A functional polymorphism in the PTHR1 promoter region is associated with adult height and BMD measured at the femoral neck in a large cohort of young caucasian women

The parathyroid hormone type 1 receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHRP). Interacting with this receptor, PTHRP contributes to skeletal development through the regulation of chondrocyte proliferation and differentiation. Recently, a tetranucleotide repeat—(AAAG) _n —in the P3 promoter of the PTHR1 gene has been shown to have functional activity in vitro, and homozygosity for (AAAG)₆, or the 6/6 genotype, has been associated with greater adult height compared to the 5/5 genotype. In this study, we evaluated the association of (AAAG) _n with height and bone mineral density (BMD) measured at lumbar spine (LS) and femoral neck (FN) in a cohort of 677 young caucasian women 18–35 years of age. Genomic DNA was amplified and genotyped by comparison with sequenced controls following electrophoretic separation through high-resolution polyacrylamide gels. Allele frequencies for (AAAG) _n were: 76.8% (n=5); 20.9% (n=6); 1.8% (n=7); 0.18% (n=8); 0.27% (n=9); 0.08% (n=2), and there was no evidence for Hardy–Weinberg disequilibrium. Analysis of variance showed that subjects bearing one or two (AAAG)₆ alleles (6/X & 6/6) were significantly taller (165.7±0.5 cm) than the others (X/X, 164.5±0.3 cm; P=0.034). This association was significant after adjusting for multiple covariates—current age, age at menarche, physical activity, smoking status, and intakes of caffeine and calcium. Comparison of genotype groups for BMD was not significant at LS, but BMD was significantly higher at FN in the group with at least one (AAAG)₆ allele (adjusted means: 1.021±0.008 vs. 0.999±0.006 g/cm², P=0.032). In conclusion, our data show that subjects bearing one or two (AAAG)₆ alleles are taller than subjects without, reinforcing the notion that in vivo variation in promoter activity of the PTHR1 gene may be a relevant genetic influence on final adult height and BMD.     

Processing amyloid precursor protein at the beta-site requires proper orientation to be accessed by BACE1

Membrane-bound BACE1 naturally cleaves its transmembrane substrate amyloid precursor protein (APP) at the two adjacent beta- and beta'-sites. Cleavage at these two sites generates the heterogeneous N-terminal end of APP C-terminal fragments that are further processed by gamma-secretase to release Abeta-(1-40/42) or Abeta-(11-40/42). The significance underlying Abeta-(11-40/42) in Alzheimer's disease pathogenesis has remained to be experimentally elucidated, but increased production of Abeta-(1-40/42) has been broadly demonstrated to contribute to amyloid depositions in senile plaques. In this study, we show that the cleavage of APP at the beta-site by BACE1 is readily disrupted through limited structural twists, whereas the beta'-site is relatively better positioned to gain access to the BACE1 catalytic cavity. Radical insertion or deletion of residues between beta- and beta'-site also favors cleavage of APP at the beta'-site. On the other hand, either lengthening or shortening the loop region of BACE1 has a minor impact on the selective cleavage of APP at these two adjacent sites, but significantly shortening the loop region impairs the ability of BACE1 to process APP at both sites. Thus, processing of APP by BACE1 is clearly dependent on a mutual structural compatibility in addition to the sequence feature. The knowledge gained from this study will potentially offer an opportunity for rational design of small molecule drugs to block the cleavage of APP specifically at the beta-site while not disturbing the functions of other cellular aspartyl proteases.     

Pulmonary capillary blood volume and membrane conductance in Andeans and lowlanders at high altitude: A cross-sectional study

Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis.Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm_CO) and Vc, corrected for the haemoglobin concentration (Vc_cor), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography.Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc_cor/VA and Dm_CO/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm_CO and Dm_CO/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level.The decrease in Dm_CO in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm_CO suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes.     

Uric acid deposits and estivation in the invasive apple-snail, Pomacea canaliculata

The physiological ability to estivate is relevant for the maintenance of population size in the invasive Pomacea canaliculata. However, tissue reoxygenation during arousal from estivation poses the problem of acute oxidative stress. Uric acid is a potent antioxidant in several systems and it is stored in specialized tissues of P. canaliculata. Changes in tissue concentration of thiobarbituric acid reactive substances (TBARS), uric acid and allantoin were measured during estivation and arousal in P. canaliculata. Both TBARS and uric acid increased two-fold during 45 days estivation, probably as a consequence of concomitant oxyradical production during uric acid synthesis by xanthine oxidase. However, after arousal was induced, uric acid and TBARS dropped to or near baseline levels within 20 min and remained low up to 24h after arousal induction, while the urate oxidation product allantoin continuously rose to a maximum at 24h after induction, indicating the participation of uric acid as an antioxidant during reoxygenation. Neither uric acid nor allantoin was detected in the excreta during this 24h period. Urate oxidase activity was also found in organs of active snails, but activity shut down during estivation and only a partial and sustained recovery was observed in the midgut gland.     

