Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins

Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.This project has been financed through a) The ISCIII (Miguel Servet-I, 2015), co-financed by the European Regional Development Fund (ERDF), No CP15/00071. b) The European Union’s Horizon 2020 research and innovation program, under grant agreement No 634479. c) Regional Ministry of Economy, Innovation and Science of the Junta de Andalucía, No P09-CTS-04967.info:eu-repo/semantics/publishedVersio

Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study

Background/aims: Previous evidences have shown the presence of a prolonged and exaggerated postprandial response in type 2 diabetes mellitus (T2DM) and its relation with an increase of cardiovascular risk. However, the response in prediabetes population has not been established. The objective was to analyze the degree of postprandial lipemia response in the CORDIOPREV clinical trial (NCT00924937) according to the diabetic status. Methods: 1002 patients were submitted to an oral fat load test meal (OFTT) with 0.7 g fat/kg body weight [12 % saturated fatty acids (SFA), 10 % polyunsaturated fatty acids (PUFA), 43 % monounsaturated fatty acids (MUFA), 10 % protein and 25 % carbohydrates]. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 h during postprandial state. Postprandial triglycerides (TG) concentration at any point >2.5 mmol/L (220 mg/dL) has been established as undesirable response. We explored the dynamic response in 57 non-diabetic, 364 prediabetic and 581 type 2 diabetic patients. Additionally, the postprandial response was evaluated according to basal insulin resistance subgroups in patients non-diabetic and diabetic without pharmacological treatment (N = 642). Results: Prevalence of undesirable postprandial TG was 35 % in non-diabetic, 48 % in prediabetic and 59 % in diabetic subgroup, respectively (p < 0.001). Interestingly, prediabetic patients displayed higher plasma TG and large triacylglycerol- rich lipoproteins (TRLs-TG) postprandial response compared with those non-diabetic patients (p < 0.001 and p = 0.003 respectively). Moreover, the area under the curve (AUC) of TG and AUC of TRLs-TG was greater in the prediabetic group compared with non-diabetic patients (p < 0.001 and p < 0.005 respectively). Patients with liver insulin resistance (liver-IR) showed higher postprandial response of TG compared with those patients with muscle-IR or without any insulin-resistance respectively (p < 0.001). Conclusions: Our findings demonstrate that prediabetic patients show a lower phenotypic flexibility after external aggression, such as OFTT compared with nondiabetic patients. The postprandial response increases progressively according to non-diabetic, prediabetic and type 2 diabetic state and it is higher in patients with liver insulin-resistance. To identify this subgroup of patients is important to treat more intensively in order to avoid future cardiometabolic complications

Inhibitory Effect of Azamacrocyclic Ligands on Polyphenol Oxidase in Model and Food Systems

This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in Journal of Agricultural and Food Chemistry, copyright © American Chemical Society after peer review. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jafc.0c02407[EN] Enzymatic browning is one of the main problems faced by the food industry due to the enzyme polyphenol oxidase (PPO) provoking an undesirable color change in the presence of oxygen. Here, we report the evaluation of 10 different azamacrocyclic compounds with diverse morphologies as potential inhibitors against the activity of PPO, both in model and real systems. An initial screening of 10 ligands shows that all azamacrocyclic compounds inhibit to some extent the enzymatic browning, but the molecular structure plays a crucial role on the power of inhibition. Kinetic studies of the most active ligand (L2) reveal a S-parabolic I-parabolic noncompetitive inhibition mechanism and a remarkable inhibition at micromolar concentration (IC50 = 10 mu M). Furthermore, L2 action has been proven on apple juice to significantly reduce the enzymatic browning.Financial support by the Spanish Ministerio de Ciencia, Innovacion y Universidades (project RTI2018-100910-B-C44), Ministerio de Economia y Competitividad (projects CTQ2016-78499-C6-1-R, Unidad de Excelencia MDM 2015-0038 and CTQ2017-90852-REDC), and Generalitat Valenciana (Project PROMETEOII2015-002) is gratefully acknowledged.Muñoz-Pina, S.; Ros-Lis, JV.; Delgado-Pinar, E.; Martínez-Camarena, Á.; Verdejo, B.; García-España, E.; Argüelles Foix, AL.... (2020). Inhibitory Effect of Azamacrocyclic Ligands on Polyphenol Oxidase in Model and Food Systems. Journal of Agricultural and Food Chemistry. 68(30):7964-7973. https://doi.org/10.1021/acs.jafc.0c02407796479736830Simpson, B. K. (Ed.). (2012). 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Geomorphology of the Avilés Canyon System, Cantabrian Sea (BayofBiscay)

