96491 research outputs found
Sort by
Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis.
Get PDFThrough GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient’s blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4–5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery
Humanización de la Sanidad y Salud Laboral: Implicaciones, estado de la cuestión y propuesta del Proyecto HU-CI
Get PDFThe scientific and technical evolution of health care keeps growing exponentially, thus allowing a better patient care, new treatment forms and increasing survival rates. However, these important advances that improve health care have in many cases invaded the space that once belonged to the human act of caring. Promoting more humanized organizations will imply to establish actions directed to the environment and the workplace, as well as to all involved agents (patients, relatives and professionals). To that end, the humanization policies and their application to the health context are a reality in our days. These policies are being materialized in some specific proposals of certain organizations with the support of some official agencies. In this present work, we point out the interaction between the objectives of these humanization policies and the goals of occupational health in health care contexts. Common areas of work promoting the wellbeing for health professionals and the possibilities of integral management of both concepts are explored. Lastly, we provide a concrete example, like the Humanization Project of Intensive Care Units (HU-CI)
Perception, attitude and opinion of the Spanish tourists about the episodes of extreme heat
Get PDFHere we present the perception, attitude, opinion and behaviour of Spanish tourists when faced with an episode of extreme heat, with temperatures similar to those forecast for summers at the end of the 21st century. This information should help to fill the current gap regarding knowledge of how tourist–citizens perceive certain extreme episodes and behave when faced with them, which could be highly important given that such episodes may become ‘normal phenomena’ as a result of climate change. This information may be useful in devising strategies for the adaptation and future sustainability of tourist destinations
Mutation in KARS: A novel mechanism for severe anaphylaxis
Get PDFBackground: Anaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown.
Objective: This study is based on a clinical case of a patient with extremely severe anaphylaxis to paper wasp venom. This patient has a mutation in the KARS gene, which encodes lysyl-tRNA synthetase (LysRS), a moonlight protein with a canonical function in protein synthesis and a noncanonical function in antigen dependent-FcεRI activation in mast cells. In this study, the objective was to characterize the mutation at the molecular level.
Methods: Analysis of the KARS mutation was carried out using biochemical and functional approaches, cell transfection, Western blot, confocal microscopy, cell degranulation, prostaglandin D2 secretion, and proteases gene transcription. Structural analysis using molecular dynamics simulations and well-tempered metadynamics was also performed.
Results: The mutation found, P542R (proline was replaced by arginine at aminoacid 542), affects the location of the protein as we show in biochemical and structural analyses. The mutation resembles active LysRS and causes a constitutive activation of the microphthalmia transcription factor, which is involved in critical mast cell functions such as synthesis of mediators and granule biogenesis. Moreover, the structural analysis provides insights into how LysRS works in mast cell activation.
Conclusions: A link between the aberrant LysRS-P542R function and mast cell-exacerbated activation with increase in proinflammatory mediator release after antigen-IgE-dependent response could be established
A Cathepsin B-Triggered CO-Releasing Molecule with a Non-Toxic Metal Core for Targeted Tumor Delivery
No full textCarbon monoxide (CO) has shown therapeutic potential across various diseases, including cancer. To enable controlled delivery, many CO-releasing molecules (CORMs) have been developed. However, their clinical translation has been limited due to concerns about stability, potential toxicity, and insufficient targeting ability. In this study, we report the synthesis and characterization of an enzyme-triggered CO-releasing molecule (ET-CORM) that can be site-specifically conjugated to antibodies. This novel ET-CORM is built on a biocompatible iron core, and releases CO upon cleavage by the cancer-associated protease cathepsin B (CatB). The incorporation of a bioorthogonal handle into ET-CORM enabled its efficient and site-specific conjugation to the clinically used antibody trastuzumab via the interchain disulfide bonds. The resulting ET-CORM–antibody conjugate (ET-CORM-Ab) exhibited an average drug-to-antibody ratio (DAR) of 6.8, corresponding to approximately 20 CO molecules per conjugate. This construct allowed for selective intracellular CO delivery to HER2-overexpressing and CatB-expressing cells in vitro. This study represents a metal-based CORM–antibody conjugate activated by a tumor-associated enzymatic trigger, opening new avenues for investigating CO-mediated effects and advancing CO-based cancer therapies to the clinics
Vanillin production from lignin: Rigorous process simulation results for ethyl acetate versus aliphatic-alcohol-specific process designs
Get PDFEnergy hotspots for the production of vanillin from Kraft lignin are identified and process improvements are proposed and rigorously simulated. The hotspots identified and addressed are related to the flowrate of methanol used as solvent and recycled in the process. Several alternative process designs containing fewer distillation columns and able to reduce the overall energy consumption are proposed. Recycling aqueous methanol, a distillation column is not required and the overall energy consumption is halved compared to the available literature (i.e. 42 %). In addition, based on a literature review and the screening of suitable solvents used for the liquid-liquid extraction of vanillin from the main product stream, the use of aliphatic alcohols such as hexanol is proposed as an optimal and underexplored solution. Their physicochemical properties allow for the elimination of the acidification step that takes place during the feed preparation stage at the beginning of the process. In this way, the process design can be simplified further. Two distillation columns are not required and the overall energy consumption of the process is reduced to 23% compared to previous studies. The proposed Kraft-lignin-based vanillin production process improvements contribute to the development and competitiveness enhancement of biomass-based vanillin production processes, which are currently in need of further refinement compared to the more mature petrochemical-based processes, but at the same time have the potential to be more sustainable, cleaner and energetically efficient