Fungal post-treatment of pulp mill effluents for the removal of recalcitrant pollutants

The objective of this work was to evaluate the post-treatment of an anaerobic recalcitrant effluent (anaerobically-treated weak black liquor, AnE) in an aerobic, upflow reactor packed with “biocubes” of Trametes versicolor immobilized onto small cubes of holm oak wood. The treated effluent (named anaerobic effluent; AnE) from an anaerobic fluidized bed reactor was fed to an up-flow aerobic fungal packed bed reactor (PBR). Two HRT were tested in this unit, namely 5 and 2.5 days; the PBR operated 60 days at 5-day HRT and 35 days at 2.5-day HRT. The aerobic packed bench scale reactor was a glass column 1.5 L total geometric volume containing 0.75 L biocubes of T. versicolor immobilized onto holm oak wood small cubes of 5 mm side. The reactor was operated at 25 °C. The pH of the AnE was adjusted to 4.5 before feeding; no carbohydrates or other soluble carbon source was supplemented. The fungal packed bed bioreactor averaged organic matter removals of 30% and 32% COD basis, during an experimental run of 60 days at 5-day HRT and 35 days at 2.5-day HRT, respectively. Colour and ligninoids contents were removed at higher percentages (69% and 54% respectively, average of both HRT). There was no significant difference between reactor performance at 5- and 2.5-day HRT, so, operation at 2.5-day HRT is recommended since reactor throughput is double. Activity of manganese peroxidase and laccase was found during the entire operation of the fungal PBR whereas lignin peroxidase activity practically disappeared in the second operation period. In general, enzyme activities were higher in the first period of operation (5-day HRT) than at 2.5-day HRT. To the best of our knowledge, this is one of the few works that demonstrated extended performance (3 months) of a fungal bioreactor for the treatment of a recalcitrant wastewater with no supplementation of glucose or other expensive, soluble carbohydrate.     

Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer

Omics data integration is becoming necessary to investigate the genomic mechanisms involved in complex diseases. During the integration process, many challenges arise such as data heterogeneity, the smaller number of individuals in comparison to the number of parameters, multicollinearity, and interpretation and validation of results due to their complexity and lack of knowledge about biological processes. To overcome some of these issues, innovative statistical approaches are being developed. In this work, we propose a permutation-based method to concomitantly assess significance and correct by multiple testing with the MaxT algorithm. This was applied with penalized regression methods (LASSO and ENET) when exploring relationships between common genetic variants, DNA methylation and gene expression measured in bladder tumor samples. The overall analysis flow consisted of three steps: (1) SNPs/CpGs were selected per each gene probe within 1Mb window upstream and downstream the gene; (2) LASSO and ENET were applied to assess the association between each expression probe and the selected SNPs/CpGs in three multivariable models (SNP, CPG, and Global models, the latter integrating SNPs and CPGs); and (3) the significance of each model was assessed using the permutation-based MaxT method. We identified 48 genes whose expression levels were significantly associated with both SNPs and CPGs. Importantly, 36 (75%) of them were replicated in an independent data set (TCGA) and the performance of the proposed method was checked with a simulation study. We further support our results with a biological interpretation based on an enrichment analysis. The approach we propose allows reducing computational time and is flexible and easy to implement when analyzing several types of omics data. Our results highlight the importance of integrating omics data by applying appropriate statistical strategies to discover new insights into the complex genetic mechanisms involved in disease conditions.     

Determinants of Performance of Health Systems Concerning Maternal and Child Health: A Global Approach

Aims

To assess the association of social determinants on the performance of health systems around the world.

Methods

A transnational ecological study was conducted with an observation level focused on the country. In order to research on the strength of the association between the annual maternal and child mortality in 154 countries and social determinants: corruption, democratization, income inequality and cultural fragmentation, we used a mixed linear regression model for repeated measures with random intercepts and a conglomerate-based geographical analysis, between 2000 and 2010.

Results

Health determinants with a significant association on child mortality(<1year): higher access to water (βa Quartile 4(Q4) vs Quartile 1(Q1) = -6,14; 95%CI: -11,63 to -0,73), sanitation systems, (Q4 vs Q1 = -25,58; 95%CI: -31,91 to -19,25), % measles vaccination coverage (Q4 vs Q1 = -7.35; 95%CI: -10,18 to -4,52), % of births attended by a healthcare professional (Q4 vs Q1 = -7,91; 95%CI: -11,36 to -4,52) and a % of the total health expenditure (Q3 vs Q1 = -2,85; 95%CI: -4,93 to -0,7). Ethnic fragmentation (Q4 vs Q1 = 9,93; 95%CI: -0.03 to 19.89) had a marginal effect. For child mortality<5 years, an association was found for these variables and democratization (not free vs free = 11,23; 95%CI: -0,82 to 23,29), out-of-pocket expenditure (Q1 vs Q4 = 17,71; 95%CI: 5,86 to 29,56). For MMR (Maternal mortality ratio), % of access to water for all the quartiles, % of access to sanitation systems, (Q3 vs Q1 = -171,15; 95%CI: -281,29 to -61), birth attention by a healthcare professional (Q4 vs Q1 = -231,23; 95%CI: -349,32 to -113,15), and having corrupt government (Q3 vs Q1 = 83,05; 95%CI: 33,10 to 133).

Conclusions

Improving access to water and sanitation systems, decreasing corruption in the health sector must become priorities in health systems. The ethno-linguistic cultural fragmentation and the detriment of democracy turn out to be two factors related to health results.     

Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development

BackgroundIn this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis.Conclusions/SignificanceAlthough further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.