Truncation of the lipopolysaccharide outer core affects susceptibility to antimicrobial peptides and virulence of Actinobacillus pleuropneumoniae serotype 1.

Abstract We reported previously that the core oligosaccharide region of the lipopolysaccharide (LPS) is essential for optimal adhesion of Actinobacillus pleuropneumoniae, an important swine pathogen, to respiratory tract cells. Rough LPS and core LPS mutants of A. pleuropneumoniae serotype 1 were generated by using a mini-Tn10 transposon mutagenesis system. Here we performed a structural analysis of the oligosaccharide region of three core LPS mutants that still produce the same O-antigen by using methylation analyses and mass spectrometry. We also performed a kinetic study of proinflammatory cytokines production such as interleukin (IL)-6, tumor necrosis factor-α, IL1-β, MCP-1, and IL8 by LPS-stimulated porcine alveolar macrophages, which showed that purified LPS of the parent strain, the rough LPS and core LPS mutants, had the same ability to stimulate the production of cytokines. Most interestingly, an in vitro susceptibility test of these LPS mutants to antimicrobial peptides showed that the three core LPS mutants were more susceptible to cationic peptides than both the rough LPS mutant and the wild type parent strain. Furthermore, experimental pig infections with these mutants revealed that the galactose (Gal I) and d,d-heptose (Hep IV) residues present in the outer core of A. pleuropneumoniae serotype 1 LPS are important for adhesion and overall virulence in the natural host, whereas deletion of the terminal GalNAc-Gal II disaccharide had no effect. Our data suggest that an intact core-lipid A region is required for optimal protection of A. pleuropneumoniae against cationic peptides and that deletion of specific residues in the outer LPS core results in the attenuation of the virulence of A. pleuropneumoniae serotype 1

Under-ascertainment of Aboriginality in records of cardiovascular disease in hospital morbidity and mortality data in Western Australia: a record linkage study

<p>Abstract</p> <p>Background</p> <p>Measuring the real burden of cardiovascular disease in Australian Aboriginals is complicated by under-identification of Aboriginality in administrative health data collections. Accurate data is essential to measure Australia's progress in its efforts to intervene to improve health outcomes of Australian Aboriginals. We estimated the under-ascertainment of Aboriginal status in linked morbidity and mortality databases in patients hospitalised with cardiovascular disease.</p> <p>Methods</p> <p>Persons with public hospital admissions for cardiovascular disease in Western Australia during 2000-2005 (and their 20-year admission history) or who subsequently died were identified from linkage data. The Aboriginal status flag in all records for a given individual was variously used to determine their ethnicity (index positive, and in all records both majority positive or ever positive) and stratified by region, age and gender. The index admission was the baseline comparator.</p> <p>Results</p> <p>Index cases comprised 62,692 individuals who shared a total of 778,714 hospital admissions over 20 years, of which 19,809 subsequently died. There were 3,060 (4.9%) persons identified as Aboriginal on index admission. An additional 83 (2.7%) Aboriginal cases were identified through death records, increasing to 3.7% when cases with a positive Aboriginal identifier in the majority (≥50%) of previous hospital admissions over twenty years were added and by 20.8% when those with a positive flag in any record over 20 years were incorporated. These results equated to underestimating Aboriginal status in unlinked index admission by 2.6%, 3.5% and 17.2%, respectively. Deaths classified as Aboriginal in official records would underestimate total Aboriginal deaths by 26.8% (95% Confidence Interval 24.1 to 29.6%).</p> <p>Conclusions</p> <p>Combining Aboriginal determinations in morbidity and official death records increases ascertainment of unlinked cardiovascular morbidity in Western Australian Aboriginals. Under-identification of Aboriginal status is high in death records.</p

Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel KV6.4 Subunit.

