205 research outputs found
Effects of Dipeptidyl Peptidase-4 Inhibitor Linagliptin on Left Ventricular Dysfunction in Patients with Type 2 Diabetes and Concentric Left Ventricular Geometry (the DYDA 2TM Trial). Rationale, Design, and Baseline Characteristics of the Study Population
Purpose: A multicentre, randomized, double-blind, placebo-controlled, parallel-group study aimed to define the potential positive effect of dipeptidyl peptidase-4 inhibition on left ventricular systolic function (LVSF) beyond glycemic control in type 2 diabetes mellitus (T2DM) (DYDA 2TM trial).
Methods: Individuals with fairly controlled T2DM and asymptomatic impaired LVSF were randomized in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their stable diabetes therapy. Eligibility criteria were age ≥ 40 years, history of T2DM with a duration of at least 6 months, HbA1c ≤ 8.0% (≤ 64 mmol/mol), no history or clinical signs/symptoms of cardiac disease, evidence at baseline echocardiography of concentric LV geometry (relative wall thickness ≥ 0.42), and impaired LVSF defined as midwall fractional shortening (MFS) ≤ 15%. The primary end-point was the modification from baseline to 48 weeks of MFS. As an exploratory analysis, significant changes in LV global longitudinal strain and global circumferential strain, measured by speckle tracking echocardiography, were also considered. Secondary objectives were changes in diastolic and/or in systolic longitudinal function as measured by tissue Doppler.
Results: A total of 188 patients were enrolled. They were predominantly males, mildly obese, with typical insulin-resistance co-morbidities such as hypertension and dyslipidemia. Mean relative wall thickness was 0.51 ± 0.09 and mean MFS 13.3% ± 2.5.
Conclusions: DYDA 2 is the first randomized, double-blind, placebo-controlled trial to explore the effect of a dipeptidyl peptidase-4 inhibitor on LVSF in T2DM patients in primary prevention regardless of glycemic control. The main characteristics of the enrolled population are reported
The Long Stare at Hercules X-1. I. Emission Lines from the Outer Disk, the Magnetosphere Boundary, and the Accretion Curtain
© 2022. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/Hercules X-1 is a nearly edge-on accreting X-ray pulsar with a warped accretion disk, precessing with a period of about 35 days. The disk precession allows for unique and changing sightlines toward the X-ray source. To investigate the accretion flow at a variety of sightlines, we obtained a large observational campaign on Her X-1 with XMM-Newton (380 ks exposure) and Chandra (50 ks exposure) for a significant fraction of a single disk precession cycle, resulting in one of the best data sets taken to date on a neutron star X-ray binary. Here we present the spectral analysis of the high state high-resolution grating and CCD data sets, including the extensive archival data available for this famous system. The observations reveal a complex Fe K region structure, with three emission line components of different velocity widths. Similarly, the high-resolution soft X-ray spectra reveal a number of emission lines of various widths. We correct for the uncertain gain of the European Photon Imaging Camera pn Timing mode spectra, and track the evolution of these spectral components with Her X-1 precession phase and observed luminosity. We find evidence for three groups of emission lines, the first of which originates in the outer accretion disk (105 R G from the neutron star). The second line group plausibly originates at the boundary between the inner disk and the pulsar magnetosphere (103 R G). The last group is too broad to arise in the magnetically truncated disk and instead must originate very close to the neutron star surface, likely from X-ray reflection from the accretion curtain (∼102 R G).Peer reviewe
A Helitron transposon reconstructed from bats reveals a novel mechanism of genome shuffling in eukaryotes
Helitron transposons capture and mobilize gene fragments in eukaryotes, but experimental evidence for their transposition is lacking in the absence of an isolated active element. Here we reconstruct Helraiser, an ancient element from the bat genome, and use this transposon as an experimental tool to unravel the mechanism of Helitron transposition. A hairpin close to the 3'-end of the transposon functions as a transposition terminator. However, the 3'-end can be bypassed by the transposase, resulting in transduction of flanking sequences to new genomic locations. Helraiser transposition generates covalently closed circular intermediates, suggestive of a replicative transposition mechanism, which provides a powerful means to disseminate captured transcriptional regulatory signals across the genome. Indeed, we document the generation of novel transcripts by Helitron promoter capture both experimentally and by transcriptome analysis in bats. Our results provide mechanistic insight into Helitron transposition, and its impact on diversification of gene function by genome shuffling
Fractional Sobolev-Poincaré inequalities in irregular domains
This paper is devoted to the study of fractional (q, p)-Sobolev-Poincaré in- equalities in irregular domains. In particular, the author establishes (essentially) sharp fractional (q, p)-Sobolev-Poincaré inequalities in s-John domains and in domains satisfying the quasihyperbolic boundary conditions. When the order of the fractional derivative tends to 1, our results tend to the results for the usual derivatives. Furthermore, the author verifies that those domains which support the fractional (q, p)-Sobolev-Poincaré inequalities together with a separation property are s-diam John domains for certain s, depending only on the associated data. An inaccurate statement in [Buckley, S. and Koskela, P., Sobolev-Poincaré implies John, Math. Res. Lett., 2(5), 1995, 577–593] is also pointed out
Transcriptome profiling of grapevine seedless segregants during berry development reveals candidate genes associated with berry weight
Indexación: Web of Science; PubMedBackground
Berry size is considered as one of the main selection criteria in table grape breeding programs. However, this is a quantitative and polygenic trait, and its genetic determination is still poorly understood. Considering its economic importance, it is relevant to determine its genetic architecture and elucidate the mechanisms involved in its expression. To approach this issue, an RNA-Seq experiment based on Illumina platform was performed (14 libraries), including seedless segregants with contrasting phenotypes for berry weight at fruit setting (FST) and 6–8 mm berries (B68) phenological stages.
