Modeling study on the validity of a possibly simplified representation of proteins

The folding characteristics of sequences reduced with a possibly simplified representation of five types of residues are shown to be similar to their original ones with the natural set of residues (20 types or 20 letters). The reduced sequences have a good foldability and fold to the same native structure of their optimized original ones. A large ground state gap for the native structure shows the thermodynamic stability of the reduced sequences. The general validity of such a five-letter reduction is further studied via the correlation between the reduced sequences and the original ones. As a comparison, a reduction with two letters is found not to reproduce the native structure of the original sequences due to its homopolymeric features.Comment: 6 pages with 4 figure

Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension

RATIONALE: Sildenafil, a well-known vasodilator known to interfere with purinergic signaling through effects on cGMP, is a mainstay in the treatment of pulmonary hypertension (PH). However, little is known regarding its effects on the metabolic reprogramming of vascular cells, which is a hallmark of PH. Purine metabolism, especially intracellular de novo purine biosynthesis is essential for vascular cell proliferation. Since adventitial fibroblasts are critical contributors to proliferative vascular remodeling in PH, in this study we aimed to investigate if sildenafil, beyond its well-known vasodilator role in smooth muscle cells, impacts intracellular purine metabolism and proliferation of fibroblasts derived from human PH patients. METHODS: Integrated omics approaches (plasma and cell metabolomics) and pharmacological inhibitor approaches were employed in plasma samples and cultured pulmonary artery fibroblasts from PH patients. MEASUREMENTS AND MAIN RESULTS: Plasma metabolome analysis of 27 PH patients before and after treatment with sildenafil, demonstrated a partial, but specific effect of sildenafil on purine metabolites, especially adenosine, adenine, and xanthine. However, circulating markers of cell stress, including lactate, succinate, and hypoxanthine were only decreased in a small subset of sildenafil-treated patients. To better understand potential effects of sildenafil on pathological changes in purine metabolism (especially purine synthesis) in PH, we performed studies on pulmonary fibroblasts from PAH patients (PH-Fibs) and corresponding controls (CO-Fibs), since these cells have previously been shown to demonstrate stable and marked PH associated phenotypic and metabolic changes. We found that PH-Fibs exhibited significantly increased purine synthesis. Treatment of PH-Fibs with sildenafil was insufficient to normalize cellular metabolic phenotype and only modestly attenuated the proliferation. However, we observed that treatments which have been shown to normalize glycolysis and mitochondrial abnormalities including a PKM2 activator (TEPP-46), and the histone deacetylase inhibitors (HDACi), SAHA and Apicidin, had significant inhibitory effects on purine synthesis. Importantly, combined treatment with HDACi and sildenafil exhibited synergistic inhibitory effects on proliferation and metabolic reprogramming in PH-Fibs. CONCLUSIONS: While sildenafil alone partially rescues metabolic alterations associated with PH, treatment with HDACi, in combination with sildenafil, represent a promising and potentially more effective strategy for targeting vasoconstriction, metabolic derangement and pathological vascular remodeling in PH

Increased virulence of Puccinia coronata f. sp.avenae populations through allele frequency changes at multiple putative Avr loci

Author summary The rust fungus Puccinia coronata f. sp. avenae (Pca), which causes crown rust disease, decimates oat (Avena sativa) production in many countries of the world. While the use of genetic resistance in crop breeding programs is the most sustainable disease management strategy to control plant disease, the release of oat varieties that display genetic resistance to Pca infection is hindered by rapid evolution of this pathogen. This study aims to determine demography and determinants of adaptive evolution in Pca to minimize the risk of disease outbreaks and enhance resistance gene stewardship. We recently published two high quality genome references of P. coronata f. sp. avenae. Here, we used these resources to direct a population genomics-based study of two temporally distant sets of pathogen collections to study genotypic changes that may explain the most recent oat crown rust epidemics across the continental US. We found that the population of Pca in 1990 is significantly different to that collected in 2015 at both genotypic and phenotypic levels. Our findings are consistent with the role of sexual and asexual reproduction in the Pca population diversity. Importantly, our work identifies genomic regions and genes that may be involved in local host adaptation which in the future may assist in the development of molecular markers and diagnosis of virulence

Wind Accretion and State Transitions in Cygnus X-1

We present the results of a spectroscopic monitoring program (from 1998 to 2002) of the H-alpha emission strength in HDE 226868, the optical counterpart of the black hole binary, Cyg X-1. The H-alpha profiles consist of (1) a P Cygni component associated with the wind of the supergiant, (2) emission components that attain high velocity at the conjunctions and that probably form in enhanced outflows both towards and away from the black hole, and (3) an emission component that moves in anti-phase with the supergiant's motion. We argue that the third component forms in accreted gas near the black hole, and the radial velocity curve of the emission is consistent with a mass ratio of M_X / M_opt = 0.36 +/- 0.05. We find that there is a general anti-correlation between the H-alpha emission strength and X-ray flux in the sense that when the H-alpha emission is strong (W_\lambda < -0.5 Angstroms) the X-ray flux is weaker and the spectrum harder. On the other hand, there is no correlation between H-alpha emission strength and X-ray flux when H-alpha is weak. During the low/hard X-ray state, the strong wind is fast and the accretion rate is relatively low, while in the high/soft state the weaker, highly ionized wind attains only a moderate velocity and the accretion rate increases. We argue that the X-ray transitions from the normal low/hard to the rare high/soft state are triggered by episodes of decreased mass loss rate in the supergiant donor star.Comment: 45 pages, 16 figures, ApJ, in pres

