Phenotypes of non-alcoholic fatty liver disease (NAFLD) and all-cause mortality: Unsupervised machine learning analysis of NHANES III

Objectives: Non-alcoholic fatty liver disease (NAFLD) is a non-communicable disease with a rising prevalence worldwide and with large burden for patients and health systems. To date, the presence of unique phenotypes in patients with NAFLD has not been studied, and their identification could inform precision medicine and public health with pragmatic implications in personalised management and care for patients with NAFLD. Design: Cross-sectional and prospective (up to 31 December 2019) analysis of National Health and Nutrition Examination Survey III (1988–1994). Primary and secondary outcomes measures: NAFLD diagnosis was based on liver ultrasound. The following predictors informed an unsupervised machine learning algorithm (k-means): body mass index, waist circumference, systolic blood pressure (SBP), plasma glucose, total cholesterol, triglycerides, liver enzymes alanine aminotransferase, aspartate aminotransferase and gamma glutamyl transferase. We summarised (means) and compared the predictors across clusters. We used Cox proportional hazard models to quantify the all-cause mortality risk associated with each cluster. Results: 1652 patients with NAFLD (mean age 47.2 years and 51.5% women) were grouped into 3 clusters: anthro-SBP-glucose (6.36%; highest levels of anthropometrics, SBP and glucose), lipid-liver (10.35%; highest levels of lipid and liver enzymes) and average (83.29%; predictors at average levels). Compared with the average phenotype, the anthro-SBP-glucose phenotype had higher all-cause mortality risk (aHR=2.88; 95% CI: 2.26 to 3.67); the lipid-liver phenotype was not associated with higher all-cause mortality risk (aHR=1.11; 95% CI: 0.86 to 1.42). Conclusions: There is heterogeneity in patients with NAFLD, whom can be divided into three phenotypes with different mortality risk. These phenotypes could guide specific interventions and management plans, thus advancing precision medicine and public health for patients with NAFLD

Effects of peroxisome proliferator-activated receptor- activation in endothelin-dependent hypertension

Aims We analysed the chronic effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonist GW0742 on the renin-independent hypertension induced by deoxycorticosterone acetate (DOCA)-salt. Methods and results Rats were treated for 5 weeks with: control-vehicle, control-GW0742 (5 or 20 mg kg−1 day−1), DOCA-vehicle, DOCA-GW0742 (5 or 20 mg kg−1 day−1), DOCA-GSK0660 (1 mg kg−1 day−1), and DOCA-GSK0660-GW0742. Rats receiving DOCA-vehicle showed increased systolic blood pressure, left ventricular and kidney weight indices, endothelin-1 (ET-1), and malondialdehyde plasma levels, urinary iso-PGF2α excretion, impaired endothelium-dependent relaxation to acetylcholine, and contraction to ET-1 when compared with controls. Aortic reactive oxygen species content, NADPH oxidase activity, and p47phox, p22phox, NOX-4, glutathione peroxidase 1, hemeoxygenase-1, and preproET-1 expression were increased, whereas catalase and regulators of G protein-coupled signalling proteins (RGS)5 expression were decreased in the DOCA-vehicle group. GW0742 prevented the development of hypertension in a dose-dependent manner but the reduction of renal and cardiac hypertrophy, systemic and vascular oxidative stress markers, and improvement of endothelial dysfunction were only observed after the higher dose. GW0742, at 20 mg kg−1 day−1, attenuated ET-1 contraction by increasing RGS5 expression and restored the intracellular redox balance by reducing NADPH-oxidase activity, and by increasing the antioxidant genes expression. The PPAR-β antagonist GSK0660 prevented all vascular changes induced by GW0742 but not its antihypertensive effects. Conclusion Vascular protective effects of GW0742 operate via PPAR-β by interference with the ET-1 signalling as a result of increased expression of RGS5 and up-regulation of antioxidant genes and via PPAR-β-independent mechanisms to decrease blood pressure

Prevalence and associated factors to suicide attempts in low-income adolescents from the Caribbean region of Colombia

Objectives to establish the prevalence and associated factors to suicide attempts (SA) in low-income adolescents from the Caribbean region of Colombia Methods A cross sectional study was conducted. Adolescents between 10-24 years of age residents in 21 municipalities in the Caribbean region of Colombia were randomly selected from the population affiliated to a subsidized-regime insurance company between 2014-2018. A previously constructed questionnaire was used to obtain information regarding sociodemographic variables and potential risk factors. A self-reported antecedent of suicide attempt was defined as a case. Bivariate and multivariate logistic regression models were used to establish associated factors. Absolute and relative frequencies were reported. Relative frequencies were compared with the Chi2 test and continuous variables were compared with the t-test. A p value <0.050 was considered significan

