Glutathione limits Ero1-dependent oxidation in the endoplasmic reticulum

Many proteins of the secretory pathway contain disulfide bonds that are essential for structure and function. In the endoplasmic reticulum (ER), Ero1alpha and Ero1beta oxidize protein disulfide isomerase (PDI), which in turn transfers oxidative equivalents to newly synthesized cargo proteins. However, oxidation must be limited, as some reduced PDI is necessary for disulfide isomerization and ER-associated degradation. Here we show that in semipermeable cells, PDI is more oxidized, disulfide bonds are formed faster, and high molecular mass covalent protein aggregates accumulate in the absence of cytosol. Addition of reduced glutathione (GSH) reduces PDI and restores normal disulfide formation rates. A higher GSH concentration is needed to balance oxidative folding in semipermeable cells overexpressing Ero1alpha, indicating that cytosolic GSH and lumenal Ero1alpha play antagonistic roles in controlling the ER redox. Moreover, the overexpression of Ero1alpha significantly increases the GSH content in HeLa cells. Our data demonstrate tight connections between ER and cytosol to guarantee redox exchange across compartments: a reducing cytosol is important to ensure disulfide isomerization in secretory proteins

The impact of COVID-19 on radiological findings in patients accessing the emergency department: a multicentric study

The aim of this multicentric study is to illustrate how the COVID-19 pandemic lockdown affected the workload and outcomes of radiological examinations in emergency radiology

Seasonal trends and spatial variations of PM10-bounded polycyclic aromatic hydrocarbons in Veneto Region, Northeast Italy

The Veneto Region extends for ~18.4·103km2 in the northeastern part of the Po Valley and includes mountains, hills, plain and coastal environments with very different and discontinuous anthropogenic pressures. Although many efforts have been made to mitigate air pollution, the European air quality standards for atmospheric pollutants are frequently breached. This study investigates the levels of eight PM10-bound PAHs collected in 21 stations categorized as rural background, urban and suburban backgrounds, traffic and industrial hot-spots during one year (2011). Data were statistically processed to detect the PAH seasonal trends, their relationship with other air pollutants and micro-meteorological parameters and the space variations at a regional scale. Results show that PAHs levels are relatively high in the largest part of the region, with 10 sites exceeding the levels of BaP targeted by the European legislation. Two sites exhibited anomalously high PAHs concentrations and this anomaly became even more evident when considering the population density as a surrogate for the potential anthropogenic pressure. The PAHs levels were found directly proportional to other gaseous pollutants (CO, NO, NOx, SO2) suggesting common polluting sources. The analysis of time trends of PAH concentrations reveals significant coincidences throughout the region, i.e. simultaneous changes are observed in most sites as a consequence of similar emission sources and accumulation/removal processes. In this scenario, the control strategies currently imposed at local level (e.g. traffic limitations) have proven scarcely effective in mitigating air pollution and a real coordination at regional or even interregional level cannot be further postponed. Peculiar features of the PAHs pollution in the Veneto were also identified and some measures for protecting the human health were suggested

Estudos ambientais e paleogeografia da plataforma interna de Tramandaí-RS, com caracterização geomorfológica e sedimentar através de sonar de varredura lateral e sísmica de alta resolução

Levantamentos de ecobatimetria de detalhe, juntamente com a obtenção de registros de sonar de varredura lateral (side scan sonar) e sísmica de alta resolução a partir de Sparker, bem como operação de coleta de amostras e testemunhos sedimentares foram efetuados na Plataforma Continental Interna do Rio Grande do Sul, região de Tramandaí-RS, como parte integrante das pesquisas concernentes ao Convênio PETROBRÁS/FURG/UFRGS/UFSC/UFPR, projeto "Estudos Ambientais em Áreas Oceânicas e Costeiras no Sul do País", subprojeto "Caracterização Preliminar Sedimentar e Geomorfológica da Região de Tramandaí, RS", bem como a definição dos parâmetros ambientais na área de influência das atividades da PETROBRÁS junto à monobóia de Tramandaí. 

