Cellular binding partners of the human papillomavirus E6 protein

The high-risk strains of human papillomavirus (HR-HPV) are known to be causative agents of cervical cancer and have recently also been implicated in cancers of the oropharynx. E6 is a potent oncogene of HR-HPVs, and its role in the progression to malignancy has been and continues to be explored. E6 is known to interact with and subsequently inactivate numerous cellular proteins pivotal in the mediation of apoptosis, transcription of tumor suppressor genes, maintenance of epithelial organization, and control of cell proliferation. Binding of E6 to these proteins cumulatively contributes to the oncogenic potential of HPV. This paper provides an overview of these cellular protein partners of HR-E6, the motifs known to mediate oncoprotein binding, and the agents that have the potential to interfere with E6 expression and activity and thus prevent the subsequent progression to oncogenesis

Trends in Pretreatment HIV-1 Drug Resistance in Antiretroviral Therapy-naive Adults in South Africa, 2000–2016: A Pooled Sequence Analysis

Background: South Africa has the largest public antiretroviral therapy (ART) programme in the world. We assessed temporal trends in pretreatment HIV-1 drug resistance (PDR) in ART-naïve adults from South Africa. Methods: We included datasets from studies conducted between 2000 and 2016, with HIV-1 pol sequences from more than ten ART-naïve adults. We analysed sequences for the presence of 101 drug resistance mutations. We pooled sequences by sampling year and performed a sequence-level analysis using a generalized linear mixed model, including the dataset as a random effect. Findings: We identified 38 datasets, and retrieved 6880 HIV-1 pol sequences for analysis. The pooled annual prevalence of PDR remained below 5% until 2009, then increased to a peak of 11·9% (95% confidence interval (CI) 9·2-15·0) in 2015. The pooled annual prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) PDR remained below 5% until 2011, then increased to 10.0% (95% CI 8.4–11.8) by 2014. Between 2000 and 2016, there was a 1.18-fold (95% CI 1.13–1.23) annual increase in NNRTI PDR (p < 0.001), and a 1.10-fold (95% CI 1.05–1.16) annual increase in nucleoside reverse-transcriptase inhibitor PDR (p = 0.001). Interpretation: Increasing PDR in South Africa presents a threat to the efforts to end the HIV/AIDS epidemic. These findings support the recent decision to modify the standard first-line ART regimen, but also highlights the need for broader public health action to prevent the further emergence and transmission of drug-resistant HIV. Source of Funding: This research project was funded by the South African Medical Research Council (MRC) with funds from National Treasury under its Economic Competitiveness and Support Package. Disclaimer: The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of CDC

Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial.

This article has been accepted for publication in Clinical Infectious Diseases Published by Oxford University PressBackground: Severely immunocompromised human immunodeficiency virus (HIV)-infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods: The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children ≥5 years of age with CD4 counts .1). Results: Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/µL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/µL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/µL), but low symptom burden and maintained fat mass. The remaining groups had 4%-6% mortality. Conclusions: Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up. Clinical Trials Registration: ISRCTN43622374.REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development, the Wellcome Trust, and Medical Research Council (MRC) (grant number G1100693). Additional funding support was provided by the PENTA Foundation and core support to the MRC Clinical Trials Unit at University College London (grant numbers MC_UU_12023/23 and MC_UU_12023/26). Cipla Ltd, Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, and Merck Sharp & Dohme donated drugs for REALITY, and ready-to-use supplementary food was purchased from Valid International. A. J. P. is funded by the Wellcome Trust (grant number 108065/Z/15/Z). J. A. B. is funded by the JGHTS (grant number MR/M007367/1). The Malawi-Liverpool–Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine (grant number 101113/Z/13/Z) and the Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi (grant number 203077/Z/16/Z) are supported by strategic awards from the Wellcome Trust, United Kingdom. Permission to publish was granted by the Director of KEMRI. This supplement was supported by funds from the Bill & Melinda Gates Foundation

Household food security and coping strategies: a case study of Tembisa Township of Ekurhuleni Municipality, Gauteng Province, South Africa

This study was designed to analyse factors determining household food security and coping strategies in Tembisa township of Ekurhuleni municipality, Gauteng Province, South Africa. The systematic random sampling technique was to collect primary data using well-structured questionnaire and oral interview. Data was analysed using descriptive statistics, logistic regression model, coping strategy index and Household Food Insecurity Access Scale (HFIAS). Results from descriptive statistics showed that male headed household were more than female headed household, and the maximum household size were nine (9), minimum were one (1). Results from HFIAS revealed that 38% of the households are food secured, while 28% being mildly food insecure, 26% being severely food insecure, and 8% were moderately food insecure. The results further revealed that household size, source of income, own house, total monthly income and age of the household head influence household food security negatively and positively. Coping strategy index results showed that �Rely on less expensive and preferred food has been used by 86% of the population, followed by reduce number of meals eaten in a day (60%). Since the source of income found influencing household food security, the study recommends the creation of employment through development programmes such as Expanded Public Works Programme (EPWP). The study further recommends that household should practice back yard farming. KEYWORDS: Food security, Household food insecurity access scale, socio-economic characteristics

Household food security and coping strategies: a case study of Tembisa Township of Ekurhuleni Municipality, Gauteng Province, South Africa

