GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM

Design Constraints on a Synthetic Metabolism

A metabolism is a complex network of chemical reactions that converts sources of energy and chemical elements into biomass and other molecules. To design a metabolism from scratch and to implement it in a synthetic genome is almost within technological reach. Ideally, a synthetic metabolism should be able to synthesize a desired spectrum of molecules at a high rate, from multiple different nutrients, while using few chemical reactions, and producing little or no waste. Not all of these properties are achievable simultaneously. We here use a recently developed technique to create random metabolic networks with pre-specified properties to quantify trade-offs between these and other properties. We find that for every additional molecule to be synthesized a network needs on average three additional reactions. For every additional carbon source to be utilized, it needs on average two additional reactions. Networks able to synthesize 20 biomass molecules from each of 20 alternative sole carbon sources need to have at least 260 reactions. This number increases to 518 reactions for networks that can synthesize more than 60 molecules from each of 80 carbon sources. The maximally achievable rate of biosynthesis decreases by approximately 5 percent for every additional molecule to be synthesized. Biochemically related molecules can be synthesized at higher rates, because their synthesis produces less waste. Overall, the variables we study can explain 87 percent of variation in network size and 84 percent of the variation in synthesis rate. The constraints we identify prescribe broad boundary conditions that can help to guide synthetic metabolism design

GPR56/ADGRG1 inhibits mesenchymal differentiation and radioresistance in glioblastoma

A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM

Characterization of protein and small molecule profiles in wastewater by mass spectrometry for wastewater based epidemiology and water quality monitoring

Trabajo presentado en la 71st Conference on Mass Spectrometry and Allied Topics, celebrada en Houston, TX (Estados Unidos), del 4 al 8 de junio de 2023Introduction Wastewater-based epidemiology (WBE) is a powerful approach to assessing the health and lifestyle of a population. In this study, a comprehensive characterization of proteins, pesticides and pharmaceuticals in the influent and effluent waters of several WWTPs has provided new potential markers for industrial and living activities (1). These compounds can also give a more thorough evaluation of WWTP treatment. This is routinely evaluated through bulk parameters such as chemical and biochemical oxygen demand. However, with a plethora of dynamic and changing conditions linked to water practices, the diagnosis of water quality based on this data is far from optimal. Methods We studied the protein and small molecule composition in the influent and effluent waters of 3 WWTP in Catalonia which serve communities of different population and industrial profile. Water samples (24-h composites) were filtered and the soluble part was submitted to the different analysis. Proteins in the water samples were concentrated in a SDS-PAGE gel, digested with trypsin and analyzed by HR-LC-MS/MS. Database protein identification was done using the complete Uniprot database and a semiquantitative analysis was performed based on the area of the unique peptides of each protein (1). Small molecules were obtained through different solid phase extraction methods targeting more than 140 micropollutants, including pesticides, pharmaceuticals and antibiotics (2). Extracts were analyzed by LC-QqQ. Preliminary data We have identified hundreds of proteins from different species including human, livestock and bacteria. Our data provide a comprehensive semiquantitative description of wastewater proteins and their distribution among different organisms. Most proteins originated from main sources: excreta (urine and feces) from humans, and blood and other residues from livestock. Species-specific protein forms allowed obtaining separate profiles for species such as rat, mouse, cattle, pigs, and poultry. This capability provided useful markers of industrial activity in the areas studied. The integration of the protein and small molecule data (pharmaceuticals) reveals relations between the origin of the proteins and some drugs. For example, the amount of proteins derived from livestock correlates with higher levels of veterinary antibiotics. Our findings also provide new insights into the characterization of wastewater proteomics that allow for the proposal of specific bioindicators useful for practical purposes related to wastewater-based environmental monitoring and wastewater treatment plant management. Some relevant examples include Immunoglobulins and amylases for mammalian population monitoring (applicable, for instance, to rodent pest surveys) and albumins as indicators of the cattle processing industry. This study also provides of a full set of complementary information that can increase the understanding of the processes happening at the water treatment plants. This data will be very valuable to implement new control methodologies in the WWTPs and to investigate the effect of wastewater discharge in environmental buffers but also to identify contaminants that have been so far overlooked but are persistent or formed at a significant concentration Novel aspect Monitoring proteins and pharmaceuticals will generate complementary and unique data that will help understanding population characteristics and evaluate wastewater treatments

Shared effects of organic microcontaminants and environmental stressors on biofilms and invertebrates in impaired rivers

Land use type, physical and chemical stressors, and organic microcontaminants were investigated for their effects on the biological communities (biofilms and invertebrates) in several Mediterranean rivers. The diversity of invertebrates, and the scores of the first principal component of a PCA performed with the diatom communities were the best descriptors of the distribution patterns of the biological communities against the river stressors. These two metrics decreased according to the progressive site impairment (associated to higher area of agricultural and urban-industrial, high water conductivity, higher dissolved organic carbon and dissolved inorganic nitrogen concentrations, and higher concentration of organic microcontaminants, particularly pharmaceutical and industrial compounds). The variance partition analyses (RDAs) attributed the major share (10%) of the biological communities' response to the environmental stressors (nutrients, altered discharge, dissolved organic matter), followed by the land use occupation (6%) and of the organic microcontaminants (2%). However, the variance shared by the three groups of descriptors was very high (41%), indicating that their simultaneous occurrence determined most of the variation in the biological communities

Entry into the legal professions The law student cohort study year 6

SIGLEAvailable from British Library Document Supply Centre-DSC:7771.850(no 39) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Alya: Multiphysics engineering simulation toward exascale

Alya is a multi-physics simulation code developed at Barcelona Supercomputing Center (BSC). From its inception Alya code is designed using advanced High Performance Computing programming techniques to solve coupled problems on supercomputers efficiently. The target domain is engineering, with all its particular features: complex geometries and unstructured meshes, coupled multi-physics with exotic coupling schemes and physical models, ill-posed problems, flexibility needs for rapidly including new models, etc. Since its beginnings in 2004, Alya has scaled well in an increasing number of processors when solving single-physics problems such as fluid mechanics, solid mechanics, acoustics, etc. Over time, we have made a concerted effort to maintain and even improve scalability for multi-physics problems. This poses challenges on multiple fronts, including: numerical models, parallel implementation, physical coupling models, algorithms and solution schemes, meshing process, etc. In this paper, we introduce Alya's main features and focus particularly on its solvers. We present Alya's performance up to 100.000 processors in Blue Waters, the NCSA supercomputer with selected multi-physics tests that are representative of the engineering world. The tests are incompressible flow in a human respiratory system, low Mach combustion problem in a kiln furnace, and coupled electro-mechanical contraction of the heart. We show scalability plots for all cases and discuss all aspects of such simulations, including solver convergence.The authors would like to thank the following fellow researchers and institutions: • The Private Sector Program at NCSA and the BlueWaters sustained-petascale computing project-supported by the National Science Foundation (award number OCI 07-25070) and the state of Illinois. • Denis Doorly and Alister Bates (Imperial College London, UK), collaborators of the airways study. Part of this work was financed by European PRACE Type B/C projects. • The heart geometry was provided by Dr. A. Berruezo (Hospital Clinic de Barcelona) in collaboration with R. Sebastian (UVEG) and O. Camara (UPF), partially financed through project TIN2011-28067 from MINECO, Spain. • Part of the cardiac model development was financed by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. • Part of the kiln model development was financed by the European Commission in the framework of the FP7 Collaborative project “Advanced Technologies for the Production of Cement and Clean Aggregates from Construction and Demolition Waste (C2CA)”, Grant Agreement No 265189.Peer Reviewe

Alya: Multiphysics engineering simulation toward exascale

Alya is a multi-physics simulation code developed at Barcelona Supercomputing Center (BSC). From its inception Alya code is designed using advanced High Performance Computing programming techniques to solve coupled problems on supercomputers efficiently. The target domain is engineering, with all its particular features: complex geometries and unstructured meshes, coupled multi-physics with exotic coupling schemes and physical models, ill-posed problems, flexibility needs for rapidly including new models, etc. Since its beginnings in 2004, Alya has scaled well in an increasing number of processors when solving single-physics problems such as fluid mechanics, solid mechanics, acoustics, etc. Over time, we have made a concerted effort to maintain and even improve scalability for multi-physics problems. This poses challenges on multiple fronts, including: numerical models, parallel implementation, physical coupling models, algorithms and solution schemes, meshing process, etc. In this paper, we introduce Alya's main features and focus particularly on its solvers. We present Alya's performance up to 100.000 processors in Blue Waters, the NCSA supercomputer with selected multi-physics tests that are representative of the engineering world. The tests are incompressible flow in a human respiratory system, low Mach combustion problem in a kiln furnace, and coupled electro-mechanical contraction of the heart. We show scalability plots for all cases and discuss all aspects of such simulations, including solver convergence.Peer Reviewe

Priority and emerging organic microcontaminants in three Mediterranean river basins: Occurrence, spatial distribution, and identification of river basin specific pollutants

There is a worldwide growing use of chemicals by our developed, industrialized, and technological society. More than 100,000 chemical substances are thus commonly used both by industry and households. Depending on the amount produced, physical-chemical properties, and mode of use, many of them may reach the environment and, notably, the aquatic receiving systems. This may result in undesirable and harmful side-effects on both the human and the ecosystem's health. Mediterranean rivers are largely different from Northern and Central European rivers in terms of hydrological regime, climate conditions (e.g. air temperature, solar irradiation, precipitation), and socio-economics (e.g. land use, tourism, crop types, etc.), with all these factors leading to differences in the relative importance of the environmental stressors, in the classes and levels of the pollutants found and their environmental fate. Furthermore, water scarcity might be critical in affecting water pollution because of the lowered dilution capacity of chemicals. This work provides raw chemical data from different families of microcontaminants identified in three selected Mediterranean rivers (the Sava, Evrotas, and Adige) collected during two sampling campaigns conducted in 2014 and 2015 in three different matrices, namely, water, sediments, and biota (fish). More than 200 organic micropollutants were analyzed, including relevant groups like pharmaceuticals, personal care products, perfluorinated compounds, pesticides, pyrethroid insecticides, flame retardants, and persistent organic pollutants. Data obtained were summarized with some basic statistics for all compound families and matrices analyzed. Observed occurrence and spatial patterns were interpreted both in terms of compound physical-chemical properties and local environmental pressures. Finally, their spatial distribution was examined and their ecotoxicological risk in the water phase was assessed. This allowed locating, at each basin, the most polluted sites (“hot spots”) and identifying the respective river basin specific pollutants (RBSPs), prioritizing them in terms of the potential ecotoxicological risk posed to the aquatic ecosystems.This work has been supported by the European Communities EU 7th Framework Programme Funding under Grant agreement no. 603629-ENV-2013-6.2.1-Globaqua and partly by the Generalitat de Catalunya (Consolidate Research Group 2017-SGR-01404) and by the Spanish Ministry of Science, Innovation and Universities (Projects CEX2018-000794-S and IBERAQUA-NET RED2018-102737-T). Special thanks are due to all partners of the GLOBAQUA consortium and the peer review panel for ensuring quality results and a fruitful collaboration within the frame of the project.Peer reviewe