BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Both type 2 diabetes (T2DM) and Bβ448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BβArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BβArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BβArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BβArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bβ448Lys was longer than Bβ448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bβ448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bβ448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies

Bulk Segregant Analysis Using Single Nucleotide Polymorphism Microarrays

Bulk segregant analysis (BSA) using microarrays, and extreme array mapping (XAM) have recently been used to rapidly identify genomic regions associated with phenotypes in multiple species. These experiments, however, require the identification of single feature polymorphisms (SFP) between the cross parents for each new combination of genotypes, which raises the cost of experiments. The availability of the genomic polymorphism data in Arabidopsis thaliana, coupled with the efficient designs of Single Nucleotide Polymorphism (SNP) genotyping arrays removes the requirement for SFP detection and lowers the per array cost, thereby lowering the overall cost per experiment. To demonstrate that these approaches would be functional on SNP arrays and determine confidence intervals, we analyzed hybridizations of natural accessions to the Arabidopsis ATSNPTILE array and simulated BSA or XAM given a variety of gene models, populations, and bulk selection parameters. Our results show a striking degree of correlation between the genotyping output of both methods, which suggests that the benefit of SFP genotyping in context of BSA can be had with the cheaper, more efficient SNP arrays. As a final proof of concept, we hybridized the DNA from bulks of an F2 mapping population of a Sulfur and Selenium ionomics mutant to both the Arabidopsis ATTILE1R and ATSNPTILE arrays, which produced almost identical results. We have produced R scripts that prompt the user for the required parameters and perform the BSA analysis using the ATSNPTILE1 array and have provided them as supplemental data files

Quivers, YBE and 3-manifolds

We study 4d superconformal indices for a large class of N=1 superconformal quiver gauge theories realized combinatorially as a bipartite graph or a set of "zig-zag paths" on a two-dimensional torus T^2. An exchange of loops, which we call a "double Yang-Baxter move", gives the Seiberg duality of the gauge theory, and the invariance of the index under the duality is translated into the Yang-Baxter-type equation of a spin system defined on a "Z-invariant" lattice on T^2. When we compactify the gauge theory to 3d, Higgs the theory and then compactify further to 2d, the superconformal index reduces to an integral of quantum/classical dilogarithm functions. The saddle point of this integral unexpectedly reproduces the hyperbolic volume of a hyperbolic 3-manifold. The 3-manifold is obtained by gluing hyperbolic ideal polyhedra in H^3, each of which could be thought of as a 3d lift of the faces of the 2d bipartite graph.The same quantity is also related with the thermodynamic limit of the BPS partition function, or equivalently the genus 0 topological string partition function, on a toric Calabi-Yau manifold dual to quiver gauge theories. We also comment on brane realization of our theories. This paper is a companion to another paper summarizing the results.Comment: 61 pages, 16 figures; v2: typos correcte

ReAS: Recovery of Ancestral Sequences for Transposable Elements from the Unassembled Reads of a Whole Genome Shotgun

We describe an algorithm, ReAS, to recover ancestral sequences for transposable elements (TEs) from the unassembled reads of a whole genome shotgun. The main assumptions are that these TEs must exist at high copy numbers across the genome and must not be so old that they are no longer recognizable in comparison to their ancestral sequences. Tested on the japonica rice genome, ReAS was able to reconstruct all of the high copy sequences in the Repbase repository of known TEs, and increase the effectiveness of RepeatMasker in identifying TEs from genome sequences

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Use of Confocal Laser as Light Source Reveals Stomata-Autonomous Function

