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Melanin-concentrating hormone acts through hypothalamic kappa opioid system and p70S6K to stimulate acute food intake

  • Romero-Picó, Amparo
  • Sanchez-Rebordelo, Estrella
  • Imbernon, Monica
  • Gónzalez-Touceda, David
  • Folgueira, Cintia
  • Senra, Ana
  • Fernø, Johan
  • Blouet, Clémence
  • Cabrera Ortega, Roberto
  • Gestel, Margriet van
  • Adan, Roger A.
  • López, Miguel
  • Maldonado, Rafael, 1961-
  • Nogueiras, Ruben
  • Diéguez, Carlos
Melanin-Concentrating Hormone (MCH) is one of the most relevant orexigenic factors specifically located in the lateral hypothalamic area (LHA), with its physiological relevance demonstrated in studies using several genetically manipulated mice models. However, the central mechanisms controlling MCH-induced hyperphagia remain largely uncharacterized. Here, we show that central injection of MCH in mice deficient for kappa opoid receptor (k-OR) failed to stimulate feeding. To determine the hypothalamic area responsible for this MCH/k-OR interaction, we performed virogenetic studies and found that downregulation of k-OR by adeno-associated viruses (shOprk1-AAV) in LHA, but not in other hypothalamic nuclei, was sufficient to block MCH-induced food intake. Next, we sought to investigate the molecular signaling pathway within the LHA that mediates acute central MCH stimulation of food intake. We found that MCH activates k-OR and that increased levels of phosphorylated extracellular signal regulated kinase (ERK) are associated with downregulation of phospho-S6 Ribosomal Protein. This effect was prevented when a pharmacological inhibitor of k-OR was co-administered with MCH. Finally, the specific activation of the direct upstream regulator of S6 (p70S6K) in the LHA attenuated MCH-stimulated food consumption. Our results reveal that lateral hypothalamic k-OR system modulates the orexigenic action of MCH via the p70S6K/S6 pathway., This work has been supported by grants from Ministerio de Economia y Competitividad (CD: BFU2014-55871; RN: BFU2015-70664-R; ML: SAF2015-71026-R), Xunta de Galicia (ML: 2015- CP079; RN: 2015-CP080 and PIE13/00024); Fundacion SEEN (RN); Helse Vest RHF (JF); Fundación AstraZeneca (RN: 2016-PO031); Centro de Investigacion Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutricion (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: RN: ERC StG281408

Association between DNA methylation and coronary heart disease or other atherosclerotic events: A systematic review

  • Fernández Sanlés, Alba
  • Sayols, Sergi
BACKGROUND AND AIMS: The aim of this study was to perform a systematic review of the association between DNA methylation and coronary heart disease (CHD) or related atherosclerotic traits. METHODS: A systematic review was designed. The condition of interest was DNA methylation, and the outcome was CHD or other atherosclerosis-related traits. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). A functional analysis was undertaken using the Ingenuity Pathway Analysis software. RESULTS: In total, 51 articles were included in the analysis: 12 global methylation, 34 candidate-gene and 11 EWAS, with six studies using more than one approach. The results of the global methylation studies were inconsistent. The candidate-gene results were consistent for some genes, suggesting that hypermethylation in ESRα, ABCG1 and FOXP3 and hypomethylation in IL-6 were associated with CHD. The EWAS identified 84 genes showing differential methylation associated with CHD in more than one study. The probability of these findings was <1.37·10-5. One third of these genes have been related to obesity in genome-wide association studies. The functional analysis identified several diseases and functions related to these set of genes: inflammatory, metabolic and cardiovascular disease. CONCLUSIONS: Global DNA methylation seems to be not associated with CHD. The evidence from candidate-gene studies was limited. The EWAS identified a set of 84 genes highlighting the relevance of obesity, inflammation, lipid and carbohydrate metabolism in CHD. This set of genes could be prioritized in future studies assessing the role of DNA methylation in CHD.

