Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great "Tree of Life" (ToL). A notable exception involves the use of Phylomatic, which provides tools ...to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user's needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces.
With the aim of building such a "phylotastic" system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three-month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta-API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service, DateLife.org, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (GitHub.com), a website (http://www.phylotastic.org), and a server image.
Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deterioration of glycaemic control in people with long-standing diabetes mellitus (diabetes) may be a possible indicator of pancreatic cancer. However, the magnitude of the association between ...diabetes deterioration and pancreatic cancer has received little attention.
We conducted a matched cohort study, nested within a population-based cohort of Australian women with diabetes. Women with unstable diabetes, defined as a change in medication after a 2-year period of stable medication use, were matched by birth year to those with stable diabetes, in a 1:4 ratio. We used flexible parametric survival models to estimate hazard ratios (HRs) and 95% confidence intervals (CI).
We included 134,954 and 539,789 women in the unstable and stable diabetes cohorts, respectively (mean age 68 years). In total, 1,315 pancreatic cancers were diagnosed. Deterioration of stable diabetes was associated with a 2.5-fold increased risk of pancreatic cancer (HR 2.55; 95% CI 2.29-2.85). The risk was particularly high within the first year after diabetes deteriorated. HRs at 3 months, 6 months and 1 year were: 5.76 (95% CI 4.72-7.04); 4.56 (95% CI 3.81-5.46); and 3.33 (95% CI 2.86-3.89), respectively. The risk was no longer significantly different after 7 years.
Deterioration in glycaemic control in people with previously stable diabetes may be an indicator of pancreatic cancer, suggesting investigations of the pancreas may be appropriate. The weaker longer-term (3-7 years) association between diabetes deterioration and pancreatic cancer may indicate that poor glycaemic control can be a risk factor for pancreatic cancer.
Genome-wide association studies have to date identified multiple coronary artery disease (CAD)-associated loci; however, for most of these loci the mechanism by which they affect CAD risk is unclear. ...The CAD-associated locus 7q32.2 is unusual in that the lead variant, rs11556924, is not in strong linkage disequilibrium with any other variant and introduces a coding change in ZC3HC1, which encodes NIPA. In this study, we show that rs11556924 polymorphism is associated with lower regulatory phosphorylation of NIPA in the risk variant, resulting in NIPA with higher activity. Using a genome-editing approach we show that this causes an effective decrease in cyclin-B1 stability in the nucleus, thereby slowing its nuclear accumulation. By perturbing the rate of nuclear cyclin-B1 accumulation, rs11556924 alters the regulation of mitotic progression resulting in an extended mitosis. This study shows that the CAD-associated coding polymorphism in ZC3HC1 alters the dynamics of cell-cycle regulation by NIPA.
Clinical outcomes in large patient populations from real-world clinical practice with a next-generation self-expanding transcatheter aortic valve are lacking.
This study sought to document the ...clinical and device performance outcomes of transcatheter aortic valve replacement (TAVR) with a next-generation, self-expanding transcatheter heart valve (THV) system in patients with severe symptomatic aortic stenosis (AS) in routine clinical practice.
The FORWARD (CoreValve Evolut R FORWARD) study is a prospective, single-arm, multinational, multicenter, observational study. An independent clinical events committee adjudicated safety endpoints based on Valve Academic Research Consortium-2 definitions. An independent echocardiographic core laboratory evaluated all echocardiograms. From January 2016 to December 2016, TAVR with the next-generation self-expanding THV was attempted in 1,038 patients with symptomatic, severe AS at 53 centers on 4 continents.
Mean age was 81.8 ± 6.2 years, 64.9% were women, the mean Society of Thoracic Surgeons Predicted Risk of Mortality was 5.5 ± 4.5%, and 33.9% of patients were deemed frail. The repositioning feature of the THV was applied in 25.8% of patients. A single valve was implanted in the proper anatomic location in 98.9% of patients. The mean aortic valve gradient was 8.5 ± 5.6 mm Hg, and moderate or severe aortic regurgitation was 1.9% at discharge. All-cause mortality was 1.9%, and disabling stroke occurred in 1.8% at 30 days. The expected-to-observed early surgical mortality ratio was 0.35. A pacemaker was implanted in 17.5% of patients.
TAVR using the next-generation THV is clinically safe and effective for treating older patients with severe AS at increased operative risk. (CoreValve Evolut R FORWARD Study FORWARD; NCT02592369).
After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the ...Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.
Background:
Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular ...function in SVDs.
Aims:
To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs.
Design:
TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose.
Outcomes:
The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv).
Discussion:
TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs.
Funding:
European Union’s Horizon 2020 programme.
Trial registration:
NCT03082014.
Abstract Objective ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an ...association with clinical outcome in epithelial ovarian cancer (EOC). Methods The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either ‘standard’ first-line paclitaxel–carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77–1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.
Assigned values derived from the GeoPT proficiency testing programme were compared with certified values for six certified reference materials that have been used as test materials in the GeoPT ...programme. Statistical analysis showed that there were few significant differences between these sets of data and that these differences had no significant impact on the GeoPT assessment when fitness‐for‐purpose criteria were taken into account.
Les valeurs attribuées dérivées du programme de test d'aptitude GeoPT ont été comparés avec les valeurs certifiées pour six matériaux de référence certifiés qui ont été utilisés comme matériaux de test dans le programme GeoPT. L'analyse statistique a montré qu'il y avait peu de différences significatives entre ces ensembles de données, et que ces différences n'ont eu aucune incidence significative sur l'appréciation GeoPT quand les critères d'usage ont été pris en compte.
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