Multi-year N and P removal of a 10-year-old surface flow constructed wetland treating agricultural drainage waters

Surface flow constructed wetlands (SFCWs) can be e\u21b5ectively used to treat agricultural drainage waters, reducing N and P surface water pollution. In the Venice Lagoon drainage basin (northeastern Italy), an SFCW was monitored during 2007\u20132013 to assess its performance in reducing water, N, and P loads more than 10 years after its creation. Nitrogen concentrations showed peaks during winter due to intense leaching from surrounding fields. Phosphorus concentrations were higher after prolonged periods with no discharge, likely due to mobilization of P of the decomposing litter inside the basin. Over the entire period, N removal eciency was 83% for NO3\u2013N and 79% for total N; P removal eciency was 48% for PO4\u2013P and 67% for total P. Values were higher than in several other studies, likely due to the fluctuating hydroperiod that produced discontinuous and reduced outflows. Nitrogen outlet concentrations were reduced by the SFCW, and N removal ratios decreased with increasing hydraulic loading, while no strong correlations were found in the case of P. The SFCW was shown to be an e\u21b5ective long-term strategy to increase water storage and reduce N and P loads in the Venice Lagoon drainage basin

Modeling rainfall-driven transport of Glyphosate in the vadose zone of two experimental sites in North-East Italy

A vertical one-dimensional analysis of infiltration processes and mobility of a tracer (potassium bromide) and a glyphosate-based herbicide, both subjected to hydrological forcing, was performed. Glyphosate is a widespread herbicide whose potential harmfulness and mobility under hydrological forcing have not been fully understood yet. Here, the spatio-temporal evolution of the two compounds was monitored for one year in two experimental sites (Settolo - Valdobbiadene, Colnù - Conegliano), located within the production area of the Prosecco wine (Treviso, Italy). In each experimental site the activities were carried out on two 25 m2 plots located at distances of 50-100 m from each other. The interpretative analyses considered rainwater infiltration as the driving mechanism of the herbicide transport and allowed us to obtain the calibration of a one-dimensional hydrologic model in each monitored plot. Different scenarios of the tracer evolution were simulated considering the pedologic properties of the shallower soil layers, the status of the plant coverage and of the root apparati, leading to a satisfactory reproduction of the observations in both the experimental sites. Modeling the mobility of the herbicide, considering also the degradation to its metabolite AMPA, proved to be more challenging, due to the tendency of glyphosate to be adsorbed to the soil matrix rather than be dissolved in water and transported toward deeper soil layers. Nevertheless, the analysis of model results for tracer and herbicide, compared with in situ observations, suggests that the transport of the glyphosate can take place even when it is adsorbed to the soil, through the movement, triggered by intense precipitation events, of microscopic soil particles within preferential flow paths

Mutant p53 improves cancer cells\u2019 resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6

Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress

Start of SPIDER operation towards ITER neutral beams

Heating Neutral Beam (HNB) Injectors will constitute the main plasma heating and current drive tool both in ITER and JT60-SA, which are the next major experimental steps for demonstrating nuclear fusion as viable energy source. In ITER, in order to achieve the required thermonuclear fusion power gain Q=10 for short pulse operation and Q=5 for long pulse operation (up to 3600s), two HNB injectors will be needed [1], each delivering a total power of about 16.5 MW into the magnetically-confined plasma, by means of neutral hydrogen or deuterium particles having a specific energy of about 1 MeV. Since only negatively charged particles can be efficiently neutralized at such energy, the ITER HNB injectors [2] will be based on negative ions, generated by caesium-catalysed surface conversion of atoms in a radio-frequency driven plasma source. A negative deuterium ion current of more than 40 A will be extracted, accelerated and focused in a multi-aperture, multi-stage electrostatic accelerator, having 1280 apertures (~ 14 mm diam.) and 5 acceleration stages (~200 kV each) [3]. After passing through a narrow gas-cell neutralizer, the residual ions will be deflected and discarded, whereas the neutralized particles will continue their trajectory through a duct into the tokamak vessels to deliver the required heating power to the ITER plasma for a pulse duration of about 3600 s. Although the operating principles and the implementation of the most critical parts of the injector have been tested in different experiments, the ITER NBI requirements have never been simultaneously attained. In order to reduce the risks and to optimize the design and operating procedures of the HNB for ITER, a dedicated Neutral Beam Test Facility (NBTF) [4] has been promoted by the ITER Organization with the contribution of the European Union\u2019s Joint Undertaking for ITER and of the Italian Government, with the participation of the Japanese and Indian Domestic Agencies (JADA and INDA) and of several European laboratories, such as IPP-Garching, KIT-Karlsruhe, CCFE-Culham, CEA-Cadarache. The NBTF, nicknamed PRIMA, has been set up at Consorzio RFX in Padova, Italy [5]. The planned experiments will verify continuous HNB operation for one hour, under stringent requirements for beam divergence (< 7 mrad) and aiming (within 2 mrad). To study and optimise HNB performances, the NBTF includes two experiments: MITICA, full-scale NBI prototype with 1 MeV particle energy and SPIDER, with 100 keV particle energy and 40 A current, aiming at testing and optimizing the full-scale ion source. SPIDER will focus on source uniformity, negative ion current density and beam optics. In June 2018 the experimental operation of SPIDER has started

Real-world data on treatment outcomes in EGFR-mutant non-small-cell lung cancer patients receiving osimertinib in second or further lines

Aims: This study describes real-world outcomes of pretreated EGFR T790M-positive (T790M+) advanced non-small-cell lung cancer patients progressing after first- or second-generation tyrosine kinase inhibitors and receiving osimertinib, compared with T790M-negative (T790M-) patients. We have also described progression patterns and treatment sequences. Patients & methods: This is a retrospective multicenter Italian observational study including consecutive Caucasian patients referred between 2014 and 2018. Results: 167 patients were included. Median progression-free survival was 9.8 months (95% CI: 8.3-13.3) for T790M+ and 6.0 months (95% CI: 4.9-7.2) for T790M- patients, respectively. Median overall survival was 20.7 months (95% CI: 18.9-28.4) for T790M+ and 10.6 months (95% CI: 8.6-23.6) for T790M- patients, respectively. The T790M mutation correlated with absence of new sites of disease. After progression, most T790M+ patients continued osimertinib, whereas most T790M- patients received a different treatment line. Conclusion: Better outcomes were shown in patients receiving osimertinib. A more limited progression pattern for T790M+ was suggested

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS &lt; 12 months) and 12 patients had long survival (OS &gt; 36 months). Three prognostic miRNAs (mir- 99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18-8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM

Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy

Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level

The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy

Mutations in LMNA, which encodes the nuclear proteins Lamin A/C, can cause cardiomyopathy and conduction disorders. Here, we employ induced pluripotent stem cells (iPSCs) generated from human cells carrying heterozygous K219T mutation on LMNA to develop a disease model. Cardiomyocytes differentiated from these iPSCs, and which thus carry K219T-LMNA, have altered action potential, reduced peak sodium current and diminished conduction velocity. Moreover, they have significantly downregulated Nav1.5 channel expression and increased binding of Lamin A/C to the promoter of SCN5A, the channel’s gene. Coherently, binding of the Polycomb Repressive Complex 2 (PRC2) protein SUZ12 and deposition of the repressive histone mark H3K27me3 are increased at SCN5A. CRISPR/Cas9-mediated correction of the mutation re-establishes sodium current density and SCN5A expression. Thus, K219T-LMNA cooperates with PRC2 in downregulating SCN5A, leading to decreased sodium current density and slower conduction velocity. This mechanism may underlie the conduction abnormalities associated with LMNA-cardiomyopathy

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene

BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes