TssA forms a gp6-like ring attached to the type VI secretion sheath

The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a killing machine which fires toxins into target cells upon contraction of its TssBC sheath. Here, we show that TssA1 is a T6SS component forming dodecameric ring structures whose dimensions match those of the TssBC sheath and which can accommodate the inner Hcp tube. The TssA1 ring complex binds the T6SS sheath and impacts its behaviour in vivo. In the phage, the first disc of the gp18 sheath sits on a baseplate wherein gp6 is a dodecameric ring. We found remarkable sequence and structural similarities between TssA1 and gp6 C-termini, and propose that TssA1 could be a baseplate component of the T6SS. Furthermore, we identified similarities between TssK1 and gp8, the former interacting with TssA1 while the latter is found in the outer radius of the gp6 ring. These observations, combined with similarities between TssF and gp6Nterminus or TssG and gp53, lead us to propose a comparative model between the phage baseplate and the T6SS

Anomaly detection based on intelligent techniques over a bicomponent production plant used on wind generator blades manufacturing

[ES] Los avances tecnológicos en general, y en el ámbito de la industria en particular, conllevan el desarrollo y optimización de las actividades que en ella tienen lugar. Para alcanzar este objetivo, resulta de vital importancia detectar cualquier tipo de anomalía en su fase más incipiente, contribuyendo, entre otros, al ahorro energético y económico, y a una reducción del impacto ambiental. En un contexto en el que se fomenta la reducción de emisión de gases contaminantes, las energías alternativas, especialmente la energía eólica, juegan un papel crucial. En la fabricación de las palas de aerogenerador se recurre comúnmente a materiales de tipo bicomponente, obtenidos a través del mezclado de dos substancias primarias. En la presente investigación se evalúan distintas técnicas inteligentes de clasificación one-class para detectar anomalías en un sistema de mezclado para la obtención de materiales bicomponente empleados en la elaboración de palas de aerogenerador. Para lograr los modelos[EN] Technological advances, especially in the industrial field, have led to the development and optimization of the activities that takes place on it. To achieve this goal, an early detection of any kind of anomaly is very important. This can contribute to energy and economic savings and an environmental impact reduction. In a context where the reduction of pollution gasses emission is promoted, the use of alternative energies, specially the wind energy, plays a key role. The wind generator blades are usually manufactured from bicomponent material, obtained from the mixture of two dierent primary components. The present research assesses dierent one-class intelligent techniques to perform anomaly detection on a bicomponent mixing system used on the wind generator manufacturing. To perform the anomaly detection, the intelligent models were obtained from real dataset recorded during the right operation of a bicomponent mixing plant. 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Metodología de reducción del tiempo de ajuste de controladores PID autoajustables basado en hiperesferas

[ES] Hoy en día, los controladores adaptativos son ampliamente utilizados en el control de una gran variedad de procesos industriales. En ese tipo de controladores destacan los reguladores PIDs autoajustables, por ser una solución robusta y de fácil implementación. Sin embargo, este tipo de controladores suelen caracterizarse por tener elevados tiempos de estabilización debido al proceso de identificación que ejecutan en paralelo. Por ello, en el presente trabajo de investigación se presenta un método basado en el uso de hiperesferas y centroides para reducir los tiempos de ajuste y mejorar el rendimiento del lazo de control en los algoritmos PID autoajustables.[EN] Nowadays, adaptive controllers are widely used to control a wide variety of industrial processes. In this kind of controllers selftuning PID highlight for being a robust and easy implementation solution. However, this type of controllers are usually characterized by large settling times, due to the identification process they execute in parallel. Therefore, this research work presents a method based on hyperspheres and centroids to reduce settling times and improve control loop performance in self-tuning PID algorithms