Translation affects YoeB and MazF messenger RNA interferase activities by different mechanisms

Prokaryotic toxin–antitoxin loci encode mRNA cleaving enzymes that inhibit translation. Two types are known: those that cleave mRNA codons at the ribosomal A site and those that cleave any RNA site specifically. RelE of Escherichia coli cleaves mRNA at the ribosomal A site in vivo and in vitro but does not cleave pure RNA in vitro. RelE exhibits an incomplete RNase fold that may explain why RelE requires its substrate mRNA to presented by the ribosome. In contrast, RelE homologue YoeB has a complete RNase fold and cleaves RNA independently of ribosomes in vitro. Here, we show that YoeB cleavage of mRNA is strictly dependent on translation of the mRNA in vivo. Non-translated model mRNAs were not cleaved whereas the corresponding wild-type mRNAs were cleaved efficiently. Model mRNAs carrying frameshift mutations exhibited a YoeB-mediated cleavage pattern consistent with the reading frameshift thus giving strong evidence that YoeB cleavage specificity was determined by the translational reading frame. In contrast, site-specific mRNA cleavage by MazF occurred independently of translation. In one case, translation seriously influenced MazF cleavage efficiency, thus solving a previous apparent paradox. We propose that translation enhances MazF-mediated cleavage of mRNA by destabilization of the mRNA secondary structure

Effectiveness of a cardiovascular risk management program in the incidence of cardiovascular events in a low-income population from the caribbean region of Colombia

Methods This was a retrospective cohort study. Patients with 20 to 76 years affiliated to insurer company and enrolled to the DTC program were considered as the study population. The data source was an administrative database of all 128,263 patients between Jan 2015 and Dec 2018. The main outcome was the reduction in the risk of a CVE (stroke, AMI or CHF) based in the time-person exposed to the intervention. Four different time thresholds were considered for stablishing exposure status: six months, one year, two years and four years. Propensity score-weighted Cox regression models were used to evaluate the association between exposure to the program and the incidence of CVE

Infall Signatures in a Prestellar Core embedded in the High-Mass 70 μ\mum Dark IRDC G331.372-00.116

Using Galactic Plane surveys, we have selected a massive (1200 M$_\odot$), cold (14 K) 3.6-70 $\mu$m dark IRDC G331.372-00.116. This IRDC has the potential to form high-mass stars and, given the absence of current star formation signatures, it seems to represent the earliest stages of high-mass star formation. We have mapped the whole IRDC with the Atacama Large Millimeter/submillimeter Array (ALMA) at 1.1 and 1.3 mm in dust continuum and line emission. The dust continuum reveals 22 cores distributed across the IRDC. In this work, we analyze the physical properties of the most massive core, ALMA1, which has no molecular outflows detected in the CO (2-1), SiO (5-4), and H$_2$CO (3-2) lines. This core is relatively massive ($M$ = 17.6 M$_\odot$), subvirialized (virial parameter $\alpha_{vir}=M_{vir}/M=0.14$), and is barely affected by turbulence (transonic Mach number of 1.2). Using the HCO$^+$ (3-2) line, we find the first detection of infall signatures in a relatively massive, prestellar core (ALMA1) with the potential to form a high-mass star. We estimate an infall speed of 1.54 km s$^{-1}$ and a high accretion rate of 1.96 $\times$ 10$^{-3}$ M$_\odot$ yr$^{-1}$. ALMA1 is rapidly collapsing, out of virial equilibrium, more consistent with competitive accretion scenarios rather than the turbulent core accretion model. On the other hand, ALMA1 has a mass $\sim$6 times larger than the clumps Jeans mass, being in an intermediate mass regime ($M_{J}=2.7<M\lesssim$ 30 M$_\odot$), contrary to what both the competitive accretion and turbulent core accretion theories predict.Comment: 13 Pages, 5 Figures, 3 Table

Infall Signatures in a Prestellar Core embedded in the High-Mass 70 μμm Dark IRDC G331.372-00.116

