Purity distribution for generalized random Bures mixed states

We compute the distribution of the purity for random density matrices (i.e.random mixed states) in a large quantum system, distributed according to the Bures measure. The full distribution of the purity is computed using a mapping to random matrix theory and then a Coulomb gas method. We find three regimes that correspond to two phase transitions in the associated Coulomb gas. The first transition is characterized by an explosion of the third derivative on the left of the transition point. The second transition is of first order, it is characterized by the detachement of a single charge of the Coulomb gas. A key remark in this paper is that the random Bures states are closely related to the O(n) model for n=1. This actually led us to study "generalized Bures states" by keeping $n$ general instead of specializing to n=1

Analysis of the Adherence and Safety of Second Oral Glucose-Lowering Therapy in Routine Practice From the Mediterranean Area : A Retrospective Cohort Study

Altres ajuts: AstraZeneca/ESR-16-12628Altres ajuts: Applied Research Collaboration East Midlands (ARC EM)Altres ajuts: National Institute for Health Research (NIHR)Altres ajuts: Imperial Biomedical Research Centre (NIHR)The aims of our study was compare adherence measured by the medical possession ratio (MPR), time until discontinuation and describe adverse events after adding a DPP-4i, SGLT-2i, or sulfonylureas (SU) to metformin in a primary care population with insufficient glycemic control. We used routinely-collected health data from the SIDIAP database. The included subjects were matched by propensity score. The follow-up period was up to 24 months or premature discontinuation. The primary outcomes were the percentage of subjects with good adherence, treatment discontinuation and adverse events among treatment groups. The proportion of patients with good adherence (MPR> 0.8) after the addition of DPP-4i, SGLT-2i or SU was 53.6%, 68.7%, and 43.0%, respectively. SGLT-2i users were 1.7 times more likely to achieve good adherence compared with DPP-4i users (odds ratio [OR]:1.72, 98% confidence interval [CI]:1.51, 1.96), and 2.8 times more likely compared with SU users (OR: 0.35, 98% CI: 0.07, 0.29). The discontinuation hazard ratios were 1.43 (98%CI: 1.26; 1.62) and 1.60 (98%CI: 1.42; 1.81) times higher among SGLT-2i and SU users than DPP-4i users during the follow-up period. No differences were observed for adverse events among the treatment groups. In conclusion, in our real-world setting, the combination of SGLT-2i with metformin was associated with better adherence. The mean time until discontinuation was longer in the SGLT-2i group in comparison with the DPP-4i or SU groups

Prevalence and risk factors of diabetic foot disease among the people with type 2 diabetes using real-world practice data from Catalonia during 2018

Altres ajuts: 8a Convocatòria d'Ajuts a projectes de Institut Català de la Salut with SIDIAP (financing code 4R18/187-1 and file number SIDIAP-18/7).Background: Our study aimed to assess the prevalence of diabetic foot disease (DFD) and its associated risk factors among subjects attending primary care centers in Catalonia (Spain). Methods: We undertook a cross-sectional analysis of data from the primary health care (SIDIAP) database. The presence of comorbidities and concomitant medication were analyzed for subjects with or without DFD. DFD prevalence was estimated from 1st January 2018 to 31st December 2018. Results: During the 12-month observational period, out of 394,266 people with type 2 diabetes, we identified 3,277 (0.83%) active episodes of DFD in the database. The majority of these episodes were foot ulcers (82%). The mean age of patients with DFD was 70.3 (± 12.5) years and 55% were male. In the multivariable descriptive models, male gender, diabetes duration, hypertension, macrovascular, microvascular complications, and insulin and antiplatelet agents were strongly associated with DFD. A previous history of DFD was the stronger risk factor for DFD occurrence in subjects with T2DM (OR: 13.19, 95%CI: 11.81; 14.72). Conclusions: In this real-world primary care practice database, we found a lower prevalence of DFD compared to similar previous studies. Risk factors such as male sex, duration of diabetes, diabetes complications and previous history of DFD were associated with the presence of DFD

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal–regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB or CB, or CB-CB heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CBR and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the G protein coupled to CBR. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC/EC values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (Ref. no. BFU2015-64405-R and SAF2017-84117-R; they may include FEDER funds) and by grant 201413-30 from: Fundació la Marató de TV3Peer Reviewe

Spanish Consensus Document on the Treatment Algorithm for Rosacea

Recent scientific evidence and the incorporation of new drugs into the therapeutic arsenal against rosacea have made it necessary to review and update treatment criteria and strategies. To this end, a panel of 15 dermatologists, all experts in rosacea, was formed to share experiences and discuss treatment options, response criteria, and changes to treatment. Based on a critical review of the literature and a discussion of the routine practices of Spanish dermatologists, the panel proposed and debated different options, with consideration of the experience of professionals and the preferences of patients or equality criteria. Following validation of the proposals, the final recommendations were formulated and, together with the evidence from the main international guidelines and studies, used to produce this consensus document. The goal of this consensus document is to provide dermatologists with practical recommendations for the management of rosacea. Las últimas evidencias científicas y la incorporación de nuevos fármacos al arsenal terapéutico de la rosácea hacen necesario revisar y actualizar los criterios y estrategias de tratamiento. Con este fin, un grupo de 15 dermatólogos expertos en esta enfermedad aportaron y discutieron acerca de las diferentes terapias y los criterios de respuesta y cambio de tratamiento. Partiendo de la revisión crítica de la bibliografía y de la exposición de los hábitos de los dermatólogos españoles en su práctica clínica, se formularon distintas propuestas que fueron debatidas teniendo en consideración tanto la experiencia profesional como las preferencias de los pacientes o los criterios de equidad. Una vez validadas las propuestas, se formularon las recomendaciones finales que, junto con la evidencia aportada por las principales guías y estudios internacionales, dieron lugar al presente documento. El objetivo de este consenso es ofrecer al dermatólogo un enfoque práctico para abordar la rosácea

Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs

Non-conding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.Comment: review article, 29 pages, 7 figure

Ask yeast how to burn your fats: lessons learned from the metabolic adaptation to salt stress

[EN] Here, we review and update the recent advances in the metabolic control during the adaptive response of budding yeast to hyperosmotic and salt stress, which is one of the best understood signaling events at the molecular level. This environmental stress can be easily applied and hence has been exploited in the past to generate an impressively detailed and comprehensive model of cellular adaptation. It is clear now that this stress modulates a great number of different physiological functions of the cell, which altogether contribute to cellular survival and adaptation. Primary defense mechanisms are the massive induction of stress tolerance genes in the nucleus, the activation of cation transport at the plasma membrane, or the production and intracellular accumulation of osmolytes. At the same time and in a coordinated manner, the cell shuts down the expression of housekeeping genes, delays the progression of the cell cycle, inhibits genomic replication, and modulates translation efficiency to optimize the response and to avoid cellular damage. To this fascinating interplay of cellular functions directly regulated by the stress, we have to add yet another layer of control, which is physiologically relevant for stress tolerance. Salt stress induces an immediate metabolic readjustment, which includes the up-regulation of peroxisomal biomass and activity in a coordinated manner with the reinforcement of mitochondrial respiratory metabolism. Our recent findings are consistent with a model, where salt stress triggers a metabolic shift from fermentation to respiration fueled by the enhanced peroxisomal oxidation of fatty acids. We discuss here the regulatory details of this stress-induced metabolic shift and its possible roles in the context of the previously known adaptive functions.The work of the authors was supported by grants from Ministerio de Economía y Competitividad (BFU2011- 23326 and BFU2016-75792-R).Pascual-Ahuir Giner, MD.; Manzanares-Estreder, S.; Timón Gómez, A.; Proft ., MH. (2017). Ask yeast how to burn your fats: lessons learned from the metabolic adaptation to salt stress. Current Genetics. 64(1):63-69. https://doi.org/10.1007/s00294-017-0724-5S6369641Aguilera J, Prieto JA (2001) The Saccharomyces cerevisiae aldose reductase is implied in the metabolism of methylglyoxal in response to stress conditions. Curr Genet 39:273–283Albertyn J, Hohmann S, Thevelein JM, Prior BA (1994) GPD1, which encodes glycerol-3-phosphate dehydrogenase, is essential for growth under osmotic stress in Saccharomyces cerevisiae, and its expression is regulated by the high-osmolarity glycerol response pathway. 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Inhibition of Reactive Gliosis Attenuates Excitotoxicity-Mediated Death of Retinal Ganglion Cells

Reactive gliosis is a hallmark of many retinal neurodegenerative conditions, including glaucoma. Although a majority of studies to date have concentrated on reactive gliosis in the optic nerve head, very few studies have been initiated to investigate the role of reactive gliosis in the retina. We have previously shown that reactive glial cells synthesize elevated levels of proteases, and these proteases, in turn, promote the death of retinal ganglion cells (RGCs). In this investigation, we have used two glial toxins to inhibit reactive gliosis and have evaluated their effect on protease-mediated death of RGCs. Kainic acid was injected into the vitreous humor of C57BL/6 mice to induce reactive gliosis and death of RGCs. C57BL/6 mice were also treated with glial toxins, alpha-aminoadipic acid (AAA) or Neurostatin, along with KA. Reactive gliosis was assessed by immunostaining of retinal cross sections and retinal flat-mounts with glial fibrillary acidic protein (GFAP) and vimentin antibodies. Apoptotic cell death was assessed by TUNEL assays. Loss of RGCs was determined by immunostaining of flat-mounted retinas with Brn3a antibodies. Proteolytic activities of matrix metalloproteinase-9 (MMP-9), tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) were assessed by zymography assays. GFAP-immunoreactivity indicated that KA induced reactive gliosis in both retinal astrocytes and in Muller cells. AAA alone or in combination with KA decreased GFAP and vimentin-immunoreactivity in Mϋller cells, but not in astrocytes. In addition AAA failed to decrease KA-mediated protease levels and apoptotic death of RGCs. In contrast, Neurostatin either alone or in combination with KA, decreased reactive gliosis in both astrocytes and Mϋller cells. Furthermore, Neurostatin decreased protease levels and prevented apoptotic death of RGCs. Our findings, for the first time, indicate that inhibition of reactive gliosis decreases protease levels in the retina, prevents apoptotic death of retinal neurons, and provides substantial neuroprotection