Two-layer elastographic 3-D traction force microscopy
Get PDFCellular traction force microscopy (TFM) requires knowledge of the mechanical properties of the substratum where the cells adhere to calculate cell-generated forces from measurements of substratum deformation. Polymer-based hydrogels are broadly used for TFM due to their linearly elastic behavior in the range of measured deformations. However, the calculated stresses, particularly their spatial patterns, can be highly sensitive to the substratum’s Poisson’s ratio. We present two-layer elastographic TFM (2LETFM), a method that allows for simultaneously measuring the Poisson’s ratio of the substratum while also determining the cell-generated forces. The new method exploits the analytical solution of the elastostatic equation and deformation measurements from two layers of the substratum. We perform an in silico analysis of 2LETFM concluding that this technique is robust with respect to TFM experimental parameters, and remains accurate even for noisy measurement data. We also provide experimental proof of principle of 2LETFM by simultaneously measuring the stresses exerted by migrating Physarum amoeboae on the surface of polyacrylamide substrata, and the Poisson’s ratio of the substrata. The 2LETFM method could be generalized to concurrently determine the mechanical properties and cell-generated forces in more physiologically relevant extracellular environments, opening new possibilities to study cell-matrix interactions
Epoxy coating to prolog actuation time in degas-driven PDM micropums
Get PDFTo enhance the portability of Lab-on-a-Chip technology, avoiding bulky electronic flow control systems is crucial. Self-powered microfluidics can significantly improve portability by eliminating the need for electronic components. Traditionally, self-powered microsystems handle small fluid volumes for up to one or two hours. However, many experiments, such as cell culture or real-time biomarker detection assays, require flow control for longer periods. In this study, we demonstrate that polymeric micropumps can provide self-powered flow control for intermediate durations, ranging from several to more than 10 hours. By monitoring the fluid front dynamics of a solution flowing through a microchannel over 1.5 meters long, we developed calibration curves for various micropump types. Our findings reveal that the pump's actuation time is influenced by degassing time, and effective surface area. Using these calibration curves, we compare mathematical models to predict flow rates and actuation times, facilitating the design of customized self-powered microsystems for both short and long-term applications. Epoxy-coated PDMS pumps represent a notable example of a long-operating self-powered microsystem, which holds significant potential for applications requiring controlled flow over extended periods
Activitats teòrico-pràctiques per a la millora dels aprenentatges en química analítica
Get PDFUn dels problemes recurrents en ensenyaments experimentals és la dificultat que l’alumnat té per visualitzar les aplicacions quan les assignatures són merament de caire teòric, i a l’inrevés, relacionar les pràctiques experimentals amb la teoria que prèviament han estudiat. En aquesta comunicació es descriuen activitats en l’àmbit de la química analítica que s’han desenvolupat per tal d’establir relacions entre la pràctica i la teoria i així millorar l’aprenentatge dels estudiants
Late Ordovician deglaciation of the Murzuq Basin (SW Libya): a core to seismic-scale characterization of the depositional environments and sedimentary architecture
Get PDFGlacial reservoirs have been the focus of numerous studies in various basins around the world, often with the aim of supporting hydrocarbon exploration and development. These reservoirs present a significant challenge due to their inherently complex internal architectures and significant lateral heterogeneities. This is of significant importance, not only for both exploration and reservoir production optimization, but also as an opportunity for stratigraphic trapping and enhanced prospectivity in mature areas. This study is focused on a major glaciogenic reservoir, of Late Ordovician age, in the Murzuq Basin (SW Libya). It aims to integrate subsurface datasets, such as 3D seismic with well-based sedimentological data (core, conventional wireline logs and wellbore resistivity images). The study proposes a comprehensive facies scheme optimized for the sub-surface but consistent with outcrops, and aims to generate depositional models, characterize the complex internal architecture of the reservoir, establish a genetic stratigraphic framework and evaluate facies in terms of reservoir properties and stratigraphic trap potential. Results, integrating subsurface facies analysis and well-calibrated seismic stratigraphy support previous models, derived from outcrop analysis, suggesting that these complex reservoirs cannot be characterised by purely lithostratigraphic criteria. To aid in the assessment of these formations, a facies scheme is proposed, focused on subsurface data but also considering other published, outcrop-based, schemes. Additionally, an interpretation is presented of the internal architecture of the Upper Ordovician based on a succession of several ice advance-retreat cycles, not all of which are present across the study area. Each cycle corresponds to a seismic package interpreted to comprise the deposits of several key sedimentation phases, resulting in a complex mosaic of genetic packages generated by multiple, often areally-restricted, cut and fill events. Predictive stratigraphic models are proposed for this complex package, based on both seismic stratigraphy and well-based sedimentology. The implications for future prospectivity and the significance for stratigraphic trap potential are also discussed