IMPACTS OF REDUCING CONDITIONS IN THE SATURATED ZONE AT YUCCA MOUNTAIN

Variations in groundwater redox chemistry in the saturated zone near Yucca Mountain could have significant repository to the accessible environment. This study examines geochemical data relevant to the distribution of redox impacts on processes associated with the potential transport of redox-sensitive radionuclides from the proposed conditions in the saturated zone, the relationships between redox state and solubility and sorption coefficients for technetium and neptunium, and sensitivity in transport model simulations. Results indicate evidence for a zone of reducing conditions in the volcanic rocks of the saturated zone located to the east and south of the repository and along the inferred flow paths from the repository. A working hypothesis is that these reducing conditions are related to the presence of minor pyrite in the matrix of some volcanic units. Chemical equilibrium modeling of technetium solubility using EQ3/6 software codes is used to estimate the value of solubility limits as a function of Eh. Surface complexation modeling with the EQ3 code is used to estimate neptunium sorption coefficient values as a function of Eh. A general analytical approach, one-dimensional reactive transport modeling, and the three-dimensional saturated zone site-scale transport model using the FEHM software code are used to evaluate the impacts of solubility limits and enhanced sorption in reducing zones on the simulated transport of technetium and neptunium in the saturated zone. Results show that if precipitation occurs in response to flow through a reducing zone, then the peak concentration released to the accessible environment will be restricted to the solubility limit. Simulations also show that enhanced sorption within a reducing zone of modest width leads to significantly greater retardation of radionuclides in the saturated zone

Ras Inhibition Induces Insulin Sensitivity and Glucose Uptake

BACKGROUND: Reduced glucose uptake due to insulin resistance is a pivotal mechanism in the pathogenesis of type 2 diabetes. It is also associated with increased inflammation. Ras inhibition downregulates inflammation in various experimental models. The aim of this study was to examine the effect of Ras inhibition on insulin sensitivity and glucose uptake, as well as its influence on type 2 diabetes development. METHODS AND FINDINGS: The effect of Ras inhibition on glucose uptake was examined both in vitro and in vivo. Ras was inhibited in cells transfected with a dominant-negative form of Ras or by 5-fluoro-farnesylthiosalicylic acid (F-FTS), a small-molecule Ras inhibitor. The involvement of IκB and NF-κB in Ras-inhibited glucose uptake was investigated by immunoblotting. High fat (HF)-induced diabetic mice were treated with F-FTS to test the effect of Ras inhibition on induction of hyperglycemia. Each of the Ras-inhibitory modes resulted in increased glucose uptake, whether in insulin-resistant C2C12 myotubes in vitro or in HF-induced diabetic mice in vivo. Ras inhibition also caused increased IκB expression accompanied by decreased expression of NF-κB . In fat-induced diabetic mice treated daily with F-FTS, both the incidence of hyperglycemia and the levels of serum insulin were significantly decreased. CONCLUSIONS: Inhibition of Ras apparently induces a state of heightened insulin sensitization both in vitro and in vivo. Ras inhibition should therefore be considered as an approach worth testing for the treatment of type 2 diabetes

P73 Preliminary results of the Study of Acute Liver Transplant (SALT): NSAID exposure and risk of acute liver failure leading to transplantation in 7 European countries

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Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.

The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.This work was supported by the Fundacion Cientifica Asociacion Española Contra el Cancer-AECC (grant number GCB14142170MONT) to LMM, MS-C, and EF; the Spanish Ministry of Economy and Competitivity-MINECO (grant number SAF-2017-82186R to MS-C; Rio Hortega-CM17/00180 to MS; PROYBAR17005NADA to EN); the Health Institute Carlos III-ISCIII, Fondo Europeo de Desarrollo Regional-FEDER (grant Number PT13/0001/0044, PT17/0009/0019, PI16 01821); the Government of Navarra (grant number DIANA project); and the Ramon Areces Foundation (no grant number is applicable) to LMM and RP.S

Nuclear Energy Advanced Modeling and Simulation (NEAMS) waste Integrated Performance and Safety Codes (IPSC) : gap analysis for high fidelity and performance assessment code development.