Using Galactic Plane surveys, we have selected a massive (1200 M$_\odot$), cold (14 K) 3.6-70 $\mu$m dark IRDC G331.372-00.116. This IRDC has the potential to form high-mass stars and, given the absence of current star formation signatures, it seems to represent the earliest stages of high-mass star formation. We have mapped the whole IRDC with the Atacama Large Millimeter/submillimeter Array (ALMA) at 1.1 and 1.3 mm in dust continuum and line emission. The dust continuum reveals 22 cores distributed across the IRDC. In this work, we analyze the physical properties of the most massive core, ALMA1, which has no molecular outflows detected in the CO (2-1), SiO (5-4), and H$_2$CO (3-2) lines. This core is relatively massive ($M$ = 17.6 M$_\odot$), subvirialized (virial parameter $\alpha_{vir}=M_{vir}/M=0.14$), and is barely affected by turbulence (transonic Mach number of 1.2). Using the HCO$^+$ (3-2) line, we find the first detection of infall signatures in a relatively massive, prestellar core (ALMA1) with the potential to form a high-mass star. We estimate an infall speed of 1.54 km s$^{-1}$ and a high accretion rate of 1.96 $\times$ 10$^{-3}$ M$_\odot$ yr$^{-1}$. ALMA1 is rapidly collapsing, out of virial equilibrium, more consistent with competitive accretion scenarios rather than the turbulent core accretion model. On the other hand, ALMA1 has a mass $\sim$6 times larger than the clumps Jeans mass, being in an intermediate mass regime ($M_{J}=2.7<M\lesssim$ 30 M$_\odot$), contrary to what both the competitive accretion and turbulent core accretion theories predict

Peroxisome proliferator-activated receptor-β activation restores the high glucose-induced impairment of insulin signaling in endothelial cells

BACKGROUND AND PURPOSE: PPARβ enhances insulin sensitivity in adipocytes and skeletal muscle cells, but its effects on insulin signalling in endothelial cells are not known. We analysed the effects of the PPARβ/δ (PPARβ) agonists, GW0742 and L165041, on impaired insulin signalling induced by high glucose in HUVECs and aortic and mesenteric arteries from diabetic rats. EXPERIMENTAL APPROACH: Insulin-stimulated NO production, Akt-Ser(473) and eNOS-Ser(1177) phosphorylation, and reactive oxygen species (ROS) production were studied in HUVECs incubated in low- or high-glucose medium. Insulin-stimulated relaxations and protein phosphorylation in vessels from streptozotocin (STZ)-induced diabetic rats were also analysed. KEY RESULTS: HUVECs incubated in high-glucose medium showed a significant reduction in insulin-stimulated production of NO. High glucose also reduced insulin-induced Akt-Ser(473) and eNOS-Ser(1177) phosphorylation, increased IRS-1-Ser(636) and ERK1/2-Thr(183)-Tyr(185) phosphorylation and increased ROS production. The co-incubation with the PPARβ agonists GW0742 or L165041 prevented all these effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC were also incubated with the PPARβ antagonist GSK0660, the pyruvate dehydrogenase kinase (PDK)4 inhibitor dichloroacetate or after knockdown of both PPARβ and PDK4 with siRNA. The ERK1/2 inhibitor PD98059, ROS scavenger catalase, inhibitor of complex II thenoyltrifluoroacetone or uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone, also prevented glucose-induced insulin resistance. In STZ diabetic rats, oral GW0742 also improved insulin signalling and the impaired NO-mediated vascular relaxation. CONCLUSION AND IMPLICATIONS: PPARβ activation in vitro and in vivo restores the endothelial function, preserving the insulin-Akt-eNOS pathway impaired by high glucose, at least in part, through PDK4 activation

A 3D Photoionization Model of the Extreme Planetary Nebula NGC 6302

We present a 3D photoionization model of the PN NGC 6302, one of the most complex objects of its kind. Our Mocassin model is composed of an extremely dense circumstellar disk and a large pair of diffuse bipolar lobes, a combination necessary to reproduce the observed spectrum. The masses of these components gives a total nebular mass of 4.7Mo. Discrepancies between our model fit and the observations are attributed to complex density inhomogeneities in the nebula. The potential to resolve such discrepancies with more complex models is confirmed by a range of models introducing small-scale structures. Compared to solar abundances He is enhanced by 50%, C is slightly subsolar, O is solar, and N is enhanced by a factor of 6. These imply a significant 3rd dredge-up coupled with hot-bottom burning CN-cycle conversion of dredged-up C to N. The central star is partly obscured by the edge-on circumstellar disk and its properties are not well constrained. Emission from a number of high-ionization `coronal' lines provides constraints on the form of the high-energy ionizing flux. Using a solar abundance stellar atmosphere we are unable to fit all of the observed line fluxes, but a substantially better fit was obtained using a 220,000K H-deficient stellar atmosphere with L*=14,300 Lo. The H-deficient nature of the central star suggests it has undergone a late thermal pulse, and fits to evolutionary tracks imply a central star mass of 0.73-0.82Mo. Timescales for these tracks suggest the object left the top of the AGB ~2100 years ago, in agreement with studies of the recent mass-loss event that formed the bipolar lobes. Based on the modelled nebular and central star masses we estimate the initial mass of the central star to be 5.5Mo, in agreement with that derived from evolutionary tracks. (Abstract truncated)Comment: 23 pages, 8 figures, 10 tables. Accepted for publication in MNRA