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant KV6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of KV2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (KV6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express KV2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing KV6.4-Met419, the voltage dependence of inactivation for KV2.1 is more depolarized compared with neurons overexpressing KV6.4. Finally, KV6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that KV6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.MCL, DKM, DW, and CGW acknowledge funding from Addenbrooke’s Charitable Trust and the NIHR Cambridge Biomedical Research Centre. MN was funded by the Wellcome Trust (200183/Z/15/Z); JH and ESS by a Rosetrees Postdoctoral Grant (A1296) and the BBSRC (BB/R006210/1); GC and ESS by Versus Arthritis Grants (RG21973); VBL and FR by the Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z) and a joint MRC programme within the Metabolic Diseases Unit (MRC_MC_UU_12012/3). EF, GI and CB were funded by the Cambridge NIHR Biomedical Research Centre Integrative Genomics theme and LAP by a BBSRC-funded studentship (BB/M011194/1)

Food from the Oceans - How can more food and biomass be obtained from the oceans in a way that does not deprive future generations of their benefits?

Food from the Oceans is the first Evidence Review Report published by the SAPEA consortium. SAPEA is an integral part of the European Scientific Advice Mechanism (SAM) and this report demonstrates the outstanding commitment and knowledge of experts who were nominated by academies and learned societies. Interdisciplinarity and world-class expertise from across Europe are SAPEA’s core strengths. We assembled two international working groups for Food from the Oceans, covering both the natural sciences and the humanities/social sciences. We were delighted with SAPEA’s collaboration with the High-Level Group of Scientific Advisers (HLG), which has proved so effective in Food from the Oceans. Our Evidence Review Report informs the Scientific Opinion of the HLG. They are published together, and the aim is for them to be used by the European Commission in planning and policymaking across a range of areas. Academia Europaea performed the role of Lead Academy for the Food from the Oceans Evidence Review Report. It acted as project manager, ensuring that deadlines were met, and outputs were of the highest quality standard. By working well with academies and experts we have met all milestones leading up to and including the final deliverable, the Evidence Review Report itself. We also took a novel approach to public engagement, with encouraging results. In Food from the Oceans, we believe we have established an attractive model for future SAPEA projects. We would like to thank everyone involved in making Food from the Oceans a success and express our sincere gratitude to those who have worked hard throughout 2017

MLPerf Inference Benchmark

Machine-learning (ML) hardware and software system demand is burgeoning. Driven by ML applications, the number of different ML inference systems has exploded. Over 100 organizations are building ML inference chips, and the systems that incorporate existing models span at least three orders of magnitude in power consumption and five orders of magnitude in performance; they range from embedded devices to data-center solutions. Fueling the hardware are a dozen or more software frameworks and libraries. The myriad combinations of ML hardware and ML software make assessing ML-system performance in an architecture-neutral, representative, and reproducible manner challenging. There is a clear need for industry-wide standard ML benchmarking and evaluation criteria. MLPerf Inference answers that call. In this paper, we present our benchmarking method for evaluating ML inference systems. Driven by more than 30 organizations as well as more than 200 ML engineers and practitioners, MLPerf prescribes a set of rules and best practices to ensure comparability across systems with wildly differing architectures. The first call for submissions garnered more than 600 reproducible inference-performance measurements from 14 organizations, representing over 30 systems that showcase a wide range of capabilities. The submissions attest to the benchmark's flexibility and adaptability.Comment: ISCA 202

A novel sialylation site on Neisseria gonorrhoeae lipooligosaccharide links heptose II lactose expression with pathogenicity [preprint]

