Aims
To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non‐alcoholic fatty ...liver/non‐alcoholic steatohepatitis.
Methods
A total of 1499 participants from AWARD‐1, AWARD‐5, AWARD‐8 and AWARD‐9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non‐alcoholic fatty liver/non‐alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma‐glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c, fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non‐alcoholic fatty liver/non‐alcoholic steatohepatitis subgroup.
Results
In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels vs placebo least squares mean treatment differences: –1.7 IU/l (95% CI –2.8, –0.6), P=0.003; –1.1 IU/l (95% CI –2.1, –0.1), P=0.037; –6.6 IU/l (95% CI –12.4, –0.8), P=0.025, respectively. In the subgroup with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (–8.8 IU/l vs –6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l).
Conclusions
Once‐weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon‐like peptide‐1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.
What's new?
Non‐alcoholic fatty liver disease is present in >75% of people with Type 2 diabetes.
Dulaglutide is a once‐weekly glucagon‐like peptide‐1 receptor agonist approved for the treatment of Type 2 diabetes.
This analysis evaluated the effects of dulaglutide on liver and glycaemic/metabolic measurements in a subgroup of people with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis and Type 2 diabetes.
Treatment response of dulaglutide in the subgroup was similar to that in the overall population.
Dulaglutide improved plasma aminotransferases and gamma‐glutamyl transpeptidase in a pattern consistent with liver fat reductions.
Mechanistic models of community assembly state that biotic and abiotic filters constrain species establishment through selection on their functional traits. Predicting this assembly process is ...hampered because few studies directly incorporate environmental measurements and scale up from species to community level and because the functional traits' significance is environment dependent. We analyzed community assembly by measuring structure, environmental conditions, and species traits of secondary forests in a species-rich tropical system. We found, as hypothesized, that community structure shaped the local environment and that strong relationships existed between this environment and the traits of the most successful species of the regeneration communities. Path and multivariate analyses showed that temperature and leaf traits that regulate it were the most important factors of community differentiation. Comparisons between the trait composition of the forest's regeneration, juvenile, and adult communities showed a consistent community assembly pattern. These results allowed us to identify the major functional traits and environmental factors involved in the assembly of dry-forest communities and demonstrate that environmental filtering is a predictable and fundamental process of community assembly, even in a complex system such as a tropical forest.
We tested whether and how functional composition changes with succession in dry deciduous and wet evergreen forests of Mexico. We hypothesized that compositional changes during succession in dry ...forest were mainly determined by increasing water availability leading to community functional changes from conservative to acquisitive strategies, and in wet forest by decreasing light availability leading to changes from acquisitive to conservative strategies. Research was carried out in 15 dry secondary forest plots (5-63 years after abandonment) and 17 wet secondary forest plots (<1-25 years after abandonment). Community-level functional traits were represented by community-weighted means based on 11 functional traits measured on 132 species. Successional changes in functional composition are more marked in dry forest than in wet forest and largely characterized by different traits. During dry forest succession, conservative traits related to drought tolerance and drought avoidance decreased, as predicted. Unexpectedly acquisitive leaf traits also decreased, whereas seed size and dependence on biotic dispersal increased. In wet forest succession, functional composition changed from acquisitive to conservative leaf traits, suggesting light availability as the main driver of changes. Distinct suites of traits shape functional composition changes in dry and wet forest succession, responding to different environmental filters.
A poly(vinylpyrrolidone) end-functionalized with a carboxylic acid group (PVP–CO
2
H) was synthesized by reversible addition-fragmentation chain transfer (RAFT)/macromolecular design via the ...interchange of xanthates (MADIX) polymerization mediated by 4-(O-ethylxanthyl)methyl benzoic acid. The molecular weight of the as-synthesized PVP–CO
2
H was estimated through UV–vis spectroscopy (M
n(UV–vis)
= 7322 g/mol), gel permeation chromatography (GPC) (M
n(GPC)
= 8670 g/mol), and
1
H NMR, (M
n(NMR)
= 8207 g/mol). The values obtained were close with the theoretical molecular weight (M
n(th)
= 7925 g/mol). Subsequently, the preformed PVP–CO
2
H was activated to produce N-succinimidyl poly(vinylpyrrolidone) (PVP–NHS). This precursor was covalently coupled to papain to produce bioconjugate PVP–papain. The functional group modifications in the PVP chain-end were observed by the variations in the chemical shift values by
1
H and
13
C NMR and FTIR analysis at each step of the synthesis. The molecular weight of the PVP–papain was obtained by SEC–HPLC and suggests that, on average, four or five chains of PVP–CO
2
H were attached to one papain molecule. Compared with papain, the PVP–papain exhibited significantly improved catalytic activity, pH, and thermal stability. Additionally, the storage studies showed that the catalytic activity of PVP–papain was about 79% versus the native enzyme (29%), and this activity was maintained even when it was stored for 25 days.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cell death triggered by photodynamic therapy can occur through different mechanisms: apoptosis, necrosis or autophagy. However, recent studies have demonstrated the existence of other mechanisms with ...characteristics of both necrosis and apoptosis. These new cell death pathways, collectively termed regulated necrosis, include a variety of processes triggered by different stimuli. In this study, we evaluated the cell death mechanism induced by photodynamic treatments with two photosensitizers, meso-tetrakis (4-carboxyphenyl) porphyrin sodium salt (Na-H
TCPP) and its zinc derivative Na-ZnTCPP, in two human breast epithelial cell lines, a non-tumoral (MCF-10A) and a tumoral one (SKBR-3). Viability assays showed that photodynamic treatments with both photosensitizers induced a reduction in cell viability in a concentration-dependent manner and no dark toxicity was observed. The cell death mechanisms triggered were evaluated by several assays and cell line-dependent results were found. Most SKBR-3 cells died by either necrosis or apoptosis. By contrast, in MCF-10A cells, necrotic cells and another cell population with characteristics of both necrosis and apoptosis were predominant. In this latter population, cell death was PARP-dependent and translocation of AIF to the nucleus was observed in some cells. These characteristics are related with parthanatos, being the first evidence of this type of regulated necrosis in the field of photodynamic therapy.