psygenet2r: a R/Bioconductor package for the analysis of psychiatric disease genes

  • Gutiérrez Sacristán, Alba
  • Hernández Ferrer, Carles
  • González, Juan Ramón
  • Furlong, Laura I., 1971-
MOTIVATION: Psychiatric disorders have a great impact on morbidity and mortality. Genotype-phenotype resources for psychiatric diseases are key to enable the translation of research findings to a better care of patients. PsyGeNET is a knowledge resource on psychiatric diseases and their genes, developed by text mining and curated by domain experts. RESULTS: We present psygenet2r, an R package that contains a variety of functions for leveraging PsyGeNET database and facilitating its analysis and interpretation. The package offers different types of queries to the database along with variety of analysis and visualization tools, including the study of the anatomical structures in which the genes are expressed and gaining insight of gene's molecular function. Psygenet2r is especially suited for network medicine analysis of psychiatric disorders. AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and is available under MIT license from Bioconductor (http://bioconductor.org/packages/release/bioc/html/psygenet2r.html)., This work was supported by ISCIII-FEDER [PI13/00082, CP10/00524, CPII16/00026], MICINN [MTM2015-68140-R], IMI-JU under grants agreements no. 115191 (Open PHACTS), no. 115372 (EMIF), no. 115735 (iPiE), resources of which are composed of financial contribution from the EU-FP7 [FP7/2007–2013] and EFPIA companies in kind contribution, and the EU H2020 Programme 2014–2020 under grant agreements no. 634143 (MedBioinformatics) and no. 676559 (Elixir-Excelerate). The Research Programme on Biomedical Informatics (GRIB) is a member of ELIXIR-ES and the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001/0023, of the PE I + D+i 2013-2016, funded by ISCIII and FEDER. A.G.S. acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the ‘María de Maeztu’ Programme for Units of Excellence in R&D [MDM-2014-0370].

Large-scale external validation and comparison of prognostic models: An application to chronic obstructive pulmonary disease

  • Guerra, Beniamino
  • García Aymerich, Judith
  • Antó i Boqué, Josep Maria
  • Puhan, Milo A.
  • Crystal structure of cold-aminopeptidase from Colwellia psychrerythraea (3CIA) collaborators
BACKGROUND: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. METHODS: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. RESULTS: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUCADO - AUCBODE = 0.015 [95% confidence interval (CI) = -0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated - AUCBODE = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. CONCLUSIONS: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.

Systematic analysis of splice-site-creating mutations in cancer

  • Jayasinghe, Reyka G.
  • Eyras Jiménez, Eduardo
  • Ding, Li
  • The Cancer Genome Atlas (TCGA) Research Network
For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

Co-administration of antimicrobial peptides enhances toll-like receptor 4 antagonist activity of a synthetic glycolipid

  • Facchini, Fabio A.
  • Coelho, Helena
  • Sestito, Stefania Enza
  • Delgado, Sandra
  • Minotti, Alberto
  • Andreu Martínez, David
  • Jiménez-Barbero, Jesús J.
  • Peri, Francesco
This study examines the effect of co-administration of antimicrobial peptides and the synthetic glycolipid FP7, which is active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two lipopolysaccharide (LPS)-neutralizing peptides (a cecropin A-melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, because it also occurs if cells are stimulated by the plant lectin phytohemagglutinin, a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on the LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of the TLR4 response., This study was financially supported by the H2020‐MSC‐ETN‐642157 project TOLLerant. The Italian Ministry for Foreign Affairs and International Cooperation (MAECI) is acknowledged. Work at Pompeu Fabra University was supported by MINECO (grants SAF2011‐24899, AGL2014‐52395‐C2‐2‐R to D.A., CTQ2015‐64597‐C2‐1‐P and MINECO‐Severo Ochoa Excellence Acreditation 2017-2021 (SEV‐2016‐0644) to J.J.‐B.) with FEDER funds, and by Generalitat de Catalunya (2014SGR692).

