MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways in type 2 diabetes (T2D). Currently, little is known about how miRNAs ...influence disease pathogenesis by targeting cells at a distance. The purpose of this study was to investigate the role of exosomal miRNAs during T2D.
We show that miR-15a is increased in the plasma of diabetic patients, correlating with disease severity. miR-15 plays an important role in insulin production in pancreatic β-cells. By culturing rat pancreatic β-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic β-cells. We postulate that miR-15a, produced in pancreatic β-cells, can enter the bloodstream and contribute to retinal injury. miR-15a overexpression in Müller cells can be induced by exposing Müller cells to exosomes derived from INS-1 cells under high-glucose conditions and results in oxidative stress by targeting Akt3, which leads to apoptotic cell death. The in vivo relevance of these findings is supported by results from high-fat diet and pancreatic β-cell-specific miR-15a
mice.
This study highlights an important and underappreciated mechanism of remote cell-cell communication (exosomal transfer of miRNA) and its influence on the development of T2D complications.
Our findings suggest that circulating miR-15a contributes to the pathogenesis of diabetes and supports the concept that miRNAs released by one cell type can travel through the circulation and play a role in disease progression via their transfer to different cell types, inducing oxidative stress and cell injury. Antioxid. Redox Signal. 27, 913-930.
Introduction
Dolutegravir (DTG), Elvitegravir (EVG), Raltegravir (RAL) and Darunavir (DRV) are commonly prescribed core agents for antiretroviral therapy (ART), and a need exists to compare their ...clinical effectiveness, as defined by virologic failure risks in real-world settings.
Methods
This observational analysis of a US clinical cohort consisted of ART-naïve people living with HIV (PLWH) in the OPERA database initiating DTG-, EVG-, RAL- or DRV-based regimens between August 2013 and July 2016, with follow-up to July 2017. PLWH were observed from first core agent initiation until core agent discontinuation, clinical activity cessation, death, or study end. Key outcomes included viral suppression (HIV RNA < 50 copies/mL) and confirmed virologic failure (two consecutive viral loads > 200 copies/mL or a viral load > 200 copies/mL followed by discontinuation). Association between core agent and time to virologic failure was assessed with multivariate Cox proportional hazards models.
Results
Overall, 4049 ART-naïve PLWH initiated EVG (47.4%), DTG (34.7%), DRV (14.6%), or RAL (3.2%). DTG and EVG initiators had generally similar baseline demographics and clinical characteristics, including race, risk of infection, baseline viral load, and baseline CD4 levels. RAL and DRV initiators were older and generally sicker than DTG initiators. During follow-up, more DTG initiators achieved virologic suppression (78.7%) compared with EVG (73.6%;
p
< 0.05), RAL (51.9%;
p
< 0.0001) and DRV (48.6%;
p
< 0.0001) initiators. Compared to DTG, both RAL and DRV were associated with higher rates of virologic failure, with adjusted hazard ratios (95% confidence interval) of 4.70 (3.03, 7.30) and 2.38 (1.72, 3.29), respectively. No difference was observed between EVG and DTG with an adjusted hazard ratio of 1.24 (0.94, 1.64).
Conclusion
In this large cohort representative of PLWH in care in the US, ART-naïve PLWH prescribed DTG had better virologic outcomes than RAL and DRV, but had virologic failure risks comparable to EVG, although RAL and DRV were preferentially prescribed to sicker individuals.
Funding
ViiV Healthcare.
Abstract
Background
People living with human immunodeficiency virus (PLWH) initiating antiretroviral therapy (ART) with viral loads (VLs) ≥100 000 copies/mL are less likely to achieve virologic ...success, but few studies have characterized real-world treatment outcomes.
Methods
ART-naive PLWH with VLs ≥100 000 copies/mL initiating dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV) between 12 August 2013 and 31 July 2017 were identified from the OPERA database. Virologic failure was defined as (i) 2 consecutive VLs ≥200 copies/mL after 36 weeks of ART; (ii) 1 VL ≥200 copies/mL with core agent discontinuation after 36 weeks; (iii) 2 consecutive VLs ≥200 copies/mL after suppression (≤50 copies/mL) before 36 weeks; or (iv) 1 VL ≥200 copies/mL with discontinuation after suppression before 36 weeks. Cox modeling estimated the association between regimen and virologic failure.
Results
There were 2038 ART-naive patients with high VL who initiated DTG (36%), EVG (46%), DRV (16%), or RAL (2%). Median follow-up was 18.1 (interquartile range, 12.4–28.9) months. EVG and DTG initiators were similar at baseline, but RAL initiators were older and more likely to be female with low CD4 cell counts while DRV initiators differed notably on factors associated with treatment failure. Virologic failure was experienced by 9.2% DTG, 13.2% EVG, 18.4% RAL, and 18.8% DRV initiators. Compared to DTG, the adjusted hazard ratio (95% confidence interval) was 1.46 (1.05–2.03) for EVG, 2.24 (1.50–3.34) for DRV, and 4.13 (1.85–9.24) for RAL.