This study was designed to analyse factors determining household food security and coping strategies in Tembisa township of Ekurhuleni municipality, Gauteng Province, South Africa. The systematic random sampling technique was to collect primary data using well-structured questionnaire and oral interview. Data was analysed using descriptive statistics, logistic regression model, coping strategy index and Household Food Insecurity Access Scale (HFIAS). Results from descriptive statistics showed that male headed household were more than female headed household, and the maximum household size were nine (9), minimum were one (1). Results from HFIAS revealed that 38% of the households are food secured, while 28% being mildly food insecure, 26% being severely food insecure, and 8% were moderately food insecure. The results further revealed that household size, source of income, own house, total monthly income and age of the household head influence household food security negatively and positively. Coping strategy index results showed that �Rely on less expensive and preferred food has been used by 86% of the population, followed by reduce number of meals eaten in a day (60%). Since the source of income found influencing household food security, the study recommends the creation of employment through development programmes such as Expanded Public Works Programme (EPWP). The study further recommends that household should practice back yard farming. KEYWORDS: Food security, Household food insecurity access scale, socio-economic characteristics

Enteric pathogen co-infections in the paediatric population from rural communities in the Vhembe District, South Africa

Abstract: Background. Enteric pathogens co-infections are a serious health risk in children under the age of 5 years. Objective. The study aimed to determine the prevalence of diarrhoea-causing pathogens in children suffering from diarrhoea in rural communities of the Vhembe District. Methods. A cross-sectional study was conducted from July 2014 to June 2015. Diarrhoeal stool specimens (N=237) were collected from children attending primary healthcare facilities in rural communities of the Vhembe District. Stools were screened for enteric viral adenovirus 40/41, rotavirus and norovirus pathogens by means of enzyme immuno-assay (EIA) and enteric bacterial Escherichia coli spp. (diarrhoeagenic pathotypes), Shigella spp., Salmonella spp. and Vibrio spp. pathogens by means of multiplex polymerase chain reaction. Results. A total of 59.1% (140/237) were positive for at least one or more enteric pathogens. Enterotoxigenic E. coli (ETEC) (27.9%), enteroaggregative E. coli (EAEC) (26.8%) and atypical enteropathogenic E. coli (EPEC) (17.9%) were frequently detected in children less than 2 years of age. Bacterial-bacteria co-infections were detected in 24.5% (n=58) and bacterial-viral co-infections in 14.3% (n=34) of the stool specimens. Conclusion. The findings indicated that enteric pathogen co-infections are major causes of diarrhoea in children less than 2 years of age in the Vhembe District

The effect of Ni-doping on the stability of Li

The density functional theory with Hubbard parameter (DFT+U) incorporated within the Vienna Ab Initio Simulation Package was utilized to investigate the structural, electronic, elastic, and dynamical properties of pristine and Ni-doped Li2MnO3. The cluster expansion technique was used to generate the doped phases of Li2MnO3. The binary phase diagram predicted Li2Mn0.83Ni0.17O3 as the most stable phase with the lowest heat of formation. The study shows that Li2Mn0.83Ni0.17O3 is more thermodynamically stable than Li2MnO3 with a lower heat of formation. Additionally, the density of states showed that Li2Mn0.83Ni0.17O3 has a narrower band gap of 1.54 eV compared to the undoped structure with a band gap of 1.89 eV which leads to a higher electrical conductivity of the material. The elastic constants show that both structures are mechanically stable and lastly the phonon dispersions showed that these structures are vibrationally stable with no presence of imaginary vibrations. Finally, based on the results, Li2Mn0.83Ni0.17O3 can be proposed as potential cathode materials for use in lithium-ion batteries

Detection and molecular characterization of urinary tract HIV‑1 populations

BACKGROUND : Identification of all possible HIV reservoirs is an important aspect in HIV eradication efforts. The urinary tract has however not been well studied as a potential HIV reservoir. In this pilot study we molecularly characterized HIV-1 viruses in urine and plasma samples to investigate HIV-1 replication, compartmentalization and persistence in the urinary tract. METHODS : Prospectively collected urine and blood samples collected over 12–36 months from 20 HIV-1 infected individuals were analysed including sampling points from prior to and after ART initiation. HIV-1 pol gene RNA and DNA from urine supernatant and urine pellets respectively were analysed and compared to plasma RNA viruses from the same individual. RESULTS : HIV-1 nucleic acid was detected in urine samples from at least one time point in 8/20 (40%) treatment-naïve subjects compared to 1/13 (7.7%) individuals on antiretroviral treatment (ART) during periods of plasma viral suppression and 1/7 (14.3%) individuals with virological failure. HIV-1 RNA was undetectable in urine samples after ART initiation but HIV-1 DNA was detectable in one patient more than 6 months after treatment initiation. There was coclustering of urine-derived pol sequences but some urine-derived sequences were interspersed among the plasmaderived sequences. CONCLUSIONS : Suppressive ART reduces HIV-1 replication in the urinary tract but HIV-1 DNA may persist in these cells despite treatment. A larger number of sequences would be required to confirm HIV compartmentalization in the urinary tract.Table S1. Study subjects and time points at which urine samples were tested.South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa. The Longitudinal Study of HIV-Associated Lung Infections in Soweto was funded by the National Institutes of Health, USAhttps://ann-clinmicrob.biomedcentral.comam2020Medical Virolog

Enteropathogenic Escherichia coli infection induces diarrhea, intestinal damage, metabolic alterations, and increased intestinal permeability in a murine model

Enteropathogenic E. coli (EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC or escN mutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues. Metabolomic changes were also observed in EPEC infected mice with changes in tricarboxylic acid (TCA) cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. The escN mutant colonized the mice with no weight loss or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.</p