Tailoring negative pressure by crystal defects: Crack induced hydride formation in Al alloys

Climate change motivates the search for non-carbon-emitting energy generation and storage solutions. Metal hydrides show promising characteristics for this purpose. They can be further stabilized by tailoring the negative pressure of microstructural and structural defects. Using systematic ab initio and atomistic simulations, we demonstrate that an enhancement in the formation of hydrides at the negatively pressurized crack tip region is feasible by increasing the mechanical tensile load on the specimen. The theoretical predictions have been used to reassess and interpret atom probe tomography experiments for a high-strength 7XXX-aluminium alloy that show a substantial enhancement of hydrogen concentration at structural defects near a stress-corrosion crack tip. These results contain important implications for enhancing the capability of metals as H-storage materials.Comment: 22 pages, 9 figure

Radon measurement in karstic waters with Lucas cell technique

Based on Lucas cell technique, the portable device named “PRASSI” (SILENA mod. 5S) was used to realise discrete radon measurements in water samples. The calibration factor is (64.766.9) cpmQBq21 and, with the present set-up for measuring radon in water, the detection and the determination limits are, respectively, 0.007 and 0.020 Bq. Thus, the device is well adapted for determining low radon content in karstic waters. Several discrete radon samplings were performed nearly every week in the three main springs of the Bastareny karstic system (Catalonian Pyrenees, N-E Spain). Thus, it was possible to estimate the reproducibility of the methodology as well as to characterise every spring of the aquifer in relation to their hydrogeological features. With the portable radon monitor, some useful measurements were achieved to estimate radon loss due to degassing process over short distances, with important consequences for radon studies in karstic waters. Lastly, it was possible to perform intensive sampling during a flood and the results point out the great variability of radon levels, closely related to the flow rate trend. That permitted also an intercomparison with other radon probes installed previously in every spring, for continuous radon measurements

Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion

BACKGROUND: The conversion of the cellular prion protein (PrP(C)) into the infectious form (PrP(Sc)) is the key event in prion induced neurodegenerations. This process is believed to involve a multi-step conformational transition from an alpha-helical (PrP(C)) form to a beta-sheet-rich (PrP(Sc)) state. In addition to the conformational difference, PrP(Sc) exhibits as covalent signature the sulfoxidation of M213. To investigate whether such modification may play a role in the misfolding process we have studied the impact of methionine oxidation on the dynamics and energetics of the HuPrP(125-229) alpha-fold. METHODOLOGY/PRINCIPAL FINDINGS: Using molecular dynamics simulation, essential dynamics, correlated motions and signal propagation analysis, we have found that substitution of the sulfur atom of M213 by a sulfoxide group impacts on the stability of the native state increasing the flexibility of regions preceding the site of the modification and perturbing the network of stabilizing interactions. Together, these changes favor the population of alternative states which maybe essential in the productive pathway of the pathogenic conversion. These changes are also observed when the sulfoxidation is placed at M206 and at both, M206 and M213. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggering the initial alpha-fold destabilization required for the productive pathogenic conversion

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors

Revisiting stress-corrosion cracking and hydrogen embrittlement in 7xxx-Al alloys at the near-atomic-scale

The high-strength 7xxx series aluminium alloys can fulfil the need for light, high strength materials necessary to reduce carbon-emissions, and are extensively used in aerospace for weight reduction purposes. However, as all major high-strength materials, these alloys can be sensitive to stress-corrosion cracking (SCC) through anodic dissolution and hydrogen embrittlement (HE). Here, we study at the near-atomic-scale the intra- and inter-granular microstructure ahead and in the wake of a propagating SCC crack. Moving away from model alloys and non-industry standard tests, we perform a double cantilever beam (DCB) crack growth test on an engineering 7xxx Al-alloy. H is found segregated to planar arrays of dislocations and to grain boundaries that we can associate to the combined effects of hydrogen-enhanced localised plasticity (HELP) and hydrogen-enhanced decohesion (HEDE) mechanisms. We report on a Mg-rich amorphous hydroxide on the corroded crack surface and evidence of Mg-related diffusional processes leading to dissolution of the strengthening η-phase precipitates ahead of the crack

High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.This work was supported by projects from the Spanish Ministry of Economy and Competiveness (grant number SAF2012-35779). Government of Extremadura-AEXCID (13/A001), the RIBEF IberoAmerican Network of Pharmacogenetics and SIFF (http: //www.ribef.com). MA-R and VM are predoctoral fellows of 'la Caixa'/ CNIO international PhD programme. LI-P is supported by CIBERER. MC is a predoctoral fellow supported by Severo Ochoa. AAdC is supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259735. MEGN is supported by the European Union (FSE), Gobierno de Extremadura and Consejeria de Empleo, Empresa e Innovacion Grant PD10199.S