Sialylation of lacto-N-neotetraose (LNnT) extending from heptose I (HepI) of gonococcal lipooligosaccharide (LOS) contributes to pathogenesis. Previously, gonococcal LOS sialyltransterase (Lst) was shown to sialylate LOS in Triton X-100 extracts of strain 15253, which expresses lactose from both HepI and HepII, the minimal structure required for mAb 2C7 binding. Ongoing work has shown that growth of 15253 in cytidine monophospho-N-acetylneuraminic acid (CMP-Neu5Ac)-containing media enables binding to CD33/Siglec-3, a cell surface receptor that binds sialic acid, suggesting that lactose termini on LOS of intact gonococci can be sialylated. Neu5Ac was detected on LOSs of strains 15253 and a MS11 mutant with only lactose from HepI and HepII by mass spectrometry; deleting HepII lactose rendered Neu5Ac undetectable. Resistance of HepII lactose Neu5Ac to desialylation by α2-3-specific neuraminidase suggested an α2-6-linkage. Although not associated with increased factor H binding, HepII lactose sialylation inhibited complement C3 deposition on gonococci. 15253 mutants that lacked Lst or HepII lactose were significantly attenuated in mice, confirming the importance of HepII Neu5Ac in virulence. All 75 minimally passaged clinical isolates from Nanjing, China, expressed HepII lactose, evidenced by reactivity with mAb 2C7; mAb 2C7 was bactericidal against the first 62 (of 75) isolates that had been collected sequentially and were sialylated before testing. mAb 2C7 effectively attenuated 15253 vaginal colonization in mice. In conclusion, this novel sialylation site could explain the ubiquity of gonococcal HepII lactose in vivo. Our findings reiterate the candidacy of the 2C7 epitope as a vaccine antigen and mAb 2C7 as an immunotherapeutic antibody

Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults

Objective: To provide a management approach for adults with calcium channel blocker poisoning. Data Sources, Study Selection, and Data Extraction: Following the Appraisal of Guidelines for Research & Evaluation II instrument, initial voting statements were constructed based on summaries outlining the evidence, risks, and benefits. Data Synthesis: We recommend 1) for asymptomatic patients, observation and consideration of decontamination following a potentially toxic calcium channel blocker ingestion (1D); 2) as first-line therapies (prioritized based on desired effect), IV calcium (1D), high-dose insulin therapy (1D-2D), and norepinephrine and/or epinephrine (1D). We also suggest dobutamine or epinephrine in the presence of cardiogenic shock (2D) and atropine in the presence of symptomatic bradycardia or conduction disturbance (2D); 3) in patients refractory to the first-line treatments, we suggest incremental doses of high-dose insulin therapy if myocardial dysfunction is present (2D), IV lipid-emulsion therapy (2D), and using a pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block without significant alteration in cardiac inotropism (2D); 4) in patients with refractory shock or who are periarrest, we recommend incremental doses of high-dose insulin (1D) and IV lipid-emulsion therapy (1D) if not already tried. We suggest venoarterial extracorporeal membrane oxygenation, if available, when refractory shock has a significant cardiogenic component (2D), and using pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block in the absence of myocardial dysfunction (2D) if not already tried; 5) in patients with cardiac arrest, we recommend IV calcium in addition to the standard advanced cardiac life-support (1D), lipid-emulsion therapy (1D), and we suggest venoarterial extracorporeal membrane oxygenation if available (2D). Conclusion: We offer recommendations for the stepwise management of calcium channel blocker toxicity. For all interventions, the level of evidence was very low

Can we monitor heart attack in the troponin era: evidence from a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Troponins (highly sensitive biomarkers of myocardial damage) increase counts of myocardial infarction (MI) in clinical practice, but their impact on trends in admission rates for MI in National statistics is uncertain.</p> <p>Methods</p> <p>Cases coded as MI or other cardiac diagnoses in the Hospital Morbidity Data Collection (MI-HMDC) in Western Australia in 1998 and 2003 were classified using revised criteria for MI developed by an International panel convened by the American Heart Association (AHA criteria) using information on symptoms, ECGs and cardiac biomarkers abstracted from samples of medical notes. Age-sex standardized rates of MI-HMDC were compared with rates of MI based on AHA criteria including troponins (MI-AHA) or traditional biomarkers only (MI-AHAck).</p> <p>Results</p> <p>Between 1998 and 2003, rates of MI-HMDC decreased by 3.5% whereas rates of MI-AHA increased by 17%, a difference largely due to increased false-negative cases in the HMDC associated with marked increased use of troponin tests in cardiac admissions generally, and progressively lower test thresholds. In contrast, rates of MI-AHA_ckdeclined by 18%.</p> <p>Conclusions</p> <p>Increasing misclassification of MI-AHA by the HMDC may be due to reluctance by clinicians to diagnose MI based on relatively small increases in troponin levels. These influences are likely to continue. Monitoring MI using AHA criteria will require calibration of commercially available troponin tests and agreement on lower diagnostic thresholds for epidemiological studies. Declining rates of MI-AHA_ckare consistent with long-standing trends in MI in Western Australia, suggesting that neither MI-HMDC nor MI-AHA reflect the true underlying population trends in MI.</p