In most terrestrial plants, stomata open during the day to maximize the update of CO(2) for photosynthesis, but they close at night to minimize water loss. Blue light, among several environmental factors, controls this process. Stomata response to diverse stimuli seems to be dictated by the behaviour of neighbour stomata creating leaf areas of coordinated response. Here individual stomata of Arabidopsis leaves were illuminated with a short blue-light pulse by focusing a confocal argon laser. Beautifully, the illuminated stomata open their pores, whereas their dark-adapted neighbours unexpectedly experience no change. This induction of individual stomata opening by low fluence rates of blue light was disrupted in the phototropin1 phototropin2 (phot1 phot2) double mutant, which exhibits insensitivity of stomatal movements in blue-illuminated epidermal strips. The irradiation of all epidermal cells making direct contact with a given stoma in both wild type and phot1 phot2 plants does not trigger its movement. These results unravel the stoma autonomous function in the blue light response and illuminate the implication of PHOT1 and/or PHOT2 in such response. The micro spatial heterogeneity that solar blue light suffers in partially shaded leaves under natural conditions highlights the physiological significance of the autonomous stomatal behaviour

Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003-2010

Aims: To examine age-dependent in-hospital mortality for hospitalization with acute coronary syndromes (ACS) in England and Wales. Methods and results: Mixed-effects regression analysis using data from 616 011 ACS events at 255 hospitals as recorded in the Myocardial Ischemia National Audit Project (MINAP) 2003-2010; 102 415 (16.7%) patients were aged /=85 years. Patients >/=85 years with ST-elevation myocardial infarction (STEMI) were less likely to receive emergency reperfusion therapy than those /= 85 years, in-hospital mortality reduced from 30.1% in 2003 to 19.4% in 2010 (RR = 0.54, 95% CI: 0.38-0.75, P/= 85 years, from 31.5% in 2003 to 20.4% in 2010 (RR = 0.56, 95% CI: 0.42-0.73, P< 0.001). Findings were upheld after multi-level adjustment (base = 2003): male STEMI 2010 OR = 0.60, 95% CI: 0.48-0.75; female STEMI 2010 OR = 0.55, 95% CI: 0.42-0.71; male NSTEMI OR = 0.50, 95% CI: 0.42-0.60; female NSTEMI OR = 0.49, 95% CI: 0.40-0.59. Conclusion: For patients hospitalized with ACS in England and Wales, there have been substantial reductions in in-hospital mortality rates from 2003 to 2010 across all age groups. The temporal improvements in mortality were similar for sex and type of acute myocardial infarction. Age-dependent inequalities in the management of ACS were apparen

Genome wide association mapping of grain arsenic, copper, molybdenum and zinc in rice (Oryza sativa L.) grown at four international field sites

Peer reviewedPublisher PD

Influence of dental metallic artifact from multislice CT in the assessment of simulated mandibular lesions

OBJECTIVE: This study evaluated the influence of metallic dental artifacts on the accuracy of simulated mandibular lesion detection by using multislice technology. MATERIAL AND METHODS: Fifteen macerated mandibles were used. Perforations were done simulating bone lesions and the mandibles were subjected to axial 16 rows multislice CT images using 0.5 mm of slice thickness with 0.3 mm interval of reconstruction. Metallic dental restorations were done and the mandibles were subjected again to CT in the same protocol. The images were analyzed to detect simulated lesions in the mandibles, verifying the loci number and if there was any cortical perforation exposing medullar bone. The analysis was performed by two independent examiners using e-film software. RESULTS: The samples without artifacts presented better results compared to the gold standard (dried mandible with perforations). In the samples without artifacts, all cortical perforation were identified and 46 loci were detected (of 51) in loci number analysis. Among the samples with artifacts, 12 lesions out of 14 were recognized regarding medullar invasion, and 40 out of 51 concerning loci number. The sensitivity in samples without artifacts was 90% and 100% regarding loci number and medullar invasion, respectively. In samples with artifacts, these values dropped to 78% and 86%, respectively. The presence of metallic restorations affected the sensitivity values of the method, but the difference was not significant (p>0.05). CONCLUSIONS: Although there were differences in the results of samples with and without artifacts, the presence of metallic restoration did not lead to misinterpretation of the final diagnosis. However, the validity of multislice CT imaging in this study was established for detection of simulated mandibular bone lesions.CNPqFAPESPCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES