future change impacts carbon storage due to scarce baseline data. Here, we use the hydrogen isotope ratios of sedimentary lipids to resolve Holocene changes in Southern Hemisphere westerly wind strength. Our reconstruction reveals stable values until ~2150 years ago when aquatic compounds became more 2H-enriched. We attribute this isotope excursion to wind-driven lake water evaporation, and regional paleoclimate evidence shows it marks a trend towards a negative Southern Annular Mode – the Southern Ocean’s main mode of atmospheric variability. Because this shift is unmatched in the past 7000 years, our findings suggest that previously published millennium-long Southern Annular Mode indices used to benchmark future change may not capture the full range of natural variability.publishedVersio

WT1 and its transcriptional cofactor BASP1 redirect the differentiation pathway of an established blood cell line

The Wilms' tumour suppressor WT1 (Wilms' tumour 1) is a transcriptional regulator that plays a central role in organogenesis, and is mutated or aberrantly expressed in several childhood and adult malignancies. We previously identified BASP1 (brain acid-soluble protein 1) as a WT1 cofactor that suppresses the transcriptional activation function of WT1. In the present study we have analysed the dynamic between WT1 and BASP1 in the regulation of gene expression in myelogenous leukaemia K562 cells. Our findings reveal that BASP1 is a significant regulator of WT1 that is recruited to WT1-binding sites and suppresses WT1-mediated transcriptional activation at several WT1 target genes. We find that WT1 and BASP1 can divert the differentiation programme of K562 cells to a non-blood cell type following induction by the phorbol ester PMA. WT1 and BASP1 co-operate to induce the differentiation of K562 cells to a neuronal-like morphology that exhibits extensive arborization, and the expression of several genes involved in neurite outgrowth and synapse formation. Functional analysis revealed the relevance of the transcriptional reprogramming and morphological changes, in that the cells elicited a response to the neurotransmitter ATP. Taken together, the results of the present study reveal that WT1 and BASP1 can divert the lineage potential of an established blood cell line towards a cell with neuronal characteristics

Exploring the cognitive development of children born to adolescent mothers in South Africa

This study explores the cognitive development of children born to adolescent mothers within South Africa compared to existing reference data, and explores development by child age bands to examine relative levels of development. Cross-sectional analyses present data from 954 adolescents (10–19 years) and their first-born children (0–68 months). All adolescents completed questionnaires relating to themselves and their children, and standardized child cognitive assessments (Mullen Scales of Early Learning) were undertaken. Cognitive development scores of the sample were lower than USA reference population scores and relative performance compared to the reference population was found to decline with increasing child age. When compared to children born to adult mothers in the sub-Saharan African region, children born to adolescent mothers (human immunodeficiency virus [HIV] unexposed; n = 724) were found to have lower cognitive development scores. Findings identify critical periods of development where intervention may be required to bolster outcomes for children born to adolescent mothers. Highlights: An exploration of the cognitive development of children born to adolescent mothers within South Africa utilizing the Mullen Scales of Early Learning. Cognitive development scores of children born to adolescent mothers within South Africa were lower compared to USA norm reference data and declined with child age. Previous studies utilizing the Mullen Scales of Early Learning within sub-Saharan Africa were summarized, and comparisons were made with the current sample. Findings highlight a potential risk of developmental delay among children born to adolescent mothers compared to children of adult mothers in the sub-Saharan African region

Key normative, legal, and policy considerations for supporting pregnant and postpartum adolescents in high HIV-burden settings: a critical analysis

Rates of adolescent pregnancy within sub-Saharan Africa are increasing. Adolescent mothers ages 10-19 years face a distinct set of risks to their own and their children's health, compounded by many economic, social, and epidemiological challenges, such as living with HIV. In navigating this complex developmental period, many adolescent mothers face structural barriers impeding safe transitions to adulthood and motherhood. Drawing on existing literature and emerging data, we outline three normative, legal, and policy issues - violence and gender inequity, access to sexual and reproductive health services, and access to social and structural supports - which affect the health, wellbeing and development of adolescent mothers and their children. We also highlight emergent evidence about programming and policy changes that can better support adolescent mothers and their children. These key proposed responses include removing barriers to SRH and HIV service integration; ensuring implementation of return-to-school policies; and extending social protection systems to cater for adolescent mothers. Despite ongoing global crises and shifts in funding priorities, these normative, legal, and policy considerations remain critical to safeguard the health and wellbeing of adolescent mothers and their children

Adolescent mothers affected by HIV and their children : a scoping review of evidence and experiences from sub-Saharan Africa

CITATION: Toska, E. et al. 2020. Adolescent mothers affected by HIV and their children: A scoping review of evidence and experiences from sub-Saharan Africa, Global Public Health, 15(11):1655-1673. doi:10.1080/17441692.2020.1775867The original publication is available at https://www.tandfonline.com/journals/rgph20While adolescents have received increasing attention in the global HIV response and international strategies and commitments, adolescent mothers and their children remain largely overlooked in research, funding and, programming for health-related outcomes. We conducted an extensive scoping review of current evidence on the experiences of adolescent mothers affected by HIV and their children in this region. We included published literature and conference abstracts, complemented by consultations with key stakeholders, and a review of documents through grey literature searching. First, we summarise the experiences of adolescent mothers and their children related to HIV and key health and development indicators. The syndemic of early motherhood and HIV in sub-Saharan Africa increases the vulnerability of adolescent mothers and their children. We then highlight lessons from a series of promising programmes focused on supporting adolescent mothers through novel approaches. In sub-Saharan Africa, supporting adolescent mothers living in high HIV-risk communities is critical not only to eliminate HIV/AIDS, but also to attain the Sustainable Development Goals. While research on and programming for adolescent mothers and their children is growing, the complex needs for this vulnerable group remain unmet. We conclude with evidence gaps and programming priorities for adolescent mothers affected by HIV and their children.https://www.tandfonline.com/doi/full/10.1080/17441692.2020.1775867Publishers versio