Crystallographic Study Of The Phosphoethanolamine Transferase EptC required For Polymyxin Resistance And Motility In Campylobacter jejuni

The foodborne enteric pathogen Campylobacter jejuni decorates a variety of its cell-surface structures with phosphoethanolamine (pEtN). Modifying lipid A with pEtN promotes cationic antimicrobial peptide resistance, whereas post-translationally modifying the flagellar rod protein FlgG with pEtN promotes flagellar assembly and motility, which are processes that are important for intestinal colonization. EptC, the pEtN transferase required for all known pEtN cell-surface modifications in C. jejuni, is a predicted inner-membrane metalloenzyme with a five-helix N-terminal transmembrane domain followed by a soluble sulfatase-like catalytic domain in the periplasm. The atomic structure of the catalytic domain of EptC (cEptC) was crystallized and solved to a resolution of 2.40 angstrom. cEptC adopts the alpha/beta/alpha fold of the sulfatase protein family and harbors a zinc-binding site. A phosphorylated Thr266 residue was observed that was hypothesized to mimic a covalent pEtN-enzyme intermediate. The requirement for Thr266 as well as the nearby residues Asn308, Ser309, His358 and His440 was ascertained via in vivo activity assays on mutant strains. The results establish a basis for the design of pEtN transferase inhibitors.National Institutes of Health (grants AI064184, AI076322, GM106112Army Research Office (grantW911NF-12-1-0390)College of Natural SciencesOffice of the Executive Vice President and ProvostInstitute for Cellular and Molecular Biology at the University of Texas at AustinUS DOE DE-AC02-06CH11357National Institute of General Medical SciencesHoward Hughes Medical InstituteOffice of Science, Office of Basic Energy Sciences of the US Department of Energy DE-AC02-05CH11231Maria Person and the Proteomics Facility at the University of Texas at Austin ES007784 (CRED) and RP110782 (CPRIT)Molecular Bioscience

The effects of particulate and ozone pollution on mortality in Moscow, Russia

The objectives of this study were (1) to evaluate how acute mortality responds to changes in particulate and ozone (O3) pollution levels, (2) to identify vulnerable population groups by age and cause of death, and (3) to address the problem of interaction between the effects of O3 and particulate pollution. Time-series of daily mortality counts, air pollution, and air temperature were obtained for the city of Moscow during a 3-year period (2003–2005). To estimate the pollution-mortality relationships, we used a log-linear model that controlled for potential confounding by daily air temperature and longer term trends. The effects of 10 μg/m3 increases in daily average measures of particulate matter ≤10 μm in aerodynamic diameter (PM10) and O3 were, respectively, (1) a 0.33% [95% confidence interval (CI) 0.09–0.57] and 1.09% (95% CI 0.71–1.47) increase in all-cause non-accidental mortality in Moscow; (2) a 0.66% (0.30–1.02) and 1.61% (1.01–2.21) increase in mortality from ischemic heart disease; (3) a 0.48% (0.02–0.94) and 1.28% (0.54–2.02) increase in mortality from cerebrovascular diseases. In the age group >75 years, mortality increments were consistently higher, typically by factor of 1.2 – 1.5, depending upon the cause of death. PM10-mortality relationships were significantly modified by O3 levels. On the days with O3 concentrations above the 90th percentile, PM10 risk for all-cause mortality was threefold greater and PM10 risk for cerebrovascular disease mortality was fourfold greater than the unadjusted risk estimate

Integrating genetics and natural resource management for technology targeting and greater impact of agricultural research in the semi-arid tropics

Good management of natural resources is the key to good agriculture. This is true everywhere - and particularly in the semi-arid tropics, where over-exploitation of fragile or inherently vulnerable agro-ecosystems is leading to land and soil degradation, productivity decline, and increasing hunger and poverty. Modern crop varieties offer high yields, but the larger share of this potential yield can only be realized with good crop management. The International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), working over a vast and diverse mandate area, has learned one key lesson: that technologies and interventions must be matched not only to the crop or livestock enterprise and the biophysical environment, but also with the market and investment environment, including input supply systems and policy. Various Natural Resource Management (NRM) technologies have been developed over the years, but widespread adoption has been limited for various reasons: technical, socio-economic and institutional. To change this, ICRISAT hypothesizes that 'A research approach, founded on the need to integrate a broad consideration of technical, socio-economic and institutional issues into the generation of agricultural innovations will result in a higher level of adoption and more sustainable and diverse impacts in the rainfed systems of the semi-arid tropics.' Traditionally, crop improvement and NRM were seen as distinct but complementary disciplines. ICRISAT is deliberately blurring these boundaries to create the new paradigm of IGNRM or Integrated Genetic and Natural Resource Management. Improved varieties and improved resource management are two sides of the same coin. Most farming problems require integrated solutions, with genetic, management-related and socio-economic components. In essence, plant breeders and NRM scientists must integrate their work with that of private and public sector change agents to develop flexible cropping systems that can respond to rapid changes in market opportunities and climatic conditions. The systems approach looks at various components of the rural economy - traditional food grains, new potential cash crops, livestock and fodder production, as well as socio-economic factors such as alternative sources of employment and income. Crucially the IGNRM approach is participatory, with farmers closely involved in technology development, testing and dissemination. ICRISAT has begun to use the IGNRM approach to catalyse technology uptake and substantially improve food security and incomes in smallholder farm communities at several locations in India, Mali, Niger, Vietnam, China, Thailand and Zimbabwe