Anthrax Lethal Toxin-Induced Gene Expression Changes in Mouse Lung

A major virulence factor of Bacillus anthracis is the anthrax Lethal Toxin (LeTx), a bipartite toxin composed of Protective Antigen and Lethal Factor. Systemic administration of LeTx to laboratory animals leads to death associated with vascular leakage and pulmonary edema. In this study, we investigated whether systemic exposure of mice to LeTx would induce gene expression changes associated with vascular/capillary leakage in lung tissue. We observed enhanced susceptibility of A/J mice to death by systemic LeTx administration compared to the C57BL/6 strain. LeTx-induced groups of both up- and down-regulated genes were observed in mouse lungs 6 h after systemic administration of wild type toxin compared to lungs of mice exposed to an inactive mutant form of the toxin. Lungs of the less susceptible C57BL/6 strain showed 80% fewer differentially expressed genes compared to lungs of the more sensitive A/J strain. Expression of genes known to regulate vascular permeability was modulated by LeTx in the lungs of the more susceptible A/J strain. Unexpectedly, the largest set of genes with altered expression was immune specific, characterized by the up-regulation of lymphoid genes and the down-regulation of myeloid genes. Transcripts encoding neutrophil chemoattractants, modulators of tumor regulation and angiogenesis were also differentially expressed in both mouse strains. These studies provide new directions for the investigation of vascular leakage and pulmonary edema induced by anthrax LeTx

Environmental and societal factors affect food choice and physical activity: Rationale, influences, and leverage points

Dietary and physical activity behaviors that affect health are influenced by a wide variety of forces; changes in these behaviors require interventions and commitment to action at multiple levels.l.2 Education-based obesity-prevention strategies (e.g., mass-media promotion of healthy foods and promotion of healthy physical activity habits through schools) are viewed as the most useful and the most feasible to im~lementIm.~p licit in these strategies is the focus on the individual? Education-based strategies have met with limited long-term success in changing behavior: however, perhaps owing to a general lack of supporting environmental modifications. There is increasing recognition of the importance of the environment in shaping behavior, yet strategies that focus on changing environmental factors are much less familiar, and may therefore require partnerships with relevant sectors outside traditional health domains. As described in greater detail by Economos et al.: partnerships among researchers, educators, government, and industry have demonstrated success in smoking reduction at the population level. Interventions such as taxation and advertisement regulations have been instrumental in promoting smoking cessation in the United States and are used by agriculture and agribusiness interests to promote specific food consumption patterns. Similar models of collaborations or interventions may be successful in changing food intake and physical activity, and may potentially result in such desirable outcomes as prevention and reduction of obesity.6 It is important to appreciate the interaction among multiple environmental factors and that complex behavior changes are dependent on different influences at different levels. In Working Group 11, we took on the task of identifying broader contextual, environmental, societal, and policy variables that may improve our understanding of people's eating and physical activity behaviors and may lead to new directions for influencing shifts in behavior. Ecologic models of behavior, and most health promotion models, specify that health behaviors be influenced by biologic, demographic, psychological, sociaYcultura1, environmental, and policy variables. However, the research base that identifies specific important environmental and policy variables is very limited.'.""' Nevertheless, there are several reasons that support the need to identify environmental and policy influences on physical activity and eating behaviors