Structural and functional analysis of the tandem β-zipper interaction of a streptococcal protein with human fibronectin

Bacterial fibronectin-binding proteins (FnBPs) contain a large intrinsically disordered region (IDR) that mediates adhesion of bacteria to host tissues, and invasion of host cells, through binding to fibronectin (Fn). These FnBP IDRs consist of Fn-binding repeats (FnBRs) that form a highly extended tandem β-zipper interaction on binding to the N-terminal domain of Fn. Several FnBR residues are highly conserved across bacterial species, and here we investigate their contribution to the interaction. Mutation of these residues to alanine in SfbI-5 (a disordered FnBR from the human pathogen Streptococcus pyogenes) reduced binding, but for each residue the change in free energy of binding was <2 kcal/mol. The structure of an SfbI-5 peptide in complex with the second and third F1 modules from Fn confirms that the conserved FnBR residues play equivalent functional roles across bacterial species. Thus, in SfbI-5, the binding energy for the tandem β-zipper interaction with Fn is distributed across the interface rather than concentrated in a small number of "hot spot" residues that are frequently observed in the interactions of folded proteins. We propose that this might be a common feature of the interactions of IDRs and is likely to pose a challenge for the development of small molecule inhibitors of FnBP-mediated adhesion to and invasion of host cells

Structural analysis of X-Linked Retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function

Retinoschisin, an octameric retinal-specific protein, is essential for retinal architecture with mutations causing X-linked retinoschisis (XLRS), a monogenic form of macular degeneration. Most XLRS-associated mutations cause intracellular retention, however a subset are secreted as octamers and the cause of their pathology is ill-defined. Therefore, here we investigated the solution structure of the retinoschisin monomer and the impact of two XLRS-causing mutants using a combinatorial approach of biophysics and cryo-EM. The retinoschisin monomer has an elongated structure which persists in the octameric assembly. Retinoschisin forms a dimer of octamers with each octameric ring adopting a planar propeller structure. Comparison of the octamer with the hexadecamer structure indicated little conformational change in the retinoschisin octamer upon dimerization, suggesting that the octamer provides a stable interface for construction of the hexadecamer. The H207Q XLRS-associated mutation was found in the interface between octamers and destabilized both monomeric and octameric retinoschisin. Octamer dimerization is consistent with the adhesive function of retinoschisin supporting interactions between retinal cell layers, so disassembly would prevent structural coupling between opposing membranes. In contrast, cryo-EM structural analysis of the R141H mutation at ~4.2Å resolution was found to only cause a subtle conformational change in the propeller tips, potentially perturbing an interaction site. Together, these findings support distinct mechanisms of pathology for two classes of XLRS-associated mutations in the retinoschisin assembly

Assessing the impacts of 1.5 °C global warming – simulation protocol of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP2b)

In Paris, France, December 2015, the Conference of the Parties (COP) to the United Nations Framework Convention on Climate Change (UNFCCC) invited the Intergovernmental Panel on Climate Change (IPCC) to provide a "special report in 2018 on the impacts of global warming of 1.5°C above pre-industrial levels and related global greenhouse gas emission pathways". In Nairobi, Kenya, April 2016, the IPCC panel accepted the invitation. Here we describe the response devised within the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) to provide tailored, cross-sectorally consistent impact projections to broaden the scientific basis for the report. The simulation protocol is designed to allow for (1) separation of the impacts of historical warming starting from pre-industrial conditions from impacts of other drivers such as historical land-use changes (based on pre-industrial and historical impact model simulations); (2) quantification of the impacts of additional warming up to 1.5°C, including a potential overshoot and long-term impacts up to 2299, and comparison to higher levels of global mean temperature change (based on the low-emissions Representative Concentration Pathway RCP2.6 and a no-mitigation pathway RCP6.0) with socio-economic conditions fixed at 2005 levels; and (3) assessment of the climate effects based on the same climate scenarios while accounting for simultaneous changes in socio-economic conditions following the middle-of-the-road Shared Socioeconomic Pathway (SSP2, Fricko et al., 2016) and in particular differential bioenergy requirements associated with the transformation of the energy system to comply with RCP2.6 compared to RCP6.0. With the aim of providing the scientific basis for an aggregation of impacts across sectors and analysis of cross-sectoral interactions that may dampen or amplify sectoral impacts, the protocol is designed to facilitate consistent impact projections from a range of impact models across different sectors (global and regional hydrology, lakes, global crops, global vegetation, regional forests, global and regional marine ecosystems and fisheries, global and regional coastal infrastructure, energy supply and demand, temperature-related mortality, and global terrestrial biodiversity)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Electroweak measurements in electron–positron collisions at w-boson-pair energies at lep

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