The state of stocks of cod, whiting, sole and plaice on the west and southwest coasts of Ireland

Stocks of cod, whiting, plaice and sole in ICES Divisions VIIb,c and VIIj,k are an important part of the Irish fishing resource yet, until 1993, were not subject to any assessment. Landings of these stocks in 1996 were valued at £8.6 million, representing 17% of the overall value of all Irish landings of demersal species. In 1993, the Fisheries Research Centre initiated a stock monitoring programme with the aim of providing adequate data to enable an assessment of these stocks. This paper presents the results of growth, catch curve and yield per recruit analyses from the monitoring programme conducted between 1993 and 1996. Preliminary results show that all of these stocks but sole in VIIb,c are over-exploited. TAC levels (based on reported catches in previous years) may be inappropriate for the current stock sizes. It is also important to compare biological characteristics between ICES Divisions to determine the appropriate assessment areas. Comparisons of biological parameters between areas have so far been inconclusive.Funder: Marine Institut

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency

Heterozygous variants in GBA1 encoding glucocerebrosidase (GCase) are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants in SMPD1 are also overrepresented in PD cohorts, whilst a reduction of its encoded enzyme (ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how combined deficiencies of both enzymes may interact to modulate PD has yet to be explored. Therefore, we created a double knock out (DKO) zebrafish line for both gba1 and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO compared to single mutants. Unexpectedly, DKOs maintained conventional swimming behaviour and had normalised neuronal gene expression signatures when compared to single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKOs. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo

Ecoregional research in Africa: learning lessons from IITA's Benchmark Area Approach

Ecoregional research has the potential to help address some of the huge challenges facing agriculture in developing countries by developing technologies that work under different agro-ecological conditions, and the processes by which these technologies can be adapted to work in other areas with similar conditions. The CGIAR system has been developing ecoregional research as a new paradigm for over a decade. In this paper we evaluate one of the most ambitious of these initiatives called the Benchmark Area Approach (BAA) pioneered by the International Institute of Tropical Agriculture. We evaluate the BAA against nine good practice criteria for ecoregional research, finding that the approach is delivering, or has the potential to deliver, on all nine. Many of the lessons learnt from this evaluation will be relevant to current and future attempts to undertake co-ordinated multi-locational research for developmen

Assessment of Heat-Related Health Impacts in Brisbane, Australia: Comparison of Different Heatwave Definitions

Background: There is no global definition of a heatwave because local acclimatisation and adaptation influence the impact of extreme heat. Even at a local level there can be multiple heatwave definitions, based on varying temperature levels or time periods. We investigated the relationship between heatwaves and health outcomes using ten different heatwave definitions in Brisbane, Australia. ---------- Methodology/Principal Findings: We used daily data on climate, air pollution, and emergency hospital admissions in Brisbane between January 1996 and December 2005; and mortality between January 1996 and November 2004. Case-crossover analyses were used to assess the relationship between each of the ten heatwave definitions and health outcomes. During heatwaves there was a statistically significant increase in emergency hospital admissions for all ten definitions, with odds ratios ranging from 1.03 to 1.18. A statistically significant increase in the odds ratios of mortality was also found for eight definitions. The size of the heat-related impact varied between definitions.---------- Conclusions/Significance Even a small change in the heatwave definition had an appreciable effect on the estimated health impact. It is important to identify an appropriate definition of heatwave locally and to understand its health effects in order to develop appropriate public health intervention strategies to prevent and mitigate the impact of heatwaves

Trends and determinants of excess winter mortality in New Zealand: 1980 to 2000

<p>Abstract</p> <p>Background</p> <p>Although many countries experience an increase in mortality during winter, the magnitude of this increase varies considerably, suggesting that some winter excess may be avoidable. Conflicting evidence has been presented on the role of gender, region and deprivation. Little has been published on the magnitude of excess winter mortality (EWM) in New Zealand (NZ) and other Southern Hemisphere countries.</p> <p>Methods</p> <p>Monthly mortality rates per 100,000 population were calculated from routinely collected national mortality data for 1980 to 2000. Generalised negative binomial regression models were used to compare mortality rates between winter (June–September) and the warmer months (October–May).</p> <p>Results</p> <p>From 1980–2000 around 1600 excess winter deaths occurred each year with winter mortality rates 18% higher than expected from non-winter rates. Patterns of EWM by age group showed the young and the elderly to be particularly vulnerable. After adjusting for all major covariates, the winter:non-winter mortality rate ratio from 1996–2000 in females was 9% higher than in males. Mortality caused by diseases of the circulatory system accounted for 47% of all excess winter deaths from 1996–2000 with mortality from diseases of the respiratory system accounting for 31%. There was no evidence to suggest that patterns of EWM differed by ethnicity, region or local-area based deprivation level. No decline in seasonal mortality was evident over the two decades.</p> <p>Conclusion</p> <p>EWM in NZ is substantial and at the upper end of the range observed internationally. Interventions to reduce EWM are important, but the surprising lack of variation in EWM by ethnicity, region and deprivation, provides little guidance for how such mortality can be reduced.</p