This report describes a gap analysis performed in the process of developing the Waste Integrated Performance and Safety Codes (IPSC) in support of the U.S. Department of Energy (DOE) Office of Nuclear Energy Advanced Modeling and Simulation (NEAMS) Campaign. The goal of the Waste IPSC is to develop an integrated suite of computational modeling and simulation capabilities to quantitatively assess the long-term performance of waste forms in the engineered and geologic environments of a radioactive waste storage or disposal system. The Waste IPSC will provide this simulation capability (1) for a range of disposal concepts, waste form types, engineered repository designs, and geologic settings, (2) for a range of time scales and distances, (3) with appropriate consideration of the inherent uncertainties, and (4) in accordance with rigorous verification, validation, and software quality requirements. The gap analyses documented in this report were are performed during an initial gap analysis to identify candidate codes and tools to support the development and integration of the Waste IPSC, and during follow-on activities that delved into more detailed assessments of the various codes that were acquired, studied, and tested. The current Waste IPSC strategy is to acquire and integrate the necessary Waste IPSC capabilities wherever feasible, and develop only those capabilities that cannot be acquired or suitably integrated, verified, or validated. The gap analysis indicates that significant capabilities may already exist in the existing THC codes although there is no single code able to fully account for all physical and chemical processes involved in a waste disposal system. Large gaps exist in modeling chemical processes and their couplings with other processes. The coupling of chemical processes with flow transport and mechanical deformation remains challenging. The data for extreme environments (e.g., for elevated temperature and high ionic strength media) that are needed for repository modeling are severely lacking. In addition, most of existing reactive transport codes were developed for non-radioactive contaminants, and they need to be adapted to account for radionuclide decay and in-growth. The accessibility to the source codes is generally limited. Because the problems of interest for the Waste IPSC are likely to result in relatively large computational models, a compact memory-usage footprint and a fast/robust solution procedure will be needed. A robust massively parallel processing (MPP) capability will also be required to provide reasonable turnaround times on the analyses that will be performed with the code. A performance assessment (PA) calculation for a waste disposal system generally requires a large number (hundreds to thousands) of model simulations to quantify the effect of model parameter uncertainties on the predicted repository performance. A set of codes for a PA calculation must be sufficiently robust and fast in terms of code execution. A PA system as a whole must be able to provide multiple alternative models for a specific set of physical/chemical processes, so that the users can choose various levels of modeling complexity based on their modeling needs. This requires PA codes, preferably, to be highly modularized. Most of the existing codes have difficulties meeting these requirements. Based on the gap analysis results, we have made the following recommendations for the code selection and code development for the NEAMS waste IPSC: (1) build fully coupled high-fidelity THCMBR codes using the existing SIERRA codes (e.g., ARIA and ADAGIO) and platform, (2) use DAKOTA to build an enhanced performance assessment system (EPAS), and build a modular code architecture and key code modules for performance assessments. The key chemical calculation modules will be built by expanding the existing CANTERA capabilities as well as by extracting useful components from other existing codes

Modeling acid-gas generation from boiling chloride brines

<p>Abstract</p> <p>Background</p> <p>This study investigates the generation of HCl and other acid gases from boiling calcium chloride dominated waters at atmospheric pressure, primarily using numerical modeling. The main focus of this investigation relates to the long-term geologic disposal of nuclear waste at Yucca Mountain, Nevada, where pore waters around waste-emplacement tunnels are expected to undergo boiling and evaporative concentration as a result of the heat released by spent nuclear fuel. Processes that are modeled include boiling of highly concentrated solutions, gas transport, and gas condensation accompanied by the dissociation of acid gases, causing low-pH condensate.</p> <p>Results</p> <p>Simple calculations are first carried out to evaluate condensate pH as a function of HCl gas fugacity and condensed water fraction for a vapor equilibrated with saturated calcium chloride brine at 50-150°C and 1 bar. The distillation of a calcium-chloride-dominated brine is then simulated with a reactive transport model using a brine composition representative of partially evaporated calcium-rich pore waters at Yucca Mountain. Results show a significant increase in boiling temperature from evaporative concentration, as well as low pH in condensates, particularly for dynamic systems where partial condensation takes place, which result in enrichment of HCl in condensates. These results are in qualitative agreement with experimental data from other studies.</p> <p>Conclusion</p> <p>The combination of reactive transport with multicomponent brine chemistry to study evaporation, boiling, and the potential for acid gas generation at the proposed Yucca Mountain repository is seen as an improvement relative to previously applied simpler batch evaporation models. This approach allows the evaluation of thermal, hydrological, and chemical (THC) processes in a coupled manner, and modeling of settings much more relevant to actual field conditions than the distillation experiment considered. The actual and modeled distillation experiments do not represent expected conditions in an emplacement drift, but nevertheless illustrate the potential for acid-gas generation at moderate temperatures (<150°C).</p