Results
A group of 526 differentially expressed (DE) genes were identified, by comparing seedless segregants with contrasting phenotypes for berry weight: 101 genes from the FST stage and 463 from the B68 stage. Also, we integrated differential expression, principal components analysis (PCA), correlations and network co-expression analyses to characterize the transcriptome profiling observed in segregants with contrasting phenotypes for berry weight. After this, 68 DE genes were selected as candidate genes, and seven candidate genes were validated by real time-PCR, confirming their expression profiles.
Conclusions
We have carried out the first transcriptome analysis focused on table grape seedless segregants with contrasting phenotypes for berry weight. Our findings contributed to the understanding of the mechanisms involved in berry weight determination. Also, this comparative transcriptome profiling revealed candidate genes for berry weight which could be evaluated as selection tools in table grape breeding programs.http://bmcplantbiol.biomedcentral.com/articles/10.1186/s12870-016-0789-
The soft state of the black hole transient source MAXI J1820+070: emission from the edge of the plunge region?
The Galactic black hole X-ray binary MAXI J1820+070 had a bright outburst in 2018 when it became the second brightest X-ray source in the sky. It was too bright for X-ray CCD instruments such as XMM–Newton and Chandra, but was well observed by photon-counting instruments such as Neutron star Inner Composition Explorer (NICER) and Nuclear Spectroscopic Telescope Array(NuSTAR). We report here on the discovery of an excess-emission component during the soft state. It is best modelled with a blackbody spectrum in addition to the regular disc emission, modelled as either diskbb or kerrbb. Its temperature varies from about 0.9 to 1.1 keV, which is about 30–80 per cent higher than the inner disc temperature of diskbb. Its flux varies between 4 and 12 per cent of the disc flux. Simulations of magnetized accretion discs have predicted the possibility of excess emission associated with a non-zero torque at the innermost stable circular orbit (ISCO) about the black hole, which, from other NuSTAR studies, lies at about 5 gravitational radii or about 60 km (for a black hole, mass is 8M⊙). In this case, the emitting region at the ISCO has a width varying between 1.3 and 4.6 km and would encompass the start of the plunge region where matter begins to fall freely into the black hole
Insight on an Arginine Synthesis Metabolon from the Tetrameric Structure of Yeast Acetylglutamate Kinase
N-acetyl-L-glutamate kinase (NAGK) catalyzes the second, generally controlling, step of arginine biosynthesis. In yeasts, NAGK exists either alone or forming a metabolon with N-acetyl-L-glutamate synthase (NAGS), which catalyzes the first step and exists only within the metabolon. Yeast NAGK (yNAGK) has, in addition to the amino acid kinase (AAK) domain found in other NAGKs, a ∼150-residue C-terminal domain of unclear significance belonging to the DUF619 domain family. We deleted this domain, proving that it stabilizes yNAGK, slows catalysis and modulates feed-back inhibition by arginine. We determined the crystal structures of both the DUF619 domain-lacking yNAGK, ligand-free as well as complexed with acetylglutamate or acetylglutamate and arginine, and of complete mature yNAGK. While all other known arginine-inhibitable NAGKs are doughnut-like hexameric trimers of dimers of AAK domains, yNAGK has as central structure a flat tetramer formed by two dimers of AAK domains. These dimers differ from canonical AAK dimers in the −110° rotation of one subunit with respect to the other. In the hexameric enzymes, an N-terminal extension, found in all arginine-inhibitable NAGKs, forms a protruding helix that interlaces the dimers. In yNAGK, however, it conforms a two-helix platform that mediates interdimeric interactions. Arginine appears to freeze an open inactive AAK domain conformation. In the complete yNAGK structure, two pairs of DUF619 domains flank the AAK domain tetramer, providing a mechanism for the DUF619 domain modulatory functions. The DUF619 domain exhibits the histone acetyltransferase fold, resembling the catalytic domain of bacterial NAGS. However, the putative acetyl CoA site is blocked, explaining the lack of NAGS activity of yNAGK. We conclude that the tetrameric architecture is an adaptation to metabolon formation and propose an organization for this metabolon, suggesting that yNAGK may be a good model also for yeast and human NAGSs
Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe
Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by ana
- …