Angiocrine polyamine production regulates adiposity.

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid β-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.We thank members of the Endothelial Pathobiology and Microenvironment Group for helpful discussions. We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. The research leading to these results has received funding from la Fundación BBVA (Ayuda Fundacion BBVA a Equipos de Investigación Científica 2019, PR19BIOMET0061) and from SAF2017-82072-ERC from Ministerio de Ciencia, Innovación y Universidades (MCIU) (Spain). The laboratory of M.G. is also supported by the research grants SAF2017-89116R-P (FEDER/EU) co-funded by European Regional Developmental Fund (ERDF), a Way to Build Europe and PID2020-116184RB-I00 from MCEI; by the Catalan Government through the project 2017-SGR; PTEN Research Foundation (BRR-17-001); La Caixa Foundation (HR19-00120 and HR21-00046); by la Asociación Española contra el Cancer-Grupos Traslacionales (GCTRA18006CARR, also to A.C.); European Foundation for the Study of Diabetes/Lilly research grant, also to M.C.); and by the People Programme (Marie Curie Actions; grant agreement 317250) of the European Union’s Seventh Framework Programme FP7/2007-2013 and the Marie Skłodowska-Curie (grant agreement 675392) of the European Union’s Horizon 2020 research. The laboratory of A.C. is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the department of education (IKERTALDE IT1106-16), the MCIU (PID2019-108787RB-I00 (FEDER/ EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17, the Vencer el Cancer foundation and the European Research Council (ERC) (consolidator grant 819242). CIBERONC was co-funded with FEDER funds and funded by Instituto de Salud Carlos III (ISCIII). The laboratory of M.C. is supported by the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). The laboratory of D.S. is supported by research grants from MINECO (SAF2017- 83813-C3-1-R, also to L.H., cofounded by the ERDF), CIBEROBN (CB06/03/0001), Government of Catalonia (2017SGR278) and Fundació La Marató de TV3 (201627- 30). The laboratory of R.N. is supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (RTI2018-099413-B-I00 and and RED2018-102379-T), Xunta de Galicia (2016-PG057 and 2020-PG015), ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 810331), Fundación BBVA, Fundacion Atresmedia and CIBEROBN, which is an initiative of the ISCIII of Spain, which is supported by FEDER funds. The laboratory of J.A.V. is supported by research grants from MICINN (RTI2018-099250-B100) and by La Caixa Foundation (ID 100010434, LCF/PR/HR17/52150009). P.M.G.-R. is supported by ISCIII grant PI15/00701 cofinanced by the ERDF, A Way to Build Europe. Personal support was from Marie Curie ITN Actions (E.M.), Juan de la Cierva (IJCI-2015-23455, P.V.), CONICYT fellowship from Chile (S.Z.), Vetenskapsradet (Swedish Research Council, 2018-06591, L.G.) and NCI K99/R00 Pathway to Independence Award (K99CA245122, P. Castel).S

CARMENES input catalog of M dwarfs: VII. New rotation periods for the survey stars and their correlations with stellar activity

Abridged: We measured photometric and spectroscopic $P_{\rm rot}$ for a large sample of nearby bright M dwarfs with spectral types from M0 to M9, as part of our continual effort to fully characterize the Guaranteed Time Observation programme stars of the CARMENES survey. We determine $P_{\rm rot}$ for 129 stars. Combined with the literature, we tabulate $P_{\rm rot}$ for 261 stars, or 75% of our sample. We evaluate the plausibility of all periods available for this sample by comparing them with activity signatures and checking for consistency between multiple measurements. We find that 166 of these stars have independent evidence that confirmed their $P_{\rm rot}$. There are inconsistencies in 27 periods, which we classify as debated. A further 68 periods are identified as provisional detections that could benefit from independent verification. We provide an empirical relation for the $P_{\rm rot}$ uncertainty as a function of the $P_{\rm rot}$ value, based on the dispersion of the measurements. We show that published formal errors seem to be often underestimated for periods $\gtrsim 10$ d. We highlight the importance of independent verification on $P_{\rm rot}$ measurements, especially for inactive M dwarfs. We examine rotation-activity relations with emission in X-rays, H$\alpha$, Ca II H & K, and surface magnetic field strengths. We find overall agreement with previous works, as well as tentative differences in the partially versus fully convective subsamples. We show $P_{\rm rot}$ as a function of stellar mass, age, and galactic kinematics. With the notable exception of three transiting planet systems and TZ Ari, all known planet hosts in this sample have $P_{\rm rot} \gtrsim 15$ d. This indicates that important limitations need to be overcome before the radial velocity technique can be routinely used to detect and study planets around young and active stars.Comment: Accepted for publication in A&

Heart failure in COVID-19 patients: prevalence, incidence and prognostic implications

