Improving the resilience and workforce of health systems for women’s, children’s, and adolescents’ health

The United Nations’ first Every Woman Every Child strategy, Global Strategy for Women’s and Children’s Health, provided an impetus “to improve the health of hundreds of millions of women and children around the world and, in so doing, to improve the lives of all people.” The updated Global Strategy for Women’s, Children’s, and Adolescents’ Health calls for an even more ambitious agenda of expanding equitable coverage to a broader range of reproductive, maternal, newborn, child, and adolescent health services, as integral to the 2030 targets of the sustainable development goals.These goals cannot be realised by efforts that tackle only specific parts of the global strategy. Instead, an integrated approach is required, to include the complementary functions of stewardship, financing, workforce, supply chain, information systems, and service delivery.3 In this paper we highlight two core aspects that require urgent attention—building the resilience of health systems and ensuring sufficient human resources

3DLigandSite: predicting ligand-binding sites using similar structures

3DLigandSite is a web server for the prediction of ligand-binding sites. It is based upon successful manual methods used in the eighth round of the Critical Assessment of techniques for protein Structure Prediction (CASP8). 3DLigandSite utilizes protein-structure prediction to provide structural models for proteins that have not been solved. Ligands bound to structures similar to the query are superimposed onto the model and used to predict the binding site. In benchmarking against the CASP8 targets 3DLigandSite obtains a Matthew’s correlation co-efficient (MCC) of 0.64, and coverage and accuracy of 71 and 60%, respectively, similar results to our manual performance in CASP8. In further benchmarking using a large set of protein structures, 3DLigandSite obtains an MCC of 0.68. The web server enables users to submit either a query sequence or structure. Predictions are visually displayed via an interactive Jmol applet. 3DLigandSite is available for use at http://www.sbg.bio.ic.ac.uk/3dligandsite

SoK: Safer Digital-Safety Research Involving At-Risk Users

Research involving at-risk users -- that is, users who are more likely to experience a digital attack or to be disproportionately affected when harm from such an attack occurs -- can pose significant safety challenges to both users and researchers. Nevertheless, pursuing research in computer security and privacy is crucial to understanding how to meet the digital-safety needs of at-risk users and to design safer technology for all. To standardize and bolster safer research involving such users, we offer an analysis of 196 academic works to elicit 14 research risks and 36 safety practices used by a growing community of researchers. We pair this inconsistent set of reported safety practices with oral histories from 12 domain experts to contribute scaffolded and consolidated pragmatic guidance that researchers can use to plan, execute, and share safer digital-safety research involving at-risk users. We conclude by suggesting areas for future research regarding the reporting, study, and funding of at-risk user researchComment: 13 pages, 3 table

SERENADE: The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients : Effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes

OBJECTIVE—The purpose of this study was to assess the glucose-lowering efficacy and safety of rimonabant monotherapy in drug-naive type 2 diabetic patients

Oxygen isotope composition of a section of lower oceanic crust, ODP Hole 735B

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95244/1/ggge964.pd

Fasting Indicators of Insulin Sensitivity: Effects of Ethnicity and Pubertal Status

OBJECTIVE—To examine the relationship of fasting indicators of insulin sensitivity with a more invasive measure of insulin sensitivity (frequently sampled intravenous glucose tolerance test [FSIVGTT]) and the effect of Tanner stage and ethnicity on that relationship. RESEARCHDESIGNANDMETHODS—Data were analyzed from 149 overweight girls (97 Hispanic and 52 African American) who were either in the early stages of maturation defined by Tanner stages 1 or 2 (52Hispanic and 18 African American) or in the later stages of maturation defined by Tanner stages 4 and 5 (45 Hispanic and 34 African American). Fasting indicators of insulin sensitivity (IS) included fasting insulin and glucose and the homeostasis model assess-ment of insulin resistance (HOMA-IR). IS was derived from an FSIVGTTwithminimalmodeling. RESULTS—In Tanner stages 1 and 2, all fasting indicators were significantly associatedwith IS

The actinobacterial transcription factor RbpA binds to the principal sigma subunit of RNA polymerase

RbpA is a small non-DNA-binding transcription factor that associates with RNA polymerase holoenzyme and stimulates transcription in actinobacteria, including Streptomyces coelicolor and Mycobacterium tuberculosis. RbpA seems to show specificity for the vegetative form of RNA polymerase as opposed to alternative forms of the enzyme. Here, we explain the basis of this specificity by showing that RbpA binds directly to the principal σ subunit in these organisms, but not to more diverged alternative σ factors. Nuclear magnetic resonance spectroscopy revealed that, although differing in their requirement for structural zinc, the RbpA orthologues from S. coelicolor and M. tuberculosis share a common structural core domain, with extensive, apparently disordered, N- and C-terminal regions. The RbpA-σ interaction is mediated by the C-terminal region of RbpA and σ domain 2, and S. coelicolor RbpA mutants that are defective in binding σ are unable to stimulate transcription in vitro and are inactive in vivo. Given that RbpA is essential in M. tuberculosis and critical for growth in S. coelicolor, these data support a model in which RbpA plays a key role in the σ cycle in actinobacteria

Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies

Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be a mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role of altered glycosylation in HCV resistance to broadly neutralizing antibodies is not fully understood. Here, we have generated potent HCV neutralizing antibodies hu5B3.v3 and MRCT10.v362 that, similar to the previously described AP33 and HCV1, bind to a highly conserved linear epitope on E2. We utilize a combination of in vitro resistance selections using the cell culture infectious HCV and structural analyses to identify mechanisms of HCV resistance to hu5B3.v3 and MRCT10.v362. Ultra deep sequencing from in vitro HCV resistance selection studies identified resistance mutations at asparagine N417 (N417S, N417T and N417G) as early as 5 days post treatment. Comparison of the glycosylation status of soluble versions of the E2 glycoprotein containing the respective resistance mutations revealed a glycosylation shift from N417 to N415 in the N417S and N417T E2 proteins. The N417G E2 variant was glycosylated neither at residue 415 nor at residue 417 and remained sensitive to MRCT10.v362. Structural analyses of the E2 epitope bound to hu5B3.v3 Fab and MRCT10.v362 Fab using X-ray crystallography confirmed that residue N415 is buried within the antibody–peptide interface. Thus, in addition to previously described mutations at N415 that abrogate the β-hairpin structure of this E2 linear epitope, we identify a second escape mechanism, termed glycan shifting, that decreases the efficacy of broadly neutralizing HCV antibodies