Conclusions
ART-naive PLWH with high VLs initiating on DTG were significantly less likely to experience virologic failure compared to EVG, RAL, and DRV initiators.
Antiretroviral therapy-naïve people living with HIV (PLWH) initiating therapy with viral loads ≥100,000 copies/mL varied markedly at baseline. In adjusted models, PLWH initiating dolutegravir-based regimens were less likely to experience virologic failure as compared to elvitegravir, raltegravir and darunavir initiators.
Baseline characteristics of antiretroviral therapy–naive people living with HIV (PLWH) initiating 4 commonly prescribed core agents with high viral load varied markedly. In adjusted models, PLWH initiating dolutegravir-based regimens were significantly less likely to experience virologic failure as compared to elvitegravir, raltegravir, and darunavir initiators.
Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.9% of ...PLGAs but not in other salivary gland tumors. Functional studies demonstrated that this kinase-activating alteration likely constitutes a driver of PLGA.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We analyse the fundamental limitations for the detection of extraterrestrial planets with Extremely Large Telescopes. For this task, a coronagraphic device combined with a very high order wavefront ...correction system is required but is not sufficient to achieve the 10-10 contrast level needed to detect an Earth-like planet. The stellar residuals left uncorrected by the wavefront correction system need to be calibrated and subtracted. We consider a general model including the dynamic phase aberrations downstream of the wavefront correction system, the static phase aberrations of the instrument and some differential aberrations provided by the calibration unit. A rather optimistic case of a filled circular pupil and of a perfect coronagraph is assumed. As a result of the analytical study, the limitation is found to mostly come from the static aberrations. We confirm this result using numerical simulations and evaluate the requirements in terms of phase aberrations to detect Earth-like planets with Extremely Large Telescopes.
Aims. We compare coronagraph concepts and investigate their behavior and suitability for planet-finder projects with Extremely Large Telescopes (ELTs, 30-42 meter class telescopes). Methods. For this ...task, we analyzed the impact of major error sources that occur in a coronagraphic telescope (central obscuration, secondary support, low-order segment aberrations, segment reflectivity variations, pointing errors) for phase, amplitude, and interferometric type coronagraphs. This analysis was performed at two different levels of the detection process: under residual phase left uncorrected by an eXtreme Adaptive Optics system (XAO) for a wide range of Strehl ratios and after a general and simple model of speckle calibration, assuming common phase aberrations between the XAO and the coronagraph (static phase aberrations of the instrument) and non-common phase aberrations downstream of the coronagraph (differential aberrations provided by the calibration unit). Results. We derive critical parameters cope by each concept in order of importance. We show three coronagraph categories as function of the accessible angular separation and proposed optimal one in each case. Most of the time amplitude concepts appear more favorable, and the Apodized Pupil Lyot Coronagraph specifically gathers the adequate characteristics to be a baseline design for ELTs.
This open access book presents work collected through the Liquefaction Experiments and Analysis Projects (LEAP) in 2019 (LEAP-ASIA-2019) following the LEAP-UCD-2017 whose results have been published ...as a first volume. In addition to the research targets set in the previous one, such as the repeatability, variability, and sensitivity of lateral spreading on mildly sloping liquefiable sand, this volume includes research efforts to validate the generalized scaling law (hereafter “GSL”) for the identical prototype with the one employed in UCD-2017. In LEAP-ASIA-2019, 10 institutes around the world conducted 23 tests in total. It was the first multi-institutional attempts to investigate the validity of the generalized scaling law for the saturated sandy sloping deposit with wide range of initial conditions. The experimental data provided a unique basis for assessing the capabilities of six different simulation platforms for numerical simulation of soil liquefaction. The results of the experiments and the numerical simulations are presented and discussed in papers submitted by the project participants.
A Planet Finder instrument for the VLT Beuzit, J.-L.; Feldt, M.; Mouillet, D. ...
Proceedings of the International Astronomical Union,
10/2005, Letnik:
1, Številka:
C200
Journal Article
Recenzirano
Odprti dostop
Direct detection and spectral characterization of extrasolar planets is one of the most exciting but also one of the most challenging area in modern astronomy. For its second generation ...instrumentation on the VLT, ESO has supported two phase A studies for a so-called “Planet Finder” dedicated instrument. Based on the results of these two studies, a unique instrument is now considered for first light in early 2010, including a powerful extreme adaptive optics system, various coronagraphs, an infrared differential imaging camera, an infrared integral field spectrograph and a visible differential polarimeter. We will briefly summarize the science objectives and requirements, describe the proposed conceptual design and discuss the main limitations and corresponding instrumental issues of such a system. We will also derive the expected performance of the proposed Planet Finder and present the project organization.
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