Hypertensive disorders of pregnancy and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis protocol

Introduction Hypertensive disorders of pregnancy (HDPs), that is chronic hypertension, gestational hypertension, pre-eclampsia (de novo or superimposed on chronic hypertension) and white coat hypertension, affect approximately 5%–15% of pregnancies. HDP exposure has been linked to an increased risk of autism spectrum disorder, attention deficit/hyperactivity disorder and other neurodevelopmental disorders in children. However, findings are inconsistent, and a clear consensus on the impact of HDPs on the risk of neurodevelopmental disorders is needed. Therefore, we aim to synthesise the published literature on the relationship between HDPs and the risk of neurodevelopmental disorders in the form of a systematic review and meta-analysis. Methods and analysis We will include cohort, case– control and cross-sectional studies in which diagnosis of an HDP was reported, and neurodevelopmental disorders were the outcome of interest based on a preprepared protocol. A systematic search of PubMed, CINAHL, Embase, PsycINFO and Web of Science will be conducted in accordance with a detailed search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction using a standardised data collection form and assess study quality using a bias classification tool. Meta-analyses will be performed to calculate overall pooled estimates using the generic inverse variance method. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Ethics and dissemination This proposed systematic review and meta-analysis is based on published data, therefore, does not require ethics approval. Findings will be presented at scientific conferences and disseminated through publication in a peer-reviewed journal. Registration CRD42017068258

Targeted Nasal Vaccination Provides Antibody-Independent Protection Against Staphylococcus aureus

Despite showing promise in preclinical models, anti-Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureu

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

T-cells expressing natural killer (nk) receptors are altered in multiple sclerosis and responses to α-galactosylceramide are impaired

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Targeted disruption of nonribosomal peptide synthetase Pes3 augments the virulence of Aspergillus fumigatus

Nonribosomal peptide synthesis (NRPS) is a documented virulence factor for the opportunistic pathogen Aspergillus fumigatus and other fungi. Secreted or intracellularly located NRP products include the toxic molecule gliotoxin and the iron-chelating siderophores triacetylfusarinine C and ferricrocin. No structural or immunologically relevant NRP products have been identified in the organism. We investigated the function of the largest gene in A. fumigatus, which encodes the NRP synthetase Pes3 (AFUA_5G12730), by targeted gene deletion and extensive phenotypic analysis. It was observed that in contrast to other NRP synthetases, deletion of pes3 significantly increases the virulence of A. fumigatus, whereby the pes3 deletion strain (A. fumigatus pes3) exhibited heightened virulence (increased killing) in invertebrate (P < 0.001) and increased fungal burden (P 0.008) in a corticosteroid model of murine pulmonary aspergillosis. Complementation restored the wild-type phenotype in the invertebrate model. Deletion of pes3 also resulted in increased susceptibility to the antifungal, voriconazole (P < 0.01), shorter germlings, and significantly reduced surface -glucan (P 0.0325). Extensive metabolite profiling revealed that Pes3 does not produce a secreted or intracellularly stored NRP in A. fumigatus. Macrophage infections and histological analysis of infected murine tissue indicate that Pes3 heightened virulence appears to be mediated by aberrant innate immune recognition of the fungus. Proteome alterations in A. fumigatus Pes3 strongly suggest impaired germination capacity. Uniquely, our data strongly indicate a structural role for the Pes3-encoded NRP, a finding that appears to be novel for an NRP synthetase

Nasal Colonisation by <em>Staphylococcus aureus</em> Depends upon Clumping Factor B Binding to the Squamous Epithelial Cell Envelope Protein Loricrin

<div><p><em>Staphylococcus aureus</em> asymptomatically colonises the anterior nares, but the host and bacterial factors that facilitate colonisation remain incompletely understood. The <em>S. aureus</em> surface protein ClfB has been shown to mediate adherence to squamous epithelial cells <em>in vitro</em> and to promote nasal colonisation in both mice and humans. Here, we demonstrate that the squamous epithelial cell envelope protein loricrin represents the major target ligand for ClfB during <em>S. aureus</em> nasal colonisation. <em>In vitro</em> adherence assays indicated that bacteria expressing ClfB bound loricrin most likely by the “dock, lock and latch” mechanism. Using surface plasmon resonance we showed that ClfB bound cytokeratin 10 (K10), a structural protein of squamous epithelial cells, and loricrin with similar affinities that were in the low µM range. Loricrin is composed of three separate regions comprising GS-rich omega loops. Each loop was expressed separately and found to bind ClfB, However region 2 bound with highest affinity. To investigate if the specific interaction between ClfB and loricrin was sufficient to facilitate <em>S. aureus</em> nasal colonisation, we compared the ability of ClfB⁺<em>S. aureus</em> to colonise the nares of wild-type and loricrin-deficient (Lor^−/−) mice. In the absence of loricrin, <em>S. aureus</em> nasal colonisation was significantly impaired. Furthermore a ClfB⁻ mutant colonised wild-type mice less efficiently than the parental ClfB⁺ strain whereas a similar lower level of colonisation was observed with both the parental strain and the ClfB⁻ mutant in the Lor^−/− mice. The ability of ClfB to support nasal colonisation by binding loricrin <em>in vivo</em> was confirmed by the ability of <em>Lactococcus lactis</em> expressing ClfB to be retained in the nares of WT mice but not in the Lor^−/− mice. By combining <em>in vitro</em> biochemical analysis with animal model studies we have identified the squamous epithelial cell envelope protein loricrin as the target ligand for ClfB during nasal colonisation by <em>S. aureus</em>.</p> </div

Affinities of ClfB N2N3_201–542 for loricrin, keratin and fibrinogen using surface plasmon resonance.

*<p>Data representative of n = 3 individual experiments.</p

Inhibition of bacterial adherence and rClfB binding to immobilized ligands.

<p>(A) <i>L. lactis</i> NZ9800 (pNZ8037), <i>L. lactis</i> NZ9800 (pNZ8037:<i>clf</i>B) and <i>L. lactis</i> NZ9800 (pNZ8037:<i>clf</i>BQ235A) were added to wells containing immobilized GST-tagged Hlor, MLor, HK10, MK10 (0.5 µM). Bacterial adherence was measured by staining with crystal violet and measurement of the absorbance at 570 nm. The data shown is representative of two individual experiments (B). <i>S. aureus</i> Newman pre-incubated with GST or HK10 (2 µM) was added to loricrin-coated microtitre wells (0.5 µM). Bacterial adherence was measured by staining with crystal violet and measurement of the absorbance at 570 nm and was expressed as a percentage of total binding. Values represent the mean ± SD of triplicate wells. The data shown is representative of two individual experiments. (C) Recombinant ClfB N23_201–542 was pre-incubated with GST, HK10 or L2v (14 µM) before being added to loricrin-coated microtitre wells (0.5 µM). Bound protein was detected using HRP-conjugated anti-his antibodies and was expressed as a percentage of total bound protein. Values represent the mean ± SD of triplicate wells. The values shown are representative of 3 individual experiments. Statistical analysis was performed using an unpaired t-test. *** p<0.0005 versus binding of ClfB-expressing bacteria (A) or pre-incubation with GST (B, C).</p