Short-term effects of ultrafine particles on daily mortality by primary vehicle exhaust versus secondary origin in three Spanish cities

  • Tobias, Aurelio
  • Rivas, Ioar
  • Reche, Cristina
  • Alastuey, Andrés
  • Rodríguez, Sergio Betancourt
  • Fernández Camacho, Rocío
  • Sánchez de la Campa, Ana M.
  • Rosa, Jesús de la
  • Sunyer Deu, Jordi
  • Querol, Xavier
BACKGROUND: Evidence on the short-term effects of ultrafine particles (with diameter<100nm, UFP) on health is still inconsistent. New particles in ambient urban air are the result of direct emissions and also the formation of secondary UFP from gaseous precursors. We segregated UFP into these two components and investigated their impact on daily mortality in three Spanish cities affected by different sources of air pollution. METHODS: We separated the UFP using a method based on the high correlation between black carbon (BC) and particle number concentration (N). The first component accounts for aerosol constituents emitted by vehicle exhaust (N1) and the second for the photochemical new particle formation enhancements (N2). We applied city-specific Poisson regression models, adjusting for long-term trends, temperature and population dynamics. RESULTS: Mean BC levels were higher in Barcelona and Tenerife (1.8 and 1.2μg·m-3, respectively) than in Huelva (0.8μg·m-3). While mean UFP concentrations were similar in the three cities, from which N1 was 40% in Barcelona, 46% in Santa Cruz de Tenerife, and 27% in Huelva. We observed an association with N1 and daily mortality in Barcelona, by increasing approximately 1.5% between lags 0 and 2, per an interquartile increase (IQR) of 3277cm-3, but not with N2. A similar pattern was found in Santa Cruz de Tenerife, although none of the associations were significant. Conversely, in the industrial city of Huelva mortality was associated with N2 at lag 0, by increasing 3.9% per an IQR of 12,032·cm-3. CONCLUSION: The pattern and origin of UFP determines their short-term effect on human health. BC is possibly the better parameter to evaluate the health effects of particulate vehicle exhaust emissions, although in areas influenced by domestic solid fuel combustion this should also be taken into account., This study was supported by the National Plan for I+D+I (project PI15/00515) co-funded by the ISCIII Directorate General for Evaluation and the European Regional Development Fund (FEDER), by the Ministry of Economy, Industry and Competitiveness and FEDER funds (project HOUSE, CGL2016-78594-R) and by the Generalitat de Catalunya (AGAUR 2015 SGR33 and DGQA).

Short-term exposure to traffic-related air pollution and ischemic stroke onset in Barcelona, Spain

  • Vivanco Hidalgo, Rosa María
  • Wellenius, Gregory A.
  • Basagaña Flores, Xavier
  • Cirach, Marta
  • González, Alejandra Gómez
  • Ceballos, Pablo de
  • Zabalza, Ana
  • Jiménez Conde, Jordi
  • Soriano Tarraga, Carolina
  • Giralt-Steinhauer, Eva
  • Alastuey, Andrés
  • Querol, Xavier
  • Sunyer Deu, Jordi
  • Roquer, Jaume
OBJECTIVE: To assess the relationship between short-term exposure to outdoor ambient air pollutants (fine particulate matter [PM2.5] and black carbon [BC]), ischemic stroke (IS) and its different subtypes, and the potential modifying effect of neighborhood greenspace and noise. METHODS: This time-stratified case-crossover study was based on IS and transient ischemic attacks (TIA) recorded in a hospital-based prospective stroke register (BASICMAR 2005-2014) in Barcelona (Catalonia, Spain). Daily and hourly pollutant concentrations and meteorological data were obtained from monitoring stations in the city. Time-lags (from previous 72h to acute stroke onset) were analyzed. Greenness and noise were determined from the Normalized Difference Vegetation Index (NDVI) and daily average noise level at the street nearest to residential address, respectively. RESULTS: The 2742 cases with known onset date and time, living in the study area, were analyzed. After adjusting for temperature, no statistically significant association between pollutants exposure and overall stroke risk was found. In subtype analysis, an association was detected between BC exposure at 24-47h (odds ratio, 1.251; 95% confidence interval [CI], 1.001-1.552; P = 0.042) and 48-72h (1.211; 95% CI, 0.988-1.484; P = 0.065) time-lag prior to stroke onset and large-artery atherosclerosis subtype. No clear modifying effect of greenness or noise was observed. CONCLUSIONS: Overall, no association was found between PM2.5 and BC exposure and acute IS risk. By stroke subtype, large-artery atherosclerotic stroke could be triggered by daily increases in BC, a diesel fuel-related pollutant in the study area.

Benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside increases human immunodeficiency virus replication and viral outgrowth efficacy in vitro

  • Olvera, Alex
  • Martínez, Javier P.
  • Casadellà, Maria
  • Llano, Anuska
  • Rosás, Míriam
  • Mothe, Beatriz
  • Ruiz Riol, Marta
  • Arsequell, Gemma
  • Valencia, Gregorio
  • Noguera Julián, Marc
  • Paredes, Roger
  • Meyerhans, Andreas
  • Brander, Christian
Glycosylation of host and viral proteins is an important posttranslational modification needed to ensure correct function of glycoproteins. For this reason, we asked whether inhibition of O-glycosylation during human immunodeficiency virus (HIV) in vitro replication could affect HIV infectivity and replication rates. We used benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (BAGN), a compound that has been widely used to inhibit O-glycosylation in several cell lines. Pretreatment and culture of PHA-blast target cells with BAGN increased the percentage of HIV-infected cells (7.6-fold, p = 0.0115), the per-cell amount of HIV p24 protein (1.3-fold, p = 0.2475), and the viral particles in culture supernatants (7.1-fold, p = 0.0029) compared to BAGN-free cultures. Initiating infection with virus previously grown in the presence of BAGN further increased percentage of infected cells (30-fold, p < 0.0001), intracellular p24 (1.5-fold, p = 0.0433), and secreted viral particles (74-fold, p < 0.0001). BAGN-treated target cells showed less CD25 and CCR5 expression, but increased HLA-DR surface expression, which positively correlated with the number of infected cells. Importantly, BAGN improved viral outgrowth kinetics in 66% of the samples tested, including samples from HIV controllers and subjects in whom no virus could be expanded in the absence of BAGN. Sequencing of the isolated virus indicated no skewing of viral quasi-species populations when compared to BAGN-free culture conditions. BAGN also increased virus production in the ACH2 latency model when used together with latency-reversing agents. Taken together, our results identify BAGN treatment as a simple strategy to improve viral outgrowth in vitro and may provide novel insights into host restriction mechanisms and O-glycosylation-related therapeutic targets for HIV control strategies., The present study was supported by grant PI12/00529 (AO) from the Instituto de Salud Carlos III, co-financed by the Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” and funding from the European Union's Horizon 2020 research and innovation program under grant European AIDS Vaccine Initiative 2020 (EAVI2020) #GA681137 (CB). JM and AM were supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness and FEDER grant no. SAF2016-75505-R (AEI/MINEICO/FEDER, UE). CB and AM are senior ICREA research professors. The HIVACAT program, Foundation Dormeur, Vaduz (Liechtenstein), and an unrestricted gift by Rafael Punter, Barcelona (Spain) and the Gala SIDA 2014-2016, further supported the work.

Acute pharmacological effects of 2C-B in humans: An observational study

  • Papaseit Fontanet, Esther
  • Farré Albaladejo, Magí
  • Pérez Mañá, Clara
  • Torrens, Marta
  • Ventura, Mireia
  • Pujadas, Mitona
  • Torre Fornell, Rafael de la
  • González, Débora
2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2-3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs.

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