Template-directed synthesis of acyclic oligonucleotide analogues

Bis-phosphoimidazolides of an analogue of adenosine (in which ribose is replaced by an acyclic chain) and of two related analogues of guanosine undergo oligomerization in the presence of complementary polynucleotide templates. Data on the template- and nontemplate-directed reactions are presented, and the possible relevance to origins of life is discussed.     

Development and Validation of the Scan of Postgraduate Educational Environment Domains (SPEED): A Brief Instrument to Assess the Educational Environment in Postgraduate Medical Education

Introduction

Current instruments to evaluate the postgraduate medical educational environment lack theoretical frameworks and are relatively long, which may reduce response rates. We aimed to develop and validate a brief instrument that, based on a solid theoretical framework for educational environments, solicits resident feedback to screen the postgraduate medical educational environment quality.

Methods

Stepwise, we developed a screening instrument, using existing instruments to assess educational environment quality and adopting a theoretical framework that defines three educational environment domains: content, atmosphere and organization. First, items from relevant existing instruments were collected and, after deleting duplicates and items not specifically addressing educational environment, grouped into the three domains. In a Delphi procedure, the item list was reduced to a set of items considered most important and comprehensively covering the three domains. These items were triangulated against the results of semi-structured interviews with 26 residents from three teaching hospitals to achieve face validity. This draft version of the Scan of Postgraduate Educational Environment Domains (SPEED) was administered to residents in a general and university hospital and further reduced and validated based on the data collected.

Results

Two hundred twenty-three residents completed the 43-item draft SPEED. We used half of the dataset for item reduction, and the other half for validating the resulting SPEED (15 items, 5 per domain). Internal consistencies were high. Correlations between domain scores in the draft and brief versions of SPEED were high (>0.85) and highly significant (p<0.001). Domain score variance of the draft instrument was explained for ≥80% by the items representing the domains in the final SPEED.

Conclusions

The SPEED comprehensively covers the three educational environment domains defined in the theoretical framework. Because of its validity and brevity, the SPEED is promising as useful and easily applicable tool to regularly screen educational environment quality in postgraduate medical education.     

DNA methylation age of blood predicts all-cause mortality in later life

BackgroundDNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age.ResultsHere we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δ_age) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δ_age and mortality. A 5-year higher Δ_age is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δ_age. A pedigree-based heritability analysis of Δ_age was conducted in a separate cohort. The heritability of Δ_age was 0.43.ConclusionsDNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.     

Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs

Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 × 10⁻⁷) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 × 10⁻¹⁰) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.     

STUDIES ON THE ELIMINATION OF DYES IN THE GASTRIC AND PANCREATIC SECRETIONS,AND INFERENCES THEREFROM CONCERNING THE MECHANISMS OF SECRETION OF ACID AND BASE

1. All dyes appearing in gastric juice after intravenous injection in the dog are characterized by having their chromogen in the electropositive ion under suitable conditions. 2. All dyes eliminated in pancreatic juice ionize with the chromogen electronegative under proper circumstances. 3. The amphoteric characteristics of certain dyestuffs, as well as the changes in charge associated with reversible reduction in others, have been taken into consideration, and the lack of success of previous investigators in finding a common characteristic of dyes secreted by the gastric glands differentiating them from those secreted by the pancreas, has been shown to have been due to failure to take these potentialities of the dyestuffs into account. 4. Several possible hypotheses concerning the mechanism of selectivity to dyestuffs have been considered. Differences in distribution in acid, neutral, and alkaline phases will not account for selective secretion without postulating also specific membrane permeability. It is pointed out that the theory most thoroughly in accord with all the facts observed is based upon the pore concept. To restrain electronegative dyes by polar adsorption, the pores of the membranes of the gastric glands would have to be positively charged. Such pores would constitute an electrostatic filter, restraining from passage all mobile ions of the same charge. The anions, which in plasma are mostly chloride, could pass this barrier into the secretion. In order to have hydrochloric acid formation, anion exchange would have to occur, bicarbonate, lactate, or some other anion from the gland lumen returning to balance chloride entering, leaving the hydrogen ion from the weaker acid in the secretion. This tentative theory can also be seen to fit many of the facts of pancreatic secretion, where electropositive dyes are restrained, and alkali is secreted.     

Phylogeny of the Drosophila saltans species group based on combined analysis of nuclear and mitochondrial DNA sequences

Nucleotide sequences from two nuclear loci, alcohol dehydrogenase and internal transcribed spacer-1 of the nuclear ribosomal DNA repeats, and two mitochondrial genes, cytochrome oxidase I and cytochrome oxidase II, were determined from nine species in the Drosophila saltans species group. The partition homogeneity test and partitioned Bremer support were used to measure incongruence between phylogenetic hypotheses generated from individual partitions. Individual loci were generally congruent with each other and consistent with the previously proposed morphological hypothesis, although they differed in level of resolution. Since extreme conflict between partitions did not exist, the data were combined and analyzed simultaneously. The total evidence method gave a more resolved and highly supported phylogeny, as indicated by bootstrap proportions and decay indices, than did any of the individual analyses. The cordata and elliptica subgroups, considered to have diverged early in the history of the D. saltans group, were sister taxa to the remainder of the saltans group. The sturtevanti subgroup, represented by D. milleri and D. sturtevanti, occupies an intermediate position in this phylogeny. The saltans and parasaltans subgroups are sister clades and occupy the most recently derived portion of the phylogeny. As with previous morphological studies, phylogenetic relationships within the saltans subgroup were not satisfactorily resolved by the molecular data.      

Meta-analysis identified the TNFA -308G > A promoter polymorphism as a risk factor for disease severity in patients with rheumatoid arthritis

Introduction

The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA).

Methods

A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR.

Results

Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals.

Conclusions

Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes.     

Simultaneous Discovery,Estimation and Prediction Analysis of Complex Traits Using a Bayesian Mixture Model

Gene discovery, estimation of heritability captured by SNP arrays, inference on genetic architecture and prediction analyses of complex traits are usually performed using different statistical models and methods, leading to inefficiency and loss of power. Here we use a Bayesian mixture model that simultaneously allows variant discovery, estimation of genetic variance explained by all variants and prediction of unobserved phenotypes in new samples. We apply the method to simulated data of quantitative traits and Welcome Trust Case Control Consortium (WTCCC) data on disease and show that it provides accurate estimates of SNP-based heritability, produces unbiased estimators of risk in new samples, and that it can estimate genetic architecture by partitioning variation across hundreds to thousands of SNPs. We estimated that, depending on the trait, 2,633 to 9,411 SNPs explain all of the SNP-based heritability in the WTCCC diseases. The majority of those SNPs (>96%) had small effects, confirming a substantial polygenic component to common diseases. The proportion of the SNP-based variance explained by large effects (each SNP explaining 1% of the variance) varied markedly between diseases, ranging from almost zero for bipolar disorder to 72% for type 1 diabetes. Prediction analyses demonstrate that for diseases with major loci, such as type 1 diabetes and rheumatoid arthritis, Bayesian methods outperform profile scoring or mixed model approaches.