Aims: Data on the impact of COVID-19 in chronic heart failure (CHF) patients and its potential to trigger acute heart failure (AHF) are lacking. The aim of this work was to study characteristics, cardiovascular outcomes and mortality in patients with confirmed COVID-19 infection and a prior diagnosis of heart failure (HF). Further aims included the identification of predictors and prognostic implications for AHF decompensation during hospital admission and the determination of a potential correlation between the withdrawal of HF guideline-directed medical therapy (GDMT) and worse outcomes during hospitalization. Methods and results: Data for a total of 3080 consecutive patients with confirmed COVID-19 infection and follow-up of at least 30 days were analysed. Patients with a previous history of CHF (n = 152, 4.9%) were more prone to the development of AHF (11.2% vs. 2.1%; P < 0.001) and had higher levels of N-terminal pro brain natriuretic peptide. In addition, patients with previous CHF had higher mortality rates (48.7% vs. 19.0%; P < 0.001). In contrast, 77 patients (2.5%) were diagnosed with AHF, which in the vast majority of cases (77.9%) developed in patients without a history of HF. Arrhythmias during hospital admission and CHF were the main predictors of AHF. Patients developing AHF had significantly higher mortality (46.8% vs. 19.7%; P < 0.001). Finally, the withdrawal of beta-blockers, mineralocorticoid receptor antagonists and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant increase in in-hospital mortality. Conclusions: Patients with COVID-19 have a significant incidence of AHF, which is associated with very high mortality rates. Moreover, patients with a history of CHF are prone to developing acute decompensation after a COVID-19 diagnosis. The withdrawal of GDMT was associated with higher mortalit

Jardins per a la salut

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia. Assignatura: Botànica farmacèutica. Curs: 2014-2015. Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són el recull de les fitxes botàniques de 128 espècies presents en el Jardí Ferran Soldevila de l’Edifici Històric de la UB. Els treballs han estat realitzats manera individual per part dels estudiants dels grups M-3 i T-1 de l’assignatura Botànica Farmacèutica durant els mesos de febrer a maig del curs 2014-15 com a resultat final del Projecte d’Innovació Docent «Jardins per a la salut: aprenentatge servei a Botànica farmacèutica» (codi 2014PID-UB/054). Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pels professors de l’assignatura. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica. També s’ha pretès motivar els estudiants a través del retorn de part del seu esforç a la societat a través d’una experiència d’Aprenentatge-Servei, deixant disponible finalment el treball dels estudiants per a poder ser consultable a través d’una Web pública amb la possibilitat de poder-ho fer in-situ en el propi jardí mitjançant codis QR amb un smartphone

Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation

Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía

El PIMCD Precariedad, exclusión social y diversidad funcional (discapacidad): lógicas y efectos subjetivos del sufrimiento social contemporáneo (III). Innovación docente en Filosofía se ocupa de conceptos que generalmente han tendido a ser eludidos en la enseñanza académica de filosofía. Se trata de la tercera edición de un PIMCD que ha venido recibiendo financiación en las últimas convocatorias PIMCD UCM, de los que se han derivado publicaciones colectivas publicadas por Ediciones Complutense y Siglo XXI

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery

Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.This research: including APC charges, was funded by the Spanish Agencia Estatal de Investigación (Ministry of Science and Innovation) and the European Regional Development Fund [grant numbers CTQ2014-56370-R, CTQ2014-53598, and CTQ2017-85658-R]; Fundación Ramón Areces; and the initiative Solidaridad Entre Montañas. J.H. acknowledges financial support from the Flemish government through long-term structural funding Methusalem (CASAS2, Meth/15/04).Ye

Influence of statin treatment in a cohort of patients admitted for COVID-19

Aims and objectives: Statins have been proposed as potentially useful agents for modulating the host response in COVID-19. However, solid evidence-based recommendations are still lacking. Our aim was to study the association between statin use and clinical outcomes in a large cohort of hospitalized patients with SARS-CoV-2 infection, as well as the specific consequences of chronic treatment withdrawal during hospital admission. Material and methods: Retrospective observational study including 2191 hospitalized patients with confirmed SARS-CoV-2 infection. Results: Mean age was 68.0±17.8 years and 597 (27.3%) patients died during follow-up. A total of 827 patients (37.7% of the whole sample), received chronic treatment with statins. Even though they underwent more frequent admissions in critical care units, chronic treatment with statins was not independently associated with all-cause mortality [HR 0.95 (0.72-1.25)]. During the whole hospital admission, 371 patients (16.9%) received at least one dose of statin. Although these patients had a significantly worse clinical profile, both treatment with statins during admission [HR 1.03 (0.78-1.35)] and withdrawal of chronic statin treatment [HR 1.01 (0.78-1.30)] showed a neutral effect in mortality. However, patients treated with statins presented more frequently hepatic cytolysis, rhabdomyolysis and thrombotic/hemorrhagic events. Conclusions: In this large cohort of hospitalized COVID-19 patients, statins were not independently associated with all-cause mortality during follow-up. Clinically relevant statin-associated adverse effects should be carefully monitored during hospital admissio