MicroRNA-222 regulates muscle alternative splicing through Rbm24 during differentiation of skeletal muscle cells

A number of microRNAs have been shown to regulate skeletal muscle development and differentiation. MicroRNA-222 is downregulated during myogenic differentiation and its overexpression leads to alteration of muscle differentiation process and specialized structures. By using RNA-induced silencing complex (RISC) pulldown followed by RNA sequencing, combined with in silico microRNA target prediction, we have identified two new targets of microRNA-222 involved in the regulation of myogenic differentiation, Ahnak and Rbm24. Specifically, the RNA-binding protein Rbm24 is a major regulator of muscle-specific alternative splicing and its downregulation by microRNA-222 results in defective exon inclusion impairing the production of muscle-specific isoforms of Coro6, Fxr1 and NACA transcripts. Reconstitution of normal levels of Rbm24 in cells overexpressing microRNA-222 rescues muscle-specific splicing. In conclusion, we have identified a new function of microRNA-222 leading to alteration of myogenic differentiation at the level of alternative splicing, and we provide evidence that this effect is mediated by Rbm24 protei

Aprendizaje del Fibrobroncoscopio del Servicio de Anestesiología del Hospital Universitario de Getafe: Programa de aprendizaje

Las complicaciones más severas en Anestesiología son las relacionadas con la Vía Aérea, y una dificultad de intubación o ventilación del paciente originan una gran mórbida/mortalidad. En los últimos años, para mejorar la seguridad del paciente en este campo, ha habido una evolución muy importante en el manejo de la Vía Aérea Difícil (VAD). Las Sociedades internacionales más prestigiosas de este campo aconsejan en sus últimos trabajos y guías (ASA [Sociedad Americana de Vía Aérea Difícil] en el algoritmo del 2013, y la DAS [Difficult Airway Society] en el NAP4 y las guías de 2015….) aconsejan que todos los miembros del servicio de Anestesiología sean capaces de poder realizar una intubación con Fibroscopio (FOB) en paciente despierto cuando se precise. Es decir, en aquellos pacientes que tienen una intubación difícil conocida, y en los que administrarles anestesia general para realizar una intubación, perdiendo la respiración espontanea, supone un riesgo muy importante para ