Can the UNAIDS modes of transmission model be improved? A comparison of the original and revised model projections using data from a setting in west Africa.

OBJECTIVE: The UNAIDS modes of transmission model (MoT) is a user-friendly model, developed to predict the distribution of new HIV infections among different subgroups. The model has been used in 29 countries to guide interventions. However, there is the risk that the simplifications inherent in the MoT produce misleading findings. Using input data from Nigeria, we compare projections from the MoT with those from a revised model that incorporates additional heterogeneity. METHODS: We revised the MoT to explicitly incorporate brothel and street-based sex-work, transactional sex, and HIV-discordant couples. Both models were parameterized using behavioural and epidemiological data from Cross River State, Nigeria. Model projections were compared, and the robustness of the revised model projections to different model assumptions, was investigated. RESULTS: The original MoT predicts 21% of new infections occur in most-at-risk-populations (MARPs), compared with 45% (40-75%, 95% Crl) once additional heterogeneity and updated parameterization is incorporated. Discordant couples, a subgroup previously not explicitly modelled, are predicted to contribute a third of new HIV infections. In addition, the new findings suggest that women engaging in transactional sex may be an important but previously less recognized risk group, with 16% of infections occurring in this subgroup. CONCLUSION: The MoT is an accessible model that can inform intervention priorities. However, the current model may be potentially misleading, with our comparisons in Nigeria suggesting that the model lacks resolution, making it challenging for the user to correctly interpret the nature of the epidemic. Our findings highlight the need for a formal review of the MoT

Slx8 removes Pli1-dependent protein-SUMO conjugates including SUMOylated Topoisomerase I to promote genome stability

Peer reviewedPublisher PD

SUMO chain formation is required for response to replication arrest in S. pombe

SUMO is a ubiquitin-like protein that is post-translationally attached to one or more lysine residues on target proteins. Despite having only 18% sequence identity with ubiquitin, SUMO contains the conserved betabetaalphabetabetaalphabeta fold present in ubiquitin. However, SUMO differs from ubiquitin in having an extended N-terminus. In S. pombe the N-terminus of SUMO/Pmt3 is significantly longer than those of SUMO in S. cerevisiae, human and Drosophila. Here we investigate the role of this N-terminal region. We have used two dimensional gel electrophoresis to demonstrate that S. pombe SUMO/Pmt3 is phosphorylated, and that this occurs on serine residues at the extreme N-terminus of the protein. Mutation of these residues (in pmt3-1) results in a dramatic reduction in both the levels of high Mr SUMO-containing species and of total SUMO/Pmt3, indicating that phosphorylation of SUMO/Pmt3 is required for its stability. Despite the significant reduction in high Mr SUMO-containing species, pmt3-1 cells do not display an aberrant cell morphology or sensitivity to genotoxins or stress. Additionally, we demonstrate that two lysine residues in the N-terminus of S. pombe SUMO/Pmt3 (K14 and K30) can act as acceptor sites for SUMO chain formation in vitro. Inability to form SUMO chains results in aberrant cell and nuclear morphologies, including stretched and fragmented chromatin. SUMO chain mutants are sensitive to the DNA synthesis inhibitor, hydroxyurea (HU), but not to other genotoxins, such as UV, MMS or CPT. This implies a role for SUMO chains in the response to replication arrest in S. pomb

Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4

The small ubiquitin-like modifier (SUMO) can form polymeric chains that are important signals in cellular processes such as meiosis, genome maintenance and stress response. The SUMO-targeted ubiquitin ligase RNF4 engages with SUMO chains on linked substrates and catalyses their ubiquitination, which targets substrates for proteasomal degradation. Here we use a segmental labelling approach combined with solution nuclear magnetic resonance (NMR) spectroscopy and biochemical characterization to reveal how RNF4 manipulates the conformation of the SUMO chain, thereby facilitating optimal delivery of the distal SUMO domain for ubiquitin transfer

SUMO-Targeted Ubiquitin Ligase, Rad60, and Nse2 SUMO Ligase Suppress Spontaneous Top1–Mediated DNA Damage and Genome Instability

Through as yet undefined proteins and pathways, the SUMO-targeted ubiquitin ligase (STUbL) suppresses genomic instability by ubiquitinating SUMO conjugated proteins and driving their proteasomal destruction. Here, we identify a critical function for fission yeast STUbL in suppressing spontaneous and chemically induced topoisomerase I (Top1)–mediated DNA damage. Strikingly, cells with reduced STUbL activity are dependent on tyrosyl–DNA phosphodiesterase 1 (Tdp1). This is notable, as cells lacking Tdp1 are largely aphenotypic in the vegetative cell cycle due to the existence of alternative pathways for the removal of covalent Top1–DNA adducts (Top1cc). We further identify Rad60, a SUMO mimetic and STUbL-interacting protein, and the SUMO E3 ligase Nse2 as critical Top1cc repair factors in cells lacking Tdp1. Detection of Top1ccs using chromatin immunoprecipitation and quantitative PCR shows that they are elevated in cells lacking Tdp1 and STUbL, Rad60, or Nse2 SUMO ligase activity. These unrepaired Top1ccs are shown to cause DNA damage, hyper-recombination, and checkpoint-mediated cell cycle arrest. We further determine that Tdp1 and the nucleotide excision repair endonuclease Rad16-Swi10 initiate the major Top1cc repair pathways of fission yeast. Tdp1-based repair is the predominant activity outside S phase, likely acting on transcription-coupled Top1cc. Epistasis analyses suggest that STUbL, Rad60, and Nse2 facilitate the Rad16-Swi10 pathway, parallel to Tdp1. Collectively, these results reveal a unified role for STUbL, Rad60, and Nse2 in protecting genome stability against spontaneous Top1-mediated DNA damage

Global diarrhoea-associated mortality estimates and models in children: Recommendations for dataset and study selection

BACKGROUND: Multiple factors contribute to variation in disease burden, including the type and quality of data, and inherent properties of the models used. Understanding how these factors affect mortality estimates is crucial, especially in the context of public health decision making. We examine how the quality of the studies selected to provide mortality data, influence estimates of burden and provide recommendations about the inclusion of studies and datasets to calculate mortality estimates. METHODS: To determine how mortality estimates are affected by the data used to generate model outputs, we compared the studies used by The Institute of Health Metrics and Evaluation (IHME) and Maternal and Child Epidemiology Estimation (MCEE) modelling groups to generate enterotoxigenic Escherichia coli (ETEC) and Shigella-associated mortality estimates for 2016. Guided by an expert WHO Working Group, we applied a modified Newcastle-Ottawa Scale (NOS) to evaluate the quality of studies used by both modelling groups. RESULTS: IHME and MCEE used different sets of ETEC and Shigella studies in their models and the majority of studies were high quality. The distribution of the NOS scores was similar between the two modelling groups. We observed an overrepresentation of studies from some countries in SEAR, AFR and WPR compared to other WHO regions. CONCLUSION: We identified key differences in study inclusion and exclusion criteria used by IHME and MCEE and discuss their impact on datasets used to generate diarrhoea-associated mortality estimates. Based on these observations, we provide a set of recommendations for future estimates of mortality associated with enteric diseases

Targeting of SUMO substrates to a Cdc48-Ufd1-Npl4 segregase and STUbL pathway in fission yeast

In eukaryotes, the conjugation of proteins to the small ubiquitin-like modifier (SUMO) regulates numerous cellular functions. A proportion of SUMO conjugates are targeted for degradation by SUMO-targeted ubiquitin ligases (STUbLs) and it has been proposed that the ubiquitin-selective chaperone Cdc48/p97-Ufd1-Npl4 facilitates this process. However, the extent to which the two pathways overlap, and how substrates are selected, remains unknown. Here we address these questions in fission yeast through proteome-wide analyses of SUMO modification sites. We identify over a thousand sumoylated lysines in a total of 468 proteins and quantify changes occurring in the SUMO modification status when the STUbL or Ufd1 pathways are compromised by mutations. The data suggest the coordinated processing of several classes of SUMO conjugates, many dynamically associated with centromeres or telomeres. They provide new insights into subnuclear organization and chromosome biology, and, altogether, constitute an extensive resource for the molecular characterization of SUMO function and dynamics

Transactional sex among young women in rural South Africa: prevalence, mediators and association with HIV infection.

INTRODUCTION: Young adolescent women in sub-Saharan Africa are three to four times more likely to be HIV-positive than boys or men. One of the relationship dynamics that is likely to be associated with young women's increased vulnerability to HIV is transactional sex. There are a range of HIV-related risk behaviours that may drive this vulnerability. However, to date, limited epidemiological data exist on the role of transactional sex in increasing HIV acquisition, especially among young women in sub-Saharan Africa. Our paper presents data on the prevalence of self-reported engagement in transactional sex and explores whether transactional sex is associated with increased risk of HIV infection among a cohort of young, rural, sexually active South African women. We also explore whether this relationship is mediated through certain HIV-related risk behaviours. METHODS: We analyzed baseline data from a phase III trial of conditional cash transfers for HIV prevention of 693 sexually active, school-going young women aged 13-20 years in rural South Africa. We examined the association between young women's engagement in transactional sex and HIV infection. Transactional sex is defined as a non-commercial, non-marital sexual relationship whereby sex is exchanged for money and/or gifts. We explored whether this relationship is mediated by certain HIV-related risk behaviours. We used logistic and multinomial regression and report unadjusted and adjusted odds ratios with 95% CI. RESULTS: Overall, 14% (n=97) of sexually active young women reported engaging in transactional sex. Engagement in transactional sex was associated with an increased risk of being HIV-positive (aOR: 2.5, CI: 95% 1.19-5.25, p=0.01). The effect size of this association remained nearly unchanged when adjusted for certain other dimensions of HIV risk that might help explain the underlying pathways for this relationship. CONCLUSIONS: This study provides quantitative support demonstrating that transactional sex is associated with HIV infection in young women. Even though the specific variables tested do not mediate the relationship, a potential explanation for this association may be that the men with whom young women are having sex belong to networks of sexually connected individuals who are at a "high risk" for HIV infection. The results highlight the importance of structural intervention approaches that can alter the context of young women's HIV risk

World Health Organization Expert Working Group: Recommendations for assessing morbidity associated with enteric pathogens

BACKGROUND: Diarrhoeal infections are one of the leading causes of child's mortality and morbidity. Vaccines against Shigella, enterotoxigenic E. coli (ETEC), norovirus and invasive non-typhoidal Salmonella are in clinical development, however, their full value in terms of short and long-term health and socio-economic burden needs to be evaluated and communicated, to rationalise investment in vaccine development, and deployment. While estimates of mortality of enteric infections exist, the long-term morbidity estimates are scarce and have not been systematically collected. METHODS: The World Health Organization (WHO) has convened a Burden of Enteric Diseases Morbidity Working Group (BoED MWG) who identified key workstreams needed to characterise the morbidity burden of enteric infections. The group also identified four criteria for the prioritisation of pathogens of which impact on long-term morbidity needs to be assessed. RESULTS: The BoED MWG suggested to identify and analyse the individual level data from historical datasets to estimate the impact of enteric infections and confounders on long-term morbidity, including growth faltering and cognitive impairment in children (workstream 1); to conduct a systematic review of evidence on the association of aetiology specific diarrhoea with short- and long- term impact on growth, including stunting, and possibly cognitive impairment in children, while accounting for potential confounders (workstream 2); and to conduct a systematic review of evidence on the association of aetiology specific diarrhoea with short- and long- term impact on health outcomes in adults. The experts prioritised four pathogens for this work: Campylobacter jejuni, ETEC (LT or ST), norovirus (G1 or G2), and Shigella (dysenteriae, flexneri, sonnei). CONCLUSIONS: The proposed work will contribute to improving the understanding of the impact of enteric pathogens on long-term morbidity. The timing of this work is critical as all four pathogens have vaccine candidates in the clinical pipeline and decisions about investments in development, manufacturing or vaccine procurement and use are expected to be made soon

Uncovering Ubiquitin and Ubiquitin-like Signaling Networks

Microscopic imaging and technolog