Human coronary inflammation by computed tomography: Relationship with coronary microvascular dysfunction

Background A new imaging metric using coronary computed tomography angiography (CCTA), addressing the peri-coronary adipose tissue (PCAT) computed tomography (CT) attenuation, has been clinically validated. This method provides information regarding coronary inflammation. It is unclear how coronary inflammation affects microvascular function. The non-invasive evaluation of coronary flow velocity reserve is widely used in clinical practice using Doppler measurement on the left anterior descending coronary artery (CFVR-lad) during stress-echocardiography (SE). We hypothesize that coronary inflammation affects CFVR-lad and, in the absence of overt CAD, they are significantly correlated. Methods We evaluated the relationship between coronary inflammation (by PCAT CT attenuation) and coronary microvascular function (by CFVR-lad) in subjects with no or non-obstructive (diameter stenosis <70%) coronary artery disease (CAD). Results Two-hundred and two subjects were enrolled in the study. The relationship between PCAT CT attenuation and CFVR-lad show a significant inverse relationship in the entire group of subjects enrolled in the study (r = −0.32, p < 0.001). Correlation between PCAT CT attenuation and CFVR-lad was significant in subjects with no or mild CAD-lad, while this was not the case in subjects with intermediate CAD-lad. The R and R2 were respectively −0.40, −0.16 in subjects without CAD (p < 0.001) and − 0.35 and − 0.12 in subjects with mild CAD-lad (p = 0.001). Conclusions The main finding of the current study is the independent relationship between coronary microvascular function, by Doppler CFVR-lad during SE, in subjects without severely obstructive CAD in the left anterior descending coronary artery, and the level of local coronary inflammation, by PCAT attenuation measurement on CCTA

Relatively oxidized conditions for diamond formation at Udachnaya (Siberia)

Thanks to the physical strength of diamonds and their relatively unreactive chemical nature, their mineral inclusions may remain exceptionally preserved from alteration processes and chemical exchanges with surrounding minerals, fluids and/or melts following diamond formation. Cr-bearing spinels are relatively common inclusions found in peridotitic diamonds and important oxybarometers providing information about the oxygen fugacity (fO2) of their source mantle rocks. Here, we investigated a magnesiochromite-olivine touching pair in a diamond from the Udachnaya kimberlite (Siberia) by in situ single-crystal X-ray diffraction and energy-domain synchrotron Mossbauer spectroscopy, aiming to constrain the physical-chemical conditions of diamond formation and to explore the redox state of this portion of the Siberian craton when the diamond was formed. The P-T-fO(2) entrapment conditions of the inclusion pair, determined by thermo- and oxybarometric analyses, are similar to 5.7(0.4) GPa and similar to 1015(50) ? (although entrapment at higher T and re-equilibration during subsequent mantle storage are also possible) and fO(2) near the enstatite-magnesite-olivine-diamond (EMOD) buffer. The determined fO(2) is similar to, or slightly more oxidized than, those of xenoliths from Udachnaya, but whilst the xenoliths last equilibrated with the surrounding mantle just prior to their entrainment in the kimberlite at similar to 360 Ma, the last equilibration of the inclusion pair is much older, occurring at 3.5-3.1, similar to 2 or similar to 1.8 Ga before final encapsulation in its host diamond. Hence, the similarity between xenoliths and inclusion fO(2) values indicates that the modern redox state of this portion of the Siberian lithosphere was likely attained relatively early after its formation and may have persisted for billions of years after diamond formation, at least at the local scale. Moreover, the oxygen fugacity determination for the inclusion pair provides direct evidence of diamond formation near the EMOD buffer and is consistent with recent models suggesting relatively oxidized, water-rich CHO fluids as the most likely parents for lithospheric diamonds

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10(−5) to 10(−3). Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD