Computational studies of Brønsted acid-catalyzed transannular cycloadditions of cycloalkenone hydrazones

The contribution to the energy barrier of a series of tethers in transannular cycloadditions of cycloalkenes with hydrazones has been computationally studied by using DFT. The Houk's distortion model has been employed to evaluate the influence of the tether in the cycloaddition reaction. That model has been extended to determine the contribution of each tether and, more importantly, the effect exerted between them. In addition to the distortion induced by the tethers, the entropy effects caused by them has also been studied. The analysis of the evolution of the electron localization function along the reaction revealed the highly concerted character of the reaction

Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood

Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s−1. The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM and perfusion studies. Our results indicate that rFVIIa, PCCs and aPCCs have the potential to restore platelet and fibrin components of the hemostasis previously altered by apixaban

Antithrombin is incorporated into exosomes produced by antithrombin non-expressing cells

Antithrombin is a serine protease inhibitor that exerts a crucial role in hemostasis as the main inhibitor of the coagulation cascade. It plays also critical roles in other processes, such as inflammation and cancer. Here we show that exosomes released by Madin-Darby canine kidney (MDCK) cells cultured in the presence of heparin incorporate antithrombin from the serum. Exosomal antithrombin is found complexed with the serine protease high temperature requirement A1 (HTRA1), whose cellular levels are increased after serum deprival, the condition used to collect exosomes. Although the biological relevance of the presence of antithrombin in exosomes remains to be investigated, our results suggest a functional interplay between antithrombin and HTRA1.Ginés Luengo-Gil holds a grant from the Spanish Society of Hematology and Hemotherapy (SEHH-FEHH), Irene Martínez-Martínez holds a Miguel Servet contract from the ISCIII. Miguel Quintanilla holds a grant (SAF2017-84183-R) from the Spanish Ministry of Science, Innovation and Universities and Irene Martínez-Martínez holds grants from ISCIII (CP13/00126 & FEDER and PI17/00050 & FEDER)

El aprendizaje adaptativo de los estudiantes de un Grado de nueva creación: Análisis de su actividad en el Campus Virtual-UB

La docencia presencial de la Univ. Barcelona se apoya en su Campus virtual. Para promover el aprendizaje adaptativo, hemos analizado los Recursos/Actividades (número, tipo y frecuencia de uso) de 3 cohortes del Grado de Ciencias del Mar (30 Informes de actividad en total y 10 Registros de uso seleccionados). Predominan los Recursos (87%), pero se interactúa más en las Actividades. El análisis de los Registros ha permitido relacionar los resultados con el rendimiento, género u opcionalidad

Utilización de un equipo portátil de fluorescencia de rayos X para el estudio de metales pesados en suelos: puesta a punto y aplicación a vertederos

12 páginas, 5 tablas estadísticas y 3 figurasDado el interé s medioambiental que tiene en la actualidad la localización y determinación de metales pesado s en vertederos clau surados, se hace imprescindible no ir a tientas en la fase de toma de muestras edáficas, muchas de ellas con conte nidos banales de metales en detrimento de otros posibles puntos fuertemente contaminados . Esta situación nos ha llevado a la búsqueda de técnicas que nos permitan conocer en el menor tiempo posible y también con el menor gasto económico, los metale s pesados en suelos de emplazamientos contaminados. Por ello nos inclinamos por la utilización de un equipo portátil de fluore scencia de rayo s X (FRX). Su puesta apunto y la aplicación a vertederos, la presentamos a continuación.CTM 2008-04827!fECNOPeer reviewe

Antithrombin controls tumor migration, invasion and angiogenesis by inhibition of enteropeptidase

This work is licensed under a Creative Commons Attribution 4.0 International License.-- et al.Antithrombin is a key inhibitor of the coagulation cascade, but it may also function as an anti-inflammatory, anti-angiogenic, anti-viral and anti-apoptotic protein. Here, we report a novel function of antithrombin as a modulator of tumor cell migration and invasion. Antithrombin inhibited enteropeptidase on the membrane surface of HT-29, A549 and U-87 MG cells. The inhibitory process required the activation of antithrombin by heparin, and the reactive center loop and the heparin binding domain were essential. Surprisingly, antithrombin non-covalently inhibited enteropeptidase, revealing a novel mechanism of inhibition for this serpin. Moreover, as a consequence of this inhibition, antithrombin was cleaved, resulting in a molecule with anti-angiogenic properties that reduced vessel-like formation of endothelial cells. The addition of antithrombin and heparin to U-87 MG and A549 cells reduced motility in wound healing assays, inhibited the invasion in transwell assays and the degradation of a gelatin matrix mediated by invadopodia. These processes were controlled by enteropeptidase, as demonstrated by RNA interference experiments. Carcinoma cell xenografts in nude mice showed in vivo co-localization of enteropeptidase and antithrombin. Finally, treatment with heparin reduced experimental metastasis induced by HT29 cells in vivo. In conclusion, the inhibition of enteropeptidase by antithrombin may have a double anti-tumor effect through inhibiting a protease involved in metastasis and generating an anti-angiogenic molecule.This work was supported by CP13/00126 (ISCIII & FEDER), PI15/00079 (ISCIII), SAF2013-46183-R from the Spanish Ministry of Economy and Competitiveness) and the Programa de Movilidad Jiménez de la Espada from Seneca Foundation (Murcia). G. Luengo-Gil holds a grant from the Spanish Society of Thrombosis and Haemostasis (SETH), S. Águila holds an FPI grant from the Ministerio de Ciencia e Innovación, and I. Martínez-Martínez has a Miguel Servet contract from ISCIII. M.I. Calvo holds a postdoctoral contract associated to the project RTC-2014-2626-1, and E. Martín-Villar is the recipient of a postdoctoral research contract from the scientific foundation of Asociación Española Contra el Cáncer (AECC).Peer Reviewe

Case Report An Active Isodicentric X Chromosome in a Case of Refractory Anaemia with Ring Sideroblasts Associated with Marked Thrombocytosis

Refractory anaemia with ring sideroblasts and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organization (WHO) classification. It displays features characteristic of both myelodysplastic syndrome and myeloproliferative neoplasia plus ring sideroblasts ≥15% and marked thrombocytosis. Most patients with RARS-T show a normal karyotype. We report a 76-year-old woman diagnosed with RARS-T (76% of ring sideroblasts) with JAK2 (V617F) mutation and a load of 30-40%. Classical and molecular cytogenetic (FISH) studies of a bone marrow sample revealed the presence of isodicentric X chromosome [(idic(X)(q13)]. Moreover, HUMARA assay showed the idic(X)(q13) as the active X chromosome. This finding was correlated with the cytochemical finding of ring sideroblasts. To our knowledge, this is the first reported case of an active isodicentric X in a woman with RARS-T

The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice

Increasing evidence indicates that a key factor in neurodegenerative diseases is the activation of the unfolded protein response (UPR) caused by an accumulation of misfolded proteins in the endoplasmic reticulum (ER stress). Particularly, in Huntington's disease (HD) mutant huntingtin (mHtt) toxicity involves disruption of the ER-associated degradation pathway and loss of the ER protein homeostasis leading to neuronal dysfunction and degeneration. Besides the role of the UPR in regulating cell survival and death, studies that demonstrate the contribution of sustained UPR activation, particularly of PERK signaling, in memory disturbances and synaptic plasticity deficiencies are emerging. Given the contribution of hippocampal dysfunction to emotional and cognitive deficits seen in HD, we have analyzed the involvement of ER stress in HD memory alterations. We have demonstrated that at early disease stages, ER stress activation manifested as an increase in GRP78 and CHOP is observed in the hippocampus of R6/1 mice. Genetic reduction of GRP78 expression resulted in preventing hippocampal-dependent memory alterations but no motor deficits. Accordingly, hippocampal neuropathology namely, dendritic spine loss and accumulation of mHtt aggregates was ameliorated by GRP78 reduction. To elucidate the signaling pathways, we found that the inactivation of PERK by GSK2606414 restored spatial and recognition memories in R6/1 mice and rescued dendritic spine density in CA1 pyramidal neurons and protein levels of some specific immediate early genes. Our study unveils the critical role of the GRP78/PERK axis in memory impairment in HD mice and suggests the modulation of PERK activation as a novel therapeutic target for HD intervention

Spasticity-Plus syndrome in multiple sclerosis patients in a tertiary hospital in Spain

IntroductionSpasticity is a common symptom in multiple sclerosis (MS) and it is often associated with other symptoms such as spasms/cramps and pain. The concept of Spasticity-Plus syndrome takes into account that spasticity is accompanied by one or more symptoms (spasms/cramps, pain, bladder dysfunction, sleep disorders, fatigue and/or tremor). As these symptoms share a common cannabinoid control, therapy acting on cannabinoid receptors may be useful. The main study objectives were to determine the number of MS patients who met Spasticity-Plus syndrome criteria and to identify the most common symptoms.MethodsClinical records of MS patients treated with nabiximols in a tertiary hospital from 2002 to 2022 were reviewed retrospectively.ResultsOf the 73 patients included in the study, 53.4% were women, and most had secondary progressive MS (64.4%). All patients met the criteria for Spasticity-Plus syndrome: 100% had spasticity and at least another symptom. Pain was the second most common symptom (91.8%), followed by spasms/cramps (79.4%), and fatigue (76.7%). Sleep disturbances (p &lt; 0.0001) and tremor (p &lt; 0.027) were more frequent in patients with relapsing–remitting MS than in patients with progressive MS. No statistically significant differences were found for spasticity, pain, spasms/cramps, and fatigue between MS phenotypes. Regarding symptoms clusters, 94.4% of the patients had three or more symptoms. Spasticity was more frequently associated with pain (91.8%) and spasms/cramps (79.4%).ConclusionSpasticity-Plus syndrome was present in all the study population of patients with different MS phenotypes, and treated with nabiximols