We present the dust module in the Multiscale Online Non-hydrostatic AtmospheRe CHemistry model (MONARCH) version 2.0, a chemical weather prediction system that can be used for regional and global ...modeling at a range of resolutions. The representations of dust processes in MONARCH were upgraded with a focus on dust emission (emission parameterizations, entrainment thresholds, considerations of soil moisture and surface cover), lower boundary conditions (roughness, potential dust sources), and dust–radiation interactions. MONARCH now allows modeling of global and regional mineral dust cycles using fundamentally different paradigms, ranging from strongly simplified to physics-based parameterizations. We present a detailed description of these updates along with four global benchmark simulations, which use conceptually different dust emission parameterizations, and we evaluate the simulations against observations of dust optical depth. We determine key dust parameters, such as global annual emission/deposition flux, dust loading, dust optical depth, mass-extinction efficiency, single-scattering albedo, and direct radiative effects. For dust-particle diameters up to 20 µm, the total annual dust emission and deposition fluxes obtained with our four experiments range between about 3500 and 6000 Tg, which largely depend upon differences in the emitted size distribution. Considering ellipsoidal particle shapes and dust refractive indices that account for size-resolved mineralogy, we estimate the global total (longwave and shortwave) dust direct radiative effect (DRE) at the surface to range between about −0.90 and −0.63 W m−2 and at the top of the atmosphere between −0.20 and −0.28 W m−2. Our evaluation demonstrates that MONARCH is able to reproduce key features of the spatiotemporal variability of the global dust cycle with important and insightful differences between the different configurations.
Understanding the distribution of biodiversity across the Earth is one of the most challenging questions in biology. Much research has been directed at explaining the species latitudinal pattern ...showing that communities are richer in tropical areas; however, despite decades of research, a general consensus has not yet emerged. In addition, global biodiversity patterns are being rapidly altered by human activities. Here, we aim to describe large‐scale patterns of species richness and diversity in terrestrial vertebrate scavenger (carrion‐consuming) assemblages, which provide key ecosystem functions and services. We used a worldwide dataset comprising 43 sites, where vertebrate scavenger assemblages were identified using 2,485 carcasses monitored between 1991 and 2018. First, we evaluated how scavenger richness (number of species) and diversity (Shannon diversity index) varied among seasons (cold vs. warm, wet vs. dry). Then, we studied the potential effects of human impact and a set of macroecological variables related to climatic conditions on the scavenger assemblages. Vertebrate scavenger richness ranged from species‐poor to species rich assemblages (4–30 species). Both scavenger richness and diversity also showed some seasonal variation. However, in general, climatic variables did not drive latitudinal patterns, as scavenger richness and diversity were not affected by temperature or rainfall. Rainfall seasonality slightly increased the number of species in the community, but its effect was weak. Instead, the human impact index included in our study was the main predictor of scavenger richness. Scavenger assemblages in highly human‐impacted areas sustained the smallest number of scavenger species, suggesting human activity may be overriding other macroecological processes in shaping scavenger communities. Our results highlight the effect of human impact at a global scale. As species‐rich assemblages tend to be more functional, we warn about possible reductions in ecosystem functions and the services provided by scavengers in human‐dominated landscapes in the Anthropocene.