Contact frequency determines outcome of basal insulin initiation trials in type 2 diabetes

Aims/hypothesis The aim of the present study was to investigate whether predetermined contact frequency with the study teamand endpoint insulin dose are associated with study outcomes in basal insulin initiation trials in type 2 diabetes. Methods A systematic Medline search was performed. Using data from the selected studies, contact frequency was plotted against HbA(1c) reduction and endpoint insulin dose. The importance of face-to-face vs telephone contact was also analysed. Insulin dose was plotted against HbA(1c) reduction, hypoglycaemia rate and weight gain. To investigate non-specific study effects, the relationship between contact frequency and HbA(1c) was also assessed in dipeptidyl peptidase-4 (DPP-4) inhibitor trials. Results The reduction in HbA(1c) was highly correlated with contact frequency and endpoint insulin dose (r(2)=0.751, p<0.001 and r(2)=0.433, p=0.008, respectively). However, after adjusting for contact frequency, the relationship between insulin dose and HbA(1c) reduction was no longer significant (p=0.270). The frequency of both clinical and telephone contacts were independent predictors of HbA(1c) improvement (p=0.010 and p<0.001, respectively). We found no dose response relationship between end-of-study insulin dose and hypoglycaemia or weight gain. In DPP-4 inhibitor studies, contact frequency was not positively associated with HbA(1c). Conclusions/interpretation The frequency of contact with the study team is highly correlated with the improvement in HbA(1c) achieved in basal insulin initiation trials in type 2 diabetic patients. This has important implications for trial design and interpretation, as well as for clinical car

Does tendering create travesties of justice?

Legal aid in criminal proceedings exists to avoid defendants being presented as victims of an overbearing state, which assumes that ‘the two sides have access to roughly equivalent resources and expertise’ (Young and Wall, 1996). Recent governments have however focussed on value for money, which ignores political debate about what actually constitutes value in specific circumstances. It is against this background that the Ministry of Justice released its consultation paper including proposals to introduce Price Competitive Tendering (PCT) in most criminal proceedings

Establishing Lagrangian connections between observations within air masses crossing the Atlantic during the International Consortium for Atmospheric Research on Transport and Transformation experiment

The ITCT-Lagrangian-2K4 (Intercontinental Transport and Chemical Transformation) experiment was conceived with an aim to quantify the effects of photochemistry and mixing on the transformation of air masses in the free troposphere away from emissions. To this end, attempts were made to intercept and sample air masses several times during their journey across the North Atlantic using four aircraft based in New Hampshire (USA), Faial (Azores) and Creil (France). This article begins by describing forecasts from two Lagrangian models that were used to direct the aircraft into target air masses. A novel technique then identifies Lagrangian matches between flight segments. Two independent searches are conducted: for Lagrangian model matches and for pairs of whole air samples with matching hydrocarbon fingerprints. The information is filtered further by searching for matching hydrocarbon samples that are linked by matching trajectories. The quality of these "coincident matches'' is assessed using temperature, humidity and tracer observations. The technique pulls out five clear Lagrangian cases covering a variety of situations and these are examined in detail. The matching trajectories and hydrocarbon fingerprints are shown, and the downwind minus upwind differences in tracers are discussed

Mechanism Of Ductile Rupture In The AL/Sapphire System Elucidated Using X-Ray Tomographic Microscopy

The fracture of a thin metal foil constrained between alumina or sapphire blocks has been studied by a number of investigators. The systems that have been investigated include Al, Au, Nb, and Cu. Except for Al/Al{sub 2}O{sub 3} interfaces, these systems exhibit a common fracture mechanism: pores form at the metal/ceramic interface several foil thicknesses ahead of the crack which, under increasing load, grow and link with the initial crack. This mechanism leaves metal o none side of the fracture surface and clean ceramic on the other. This has not been the observation in Al/Al{sub 2}O{sub 3} bonds where at appropriate thicknesses of Al, the fracture appears to proceed as a ductile rupture through the metal. This paper addresses the question of why the fracture of the Al/Al{sub 2}O{sub 3} system appears to be different from other systems by probing the fracture mechanism using X-ray tomographic microscopy (XTM). The authors have experimentally duplicated the simplified geometry of the micromechanics models and subjected the specimens to a well defined stress state in bending. The bend tests were interrupted and XTM was performed to reveal the mechanism of crack extension

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster.

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function