Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury

Performance of lagoon and constructed wetland systems for tertiary wastewater treatment and potential of reclaimed water in agricultural irrigation

Climate change poses challenges to agricultural water resources, both in terms of quantity and quality. As an adaptation measure, the new European Regulation (EU) 2020/741 establishes different water quality classes for the use of reclaimed water in agricultural irrigation. Italy is also working on the definition of a new regulation on reclaimed water reuse for agricultural irrigation (in substitution of the current one) that will also include the specific requirements imposed by the European one. Nature-based Solutions (NBS) can be a cost-effective and environmentally friendly way to facilitate water reclamation and reuse. The present study reports the outcomes of a long-term monitoring campaign of two NBS (e.g., a constructed wetland (CW) and a lagoon system (LS)) comparing influent and effluent concentrations of different contaminants (e.g., E. coli, BOD5, TSS, TN and TP) with the threshold values imposed by the new regulations. The results showed that in both the case studies, E. coli (about 100 CFU 100 mL-1) and BOD5 (lower than 25 mg L-1) mean effluent concentration need to be further reduced in reclaimed water to be suitable for unlimited reuse. As a negative aspect, in both the monitored NBS, an increase in TSS mean concentration in the effluent was observed, up to 40 mg L-1 in the case of the LS, making reclaimed water unsuitable for agricultural reuse. The CW has proven to be more effective in nitrogen removal (the effluent mean concentration was 3.4 mg L-1), whereas the LS was better at phosphorus removal (with an effluent mean concentration of 0.4 mg L-1). Based on the results, recommendations were made to further improve the performance of both systems in order to have adequate water quality, even for class A. Furthermore, the capacity of reclaimed water to meet crop water and nutrient needs was analyzed, and total nitrogen removal rate coefficients were calculated for the design of future LSs

Superiority of the new sex-adjusted models to remove the female disadvantage restoring equity in liver transplant allocation

Background and Aims: Model for End-stage Liver Disease (MELD) and MELDNa are used worldwide to guide graft allocation in liver transplantation (LT). Evidence exists that females are penalized in the present allocation systems. Recently, new sex-adjusted scores have been proposed with improved performance respect to MELD and MELDNa. GEMA-Na, MELD 3.0, and sex-adjusted MELDNa were developed to improve the 90-day dropout prediction from the list. The present study aimed at evaluating the accuracy and calibration of these scores in an Italian setting. Methods: The primary outcome of the present study was the dropout from the list up to 90 days because of death or clinical deterioration. We retrospectively analysed data from 855 adults enlisted for liver transplantation in the Lazio region (Italy) (2012–2018). Ninety-day prediction of GEMA-Na, MELD 3.0 and sex-adjusted MELDNa with respect to MELD and MELDNa was analysed. Brier score and Brier Skill score were used for accuracy, and the Greenwood-Nam- D'Agostino test was used to evaluate the calibration of the models. Results: GEMA-Na (concordance = .82, 95% CI = .75–. 89), MELD 3.0 (concordance = .81, 95% CI = .74–. 87) and sex-adjusted MELDNa (concordance = .81, 95% CI = .74–.88) showed the best 90-day dropout prediction. GEMA-Na showed a higher increase in accuracy with respect to MELD (p = .03). No superiority was shown with respect to MELDNa. All the tested scores showed a good calibration of the models. Using GEMA-Na instead of MELD would potentially save one in nine dropouts and could save one dropout per 285 patients listed

Treatment with metformin in twelve patients with Lafora disease

Background: Lafora disease (LD) is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Studies on a mouse model of LD showed a good response to metformin, a drug with a well known neuroprotective effect. For this reason, in 2016, the European Medicines Agency granted orphan designation to metformin for the treatment of LD. However, no clinical data is available thus far. Methods: We retrospectively collected data on LD patients treated with metformin referred to three Italian epilepsy centres. Results: Twelve patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) at middle/late stages of disease were treated with add-on metformin for a mean period of 18 months (range: 6-36). Metformin was titrated to a mean maintenance dose of 1167 mg/day (range: 500-2000 mg). In four patients dosing was limited by gastrointestinal side-effects. No serious adverse events occurred. Three patients had a clinical response, which was temporary in two, characterized by a reduction of seizure frequency and global clinical improvement. Conclusions: Metformin was overall safe in our small cohort of LD patients. Even though the clinical outcome was poor, this may be related to the advanced stage of disease in our cases and we cannot exclude a role of metformin in slowing down LD progression. Therefore, on the grounds of the preclinical data, we believe that treatment with metformin may be attempted as early as possible in the course of LD

Origin of Sn(II) oxidation in tin halide perovskites

Tin-halide perovskites have great potential as photovoltaic materials, but their performance is hampered by undesirable oxidation of Sn(ii) to Sn(iv). NMR proves DMSO to be a main cause of oxidation

PI3Kδ Inhibition as a Potential Therapeutic Target in COVID-19

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The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signalling

AbstractTransplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. This study investigates the role of the adipokine leptin (LEP) in the regulation of human APC biological functions. Transcriptomic analysis of APCs showed components of the LEP signalling pathway are modulated by hypoxia. Kinetic studies indicate cultured APCs release high amounts of immunoreactive LEP following exposure to hypoxia, continuing upon return to normoxia. Secreted LEP activates an autocrine/paracrine loop through binding to the LEP receptor (LEPR) and induction of STAT3 phosphorylation. Titration studies using recombinant LEP and siRNA knockdown of LEP or LEPR demonstrate the adipokine exerts important regulatory roles in APC growth, survival, migration and promotion of endothelial network formation. Heterogeneity in LEP expression and secretion may influence the reparative proficiency of APC therapy. Accordingly, the levels of LEP secretion predict the microvascular outcome of APCs transplantation in a mouse limb ischemia model. Moreover, we found that the expression of the Lepr gene is upregulated on resident vascular cells from murine ischemic muscles, thus providing a permissive milieu to transplanted LEP-expressing APCs. Results highlight a new mechanism responsible for APC adaptation to hypoxia and instrumental to vascular repair.</jats:p

Study of the planetary boundary layer height in an urban environment using a combination of microwave radiometer and ceilometer

The Planetary Boundary Layer (PBL) is an important part of the atmosphere that is relevant in different atmospheric fields like pollutant dispersion, and weather forecasting. In this study, we analyze four and five-year datasets of measurements gathered with a ceilometer and a microwave radiometer to study the PBL structure respectively, in the mid-latitude urban area of Granada (Spain). The methodologies applied for the PBL Height (PBLH) detection (gradient method for ceilometer and the combination of parcel method and temperature gradient method for microwave radiometer) provided a description in agreement with the literature about the PBL structure under simple scenarios. Then, the PBLH behavior is characterized by a statistical study of the convective and stable situations, so that the PBLH was obtained from microwave radiometer measurements. The analysis of the PBLH statistical study shows some agreement with other PBLH studies such as daily pattern and yearly cycle, and the discrepancies were explained in terms of distinct latitudes, topography and climate conditions. Finally, it was performed a joint long-term analysis of the residual layer (RL) provided by ceilometer and the stable and convective layer heights determined by microwave radiometer, offering a complete picture of the PBL evolution by synergetic combination of remote sensing techniques. The PBL behavior has been used for explaining the daily cycle of Black Carbon (BC) concentration, used as tracer of the pollutants emissions associated to traffic.Grupo de Física de la Atmósfera (RNM119

Solid Organ Transplantation During COVID-19 Pandemic: An International Web-based Survey on Resources’ Allocation

Background. Solid organ transplants (SOTs) are life-saving interventions, recently challenged by coronavirus disease 2019 (COVID-19). SOTs require a multistep process, which can be affected by COVID-19 at several phases. Methods. SOT-specialists, COVID-19-specialists, and medical ethicists designed an international survey according to CHERRIES guidelines. Personal opinions about continuing SOTs, safe managing of donors and recipients, as well as equity of resources' allocation were investigated. The survey was sent by e-mail. Multiple approaches were used (corresponding authors from Scopus, websites of scientific societies, COVID-19 webinars). After the descriptive analysis, univariate and multivariate ordinal regression analysis was performed. Results. There were 1819 complete answers from 71 countries. The response rate was 49%. Data were stratified according to region, macrospecialty, and organ of interest. Answers were analyzed using univariate- multivariate ordinal regression analysis and thematic analysis. Overall, 20% of the responders thought SOTs should not stop (continue transplant without restriction); over 70% suggested SOTs should selectively stop, and almost 10% indicated they should completely stop. Furthermore, 82% agreed to shift resources from transplant to COVID-19 temporarily. Briefly, main reason for not stopping was that if the transplant will not proceed, the organ will be wasted. Focusing on SOT from living donors, 61% stated that activity should be restricted only to "urgent"cases. At the multivariate analysis, factors identified in favor of continuing transplant were Italy, ethicist, partially disagreeing on the equity question, a high number of COVID-19- related deaths on the day of the answer, a high IHDI country. Factors predicting to stop SOTs were Europe except-Italy, public university hospital, and strongly agreeing on the equity question. Conclusions. In conclusion, the majority of responders suggested that transplant activity should be continued through the implementation of isolation measures and the adoption of the COVID-19-free pathways. Differences between professional categories are less strong than supposed