The Avilés Canyon System (ACS) is a complex, structurally-controlled canyon and valley system constituted by three main canyons of different morphostructural character. They are, from east to west: La Gaviera Canyon, El Corbiro Canyon and Avilés Canyon. In addition to this ACS, a new canyon has been surveyed: Navia Canyon. We present for the first time a high resolution multibeam map showing with great detail the morphological and structural complexity of this segment of the Cantabrian margin. ACS presents a tectonic imprint marked by NW-SE, NNE-SSW and E-W structures. The morphology of their reaches as well as their single mouth, in addition to some rock dredges in their major valleys, demonstrates active down-slope flushing. The continental shelf shows a flat, uniform slope with local and well defined rock outcrops south of Aviles Canyon head. Sedimentary zones are limited, showing thin unconsolidated sedimentary cover. Strong continental margin water dynamics avoid thicker sediment deposition, being littoral sedimentary dynamics responsible for transport to the canyons heads and conduit to the Biscay Abyssal plain. Biscay Abyssal Plain shows evidence of a strong westward current affecting the surveyed strip of this more than 10 km wide plain. Presence of two parallel deep sea channels, erosive scarps, and erosion of gully divides on the lower slope, may indicate that this is part of the distal fan at the termination of the large turbiditic system fed by Cap Ferret, Capbreton and other large canyons (Santander, Torrelavega, Lastres and Llanes) to the west of ACS.Instituto Español de OceanografíaVersión del edito

Engineering of III-Nitride Semiconductors on Low Temperature Co-fired Ceramics

This work presents results in the feld of advanced substrate solutions in order to achieve high crystalline quality group-III nitrides based heterostructures for high frequency and power devices or for sensor applications. With that objective, Low Temperature Co-fred Ceramics has been used, as a noncrystalline substrate. Structures like these have never been developed before, and for economic reasons will represent a groundbreaking material in these felds of Electronic. In this sense, the report presents the characterization through various techniques of three series of specimens where GaN was deposited on this ceramic composite, using diferent bufer layers, and a singular metal-organic chemical vapor deposition related technique for low temperature deposition. Other single crystalline ceramic-based templates were also utilized as substrate materials, for comparison purposes

Maximal respiratory pressure reference equations in healthy adults and cut-off points for defining respiratory muscle weakness

[Abstract] Introduction: Maximal inspiratory and expiratory pressures (PImax/PEmax) reference equations obtained in healthy people are needed to correctly interpret respiratory muscle strength. Currently, no clear cut-off points defining respiratory muscle weakness are available. We aimed to establish sex-specific reference equations for PImax/PEmax in a large sample of healthy adults and to objectively determine cut-off points for respiratory muscle weakness. Methods: A multicentre cross-sectional study was conducted across 14 Spanish centres. Healthy non-smoking volunteers aged 18-80 years stratified by sex and age were recruited. PImax/PEmax were assessed using uniform methodology according to international standards. Multiple linear regressions were used to obtain reference equations. Cut-off points for respiratory muscle weakness were established by using T-scores. Results: The final sample consisted of 610 subjects (314 females; 48 [standard deviation, SD: 17] years). Reference equations for PImax/PEmax included body mass index and a squared term of the age as independent variables for both sexes (p<0.01). Cut-off points for respiratory muscle weakness based on T-scores ≥2.5 SD below the peak mean value achieved at a young age were: 62 and 83cmH2O for PImax and 81 and 109cmH2O for PEmax in females and males, respectively. Conclusion: These reference values, based on the largest dataset collected in a European population to date using uniform methodology, help identify cut-off points for respiratory muscle weakness in females and males. These data will help to better identify the presence of respiratory muscle weakness and to determine indications for interventions to improve respiratory muscle function

Temperament and Impulsivity Predictors of Smoking Cessation Outcomes

Aims: Temperament and impulsivity are powerful predictors of addiction treatment outcomes. However, a comprehensive assessment of these features has not been examined in relation to smoking cessation outcomes.Methods: Naturalistic prospective study. Treatment-seeking smokers (n = 140) were recruited as they engaged in an occupational health clinic providing smoking cessation treatment between 2009 and 2013. Participants were assessed at baseline with measures of temperament (Temperament and Character Inventory), trait impulsivity (Barratt Impulsivity Scale), and cognitive impulsivity (Go/No Go, Delay Discounting and Iowa Gambling Task). The outcome measure was treatment status, coded as “dropout” versus “relapse” versus “abstinence” at 3, 6, and 12 months endpoints. Participants were telephonically contacted and reminded of follow-up face to face assessments at each endpoint. The participants that failed to answer the phone calls or self-reported discontinuation of treatment and failed to attend the upcoming follow-up session were coded as dropouts. The participants that self-reported continuing treatment, and successfully attended the upcoming follow-up session were coded as either “relapse” or “abstinence”, based on the results of smoking behavior self-reports cross-validated with co-oximetry hemoglobin levels. Multinomial regression models were conducted to test whether temperament and impulsivity measures predicted dropout and relapse relative to abstinence outcomes.Results: Higher scores on temperament dimensions of novelty seeking and reward dependence predicted poorer retention across endpoints, whereas only higher scores on persistence predicted greater relapse. Higher scores on the trait dimension of non-planning impulsivity but not performance on cognitive impulsivity predicted poorer retention. Higher non-planning impulsivity and poorer performance in the Iowa Gambling Task predicted greater relapse at 3 and 6 months and 6 months respectively.Conclusion: Temperament measures, and specifically novelty seeking and reward dependence, predict smoking cessation treatment retention, whereas persistence, non-planning impulsivity and poor decision-making predict smoking relapse.This research was funded by the Occupational Medicine Area (Prevention Service); Department of Personality, Assessment and Psychological Treatment, University of Granada (Spain); and Ministerio de Economía y Competitividad grant (MINICO, ref. # PSI2013-45055-P) for the first and second authors