Reciprocal regulation by the CepIR and CciIR quorum sensing systems in Burkholderia cenocepacia

<p>Abstract</p> <p>Background</p> <p><it>Burkholderia cenocepacia </it>belongs to a group of closely related organisms called the <it>B. cepacia </it>complex (Bcc) which are important opportunistic human pathogens. <it>B. cenocepacia </it>utilizes a mechanism of cell-cell communication called quorum sensing to control gene expression including genes involved in virulence. The <it>B. cenocepacia </it>quorum sensing network includes the CepIR and CciIR regulatory systems.</p> <p>Results</p> <p>Global gene expression profiles during growth in stationary phase were generated using microarrays of <it>B. cenocepacia cepR</it>, <it>cciR </it>and <it>cepRcciIR </it>mutants. This is the first time CciR was shown to be a global regulator of quorum sensing gene expression. CepR was primarily responsible for positive regulation of gene expression while CciR generally exerted negative gene regulation. Many of the genes that were regulated by both quorum sensing systems were reciprocally regulated by CepR and CciR. Microarray analysis of the <it>cepRcciIR </it>mutant suggested that CepR is positioned upstream of CciR in the quorum sensing hierarchy in <it>B. cenocepacia</it>. A comparison of CepIR-regulated genes identified in previous studies and in the current study showed a substantial amount of overlap validating the microarray approach. Several novel quorum sensing-controlled genes were confirmed using qRT-PCR or promoter::<it>lux </it>fusions. CepR and CciR inversely regulated flagellar-associated genes, the nematocidal protein AidA and a large gene cluster on Chromosome 3. CepR and CciR also regulated genes required for iron transport, synthesis of extracellular enzymes and surface appendages, resistance to oxidative stress, and phage-related genes.</p> <p>Conclusion</p> <p>For the first time, the influence of CciIR on global gene regulation in <it>B. cenocepacia </it>has been elucidated. Novel genes under the control of the CepIR and CciIR quorum sensing systems in <it>B. cenocepacia </it>have been identified. The two quorum sensing systems exert reciprocal regulation of many genes likely enabling fine-tuned control of quorum sensing gene expression in <it>B. cenocepacia </it>strains carrying the cenocepacia island.</p

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

Exploring the diversity of anaerobic sludge towards glycerol valorization

The large amounts of glycerol produced by the biodiesel industry (10 % of the total biodiesel production) can create environmental and economic losses if sustainable strategies are not applied to utilize the surplus of this compound. The production of valuable chemical compounds by anaerobic microorganisms can be a sustainable treatment strategy to add value to waste-glycerol and to the biodiesel industry. The objective of this work was to study the diversity and physiology of anaerobic microorganisms involved in glycerol consumption and valorization. Mesophilic enrichments were developed under sulfate-reducing and methanogenic conditions, using as inoculum anaerobic granular sludge from a brewery wastewater treatment plant. After several transfers, three different stable cultures were obtained, with the capacity to grow with glycerol under different culture conditions. One enrichment, ferments glycerol mainly to propionate, with a yield of 0.88 mM propionate per mM glycerol consumed. This culture is dominated by a bacterium closely affiliated with Propionivibrio pelophilus strain asp 66, 98.5% ID based on 16S rRNA genes. The P. pelophilus strain asp 66 was reported to be unable to grow with glycerol. A second enriched culture was obtained which is constituted of Desulfovibrio alcoholivorans, 99.5% ID, and the methanogen Methanofollis liminatans strain GKZOZ, 98.8% ID. Incubations with 2-bromoethanesulfonate confirmed that this is a syntrophic co-culture. Desulfovibrio alcoholivorans converts the glycerol to acetate and H2 and the methanogenic partner consumes the H2, making glycerol degradation thermodynamically viable. In the third enriched culture, Desulfovibrio sulfodismutans strain ThAcO1, 97.5 % ID, reduces glycerol to acetate, but only in the presence of sulfate or a methanogenic partner. In conclusion, starting from the same inoculum (anaerobic sludge), glycerol could be metabolized through different pathways by the enrichment cultures obtained. Fermentative, syntrophic and sulfate-reducing cultures were enriched forming valuable products that can be used in industrial applications or as energy carriers. Thus, anaerobic microbial communities are an asset to surpass the bottleneck of biodiesel production caused by the surplus of glycerol, allowing it to be sustainably treated and valorized.info:eu-repo/semantics/publishedVersio

Is there an association between PEPFAR funding and improvement in national health indicators in Africa? A retrospective study

BACKGROUND: The US President's Emergency Plan for AIDS Relief (PEPFAR) was reauthorized in June 2008 with a three-fold increase in funds, and a broader, more explicit mandate to improve health in the low- and middle-income countries that it funded. However, the ability of a disease-specific, or vertical, programme to have a spill-over effect and improve health outcomes has been questioned. In this study, we sought to examine associations between being designated as a PEPFAR focus country (and receiving increased PEPFAR funding) and non-HIV-specific health outcomes in the World Health Organization (WHO) Africa Region, the area most affected by the HIV/AIDS epidemic. METHODS: A retrospective analysis of publicly available health outcomes data published by the World Health Organization was performed for all countries in the WHO Africa Region. Fractional changes in health indicators between 2000 and 2006 were calculated, and PEPFAR focus and non-focus countries were then compared. RESULTS: Overall, countries in the WHO Africa Region showed a small worsening in health outcomes status when all indicators were analyzed together and weighted equally. However, more health indicators improved than worsened over this six-year period. A comparison of PEPFAR focus and non-focus countries found no significant difference in the fractional change among 13 of 14 health indicators during the study period. CONCLUSIONS: This study suggests that vertical programmes, even one that is the scale of PEPFAR, may have little or no impact on health outcomes not explicitly targeted