Vertebrate scavenger (carrion‐consuming) species provide key ecosystem functions and services, but little is known about their large‐scale patterns of species richness and diversity. We found that scavenger assemblages in highly human‐impacted areas sustained the smallest number of scavenger species, suggesting human activity may be overriding other macroecological processes in shaping scavenger communities. As species‐rich assemblages tend to be more functional, we warn about possible reductions in ecosystem functions and the services provided by scavengers in human‐dominated landscapes in the Anthropocene.
ABSTRACT The Apache Point Observatory Galactic Evolution Experiment (APOGEE), part of the Sloan Digital Sky Survey III, explores the stellar populations of the Milky Way using the Sloan 2.5-m ...telescope linked to a high resolution (R ∼ 22,500), near-infrared (1.51-1.70 m) spectrograph with 300 optical fibers. For over 150,000 predominantly red giant branch stars that APOGEE targeted across the Galactic bulge, disks and halo, the collected high signal-to-noise ratio (>100 per half-resolution element) spectra provide accurate (∼0.1 km s−1) RVs, stellar atmospheric parameters, and precise ( 0.1 dex) chemical abundances for about 15 chemical species. Here we describe the basic APOGEE data reduction software that reduces multiple 3D raw data cubes into calibrated, well-sampled, combined 1D spectra, as implemented for the SDSS-III/APOGEE data releases (DR10, DR11 and DR12). The processing of the near-IR spectral data of APOGEE presents some challenges for reduction, including automated sky subtraction and telluric correction over a 3°-diameter field and the combination of spectrally dithered spectra. We also discuss areas for future improvement.
We exploit the deep and extended far-IR data sets (at 70, 100 and 160 μm) of the Herschel Guaranteed Time Observation (GTO) PACS Evolutionary Probe (PEP) Survey, in combination with the Herschel ...Multi-tiered Extragalactic Survey data at 250, 350 and 500 μm, to derive the evolution of the rest-frame 35-, 60-, 90- and total infrared (IR) luminosity functions (LFs) up to z ∼ 4. We detect very strong luminosity evolution for the total IR LF (L
IR ∝ (1 + z)3.55 ± 0.10 up to z ∼ 2, and ∝ (1 + z)1.62 ± 0.51 at 2 < z 4) combined with a density evolution (∝(1 + z)−0.57 ± 0.22 up to z ∼ 1 and ∝ (1 + z)−3.92 ± 0.34 at 1 < z 4). In agreement with previous findings, the IR luminosity density (ρIR) increases steeply to z ∼ 1, then flattens between z ∼ 1 and z ∼ 3 to decrease at z 3. Galaxies with different spectral energy distributions, masses and specific star formation rates (SFRs) evolve in very different ways and this large and deep statistical sample is the first one allowing us to separately study the different evolutionary behaviours of the individual IR populations contributing to ρIR. Galaxies occupying the well-established SFR-stellar mass main sequence (MS) are found to dominate both the total IR LF and ρIR at all redshifts, with the contribution from off-MS sources (≥0.6 dex above MS) being nearly constant (∼20 per cent of the total ρIR) and showing no significant signs of increase with increasing z over the whole 0.8 < z < 2.2 range. Sources with mass in the range 10 ≤ log(M/M) ≤ 11 are found to dominate the total IR LF, with more massive galaxies prevailing at the bright end of the high-z ( 2) LF. A two-fold evolutionary scheme for IR galaxies is envisaged: on the one hand, a starburst-dominated phase in which the Super Massive Black Holes (SMBH) grows and is obscured by dust (possibly triggered by a major merging event), is followed by an AGN-dominated phase, then evolving towards a local elliptical. On the other hand, moderately star-forming galaxies containing a low-luminosity AGN have various properties suggesting they are good candidates for systems in a transition phase preceding the formation of steady spiral galaxies.
Nanostructured BiVO4 photocatalysts were synthesized by a coprecipitation process in the presence of sodium carboxymethylcellulose (CMC), which acts as a steric stabilizer during the formation and ...growth of the BiVO4 nanoparticles. Samples with different contents of CMC were prepared in order to study the effect of the polymer on the final morphology of the oxide. The synthesized samples were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), diffuse reflectance spectroscopy (DRS), and adsorption-desorption isotherms (BET). The presence of CMC during the first stage of BiVO4 synthesis, promoted the formation of granular particles controlling its morphology and favoring its dispersion. The BiVO4 monoclinic polymorph (m-BiVO4) was obtained free of the tetragonal crystalline form (t-BiVO4) by annealing at different temperatures, which were influenced by CMC content: 400 °C (0.5 wt %), 450 °C (3.0 wt %), and 350 °C (6.0 and 9.0 wt %). BiVO4 nanoparticles showed photocatalytic activity, as they bleached an aqueous solution of rhodamine B (rhB) under visible-light irradiation. The photocatalytic activity of the BiVO4 samples was directly correlated with the amount of CMC added during the synthesis process.
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