Physical fitness and upper limb asymmetry in young padel players: differences between genders and categories

This study aimed to assess the physical fitness and upper body asymmetries of young padel players aged between 13 and 16 years and to determine the possible differences between genders and categories. A total of 60 padel players were divided into four groups: under-14 male (n = 15; age: 13.75 ± 0.45 years; height: 1.64 ± 0.07 m; weight: 54.7 ± 8.3 kg), under-14 female (n = 15; age: 13.75 ± 0.44 years; height: 1.60 ± 0.05 m; weight: 51.5 ± 6.0 kg), under-16 male (n = 15; age: 15.44 ± 0.51 years; height:1.71 ± 0.04 m; weight: 63.88 ± 6.2 kg) and under-16 female (n = 15; age:15.46 ± 0.52 years; height:1.63 ± 0.05 m; weight: 55.08 ± 3.6 kg). Handgrip strength, ischiosural flexibility, gestural speed of the dominant arm, vertical jump, cardiorespiratory capacity, lateral movement, lateral acceleration and reaction time were measured. Male players showed better results in manual grip strength, vertical jump power, cardiorespiratory capacity and lateral movement (p < 0.05). Moreover, males presented a higher percentage of asymmetry in upper limb strength. Female players showed better reaction time and greater flexibility (p < 0.05). Regarding the differences between categories, the under-16 players showed greater flexibility, gestural speed, vertical jump power, cardiorespiratory capacity and lateral movement compared to the under-14 players. These results can be used as reference values for coaches/physical trainers of younger categories to improve health control and physical performance planning

Application of reflectance parameters in the estimation of the structural order of coals and carbonaceous materials. Precision and bias of measurements derived from the ICCP structural working group

Optical reflectance of vitrinite is one of the fundamental physical properties that have been used for the study of coal and carbonaceous materials. Organic matter in coals and carbonaceous matter consists mainly of aromatic lamellae, whose dimensions and spatial orientation define its internal structure. Various reflectance parameters describe well the average degree of order of the molecular structure of organic matter. Moreover, reflectance parameters are numerical values which characterize the samples unambiguously, facilitating the comparison of the optical properties of different carbonaceous materials as well as comparison between optical parameters and other physical or chemical factors. The focus of this study is the evaluation of the precision and bias of reflectance measurements (R and R) performed by various analysts in different laboratories in order to check the applicability of reflectance parameters to the estimation of the structural order of coals and carbonaceous materials. Additionally, it was desirable to compare reflectance parameters with other parameters obtained by different analytical methods able to provide structural information. The consistency and repeatability of the reflectance measurements obtained by different participants turned out to enable the drawing of similar conclusions regarding the structural transformation of anthracite during heating. Good correlations were found between the reflectance parameters studied and structural factors obtained by comparative methods. The reflectance parameters examined proved to be very sensitive to any changes of the structural order of coals and carbonaceous materials and seem to be a perfect complement to structural studies made by X-ray diffraction or Raman spectroscopy

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Amyloid-beta 42 (A?42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A?42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A?42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

A Unique Regulator Contributes to Quorum Sensing and Virulence in Burkholderia cenocepacia

Burkholderia cenocepacia causes chronic and life-threatening respiratory infections in immunocompromized people. The B. cenocepacia N-acyl-homoserine lactone (AHL)-dependent quorum sensing system relies on the production of AHLs by the synthases CepI and CciI while CepR, CciR and CepR2 control expression of many genes important for pathogenesis. Downstream from, and co-transcribed with cepI, lies BCAM1871 encoding a hypothetical protein that was uncharacterized prior to this study. Orthologs of B. cenocepacia BCAM1871 are uniquely found in Burkholderia spp and are conserved in their genomic locations in pathogenic Burkholderia. We observed significant effects on AHL activity upon mutation or overexpression of BCAM1871, although these effects were more subtle than those observed for CepI indicating BCAM1871 acts as an enhancer of AHL activity. Transcription of cepI, cepR and cciIR was significantly reduced in the BCAM1871 mutant. Swimming and swarming motilities as well as transcription of fliC, encoding flagellin, were significantly reduced in the BCAM1871 mutant. Protease activity and transcription of zmpA and zmpB, encoding extracellular zinc metalloproteases, were undetectable in the BCAM1871 mutant indicating a more significant effect of mutating BCAM1871 than cepI. Exogenous addition of OHL restored cepI, cepR and fliC transcription but had no effect on motility, protease activity or zmpA or zmpB transcription suggesting AHL-independent effects. The BCAM1871 mutant exhibited significantly reduced virulence in rat chronic respiratory and nematode infection models. Gene expression and phenotypic assays as well as vertebrate and invertebrate infection models showed that BCAM1871 significantly contributes to pathogenesis in B. cenocepacia

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: Quantifying the epidemiological transition

Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6-6·6), from 65·3 years (65·0-65·6) in 1990 to 71·5 years (71·0-71·9) in 2013, HALE at birth rose by 5·4 years (4·9-5·8), from 56·9 years (54·5-59·1) to 62·3 years (59·7-64·8), total DALYs fell by 3·6% (0·3-7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6-29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition - in which increasing sociodemographic status brings structured change in disease burden - is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions

Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013

Background Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65·3 years (UI 65·0-65·6) in 1990, to 71·5 years (UI 71·0-71·9) in 2013, while the number of deaths increased from 47·5 million (UI 46·8-48·2) to 54·9 million (UI 53·6-56·3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10·7%, from 4·3 million deaths in 1990 to 4·8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade. Funding Bill &amp; Melinda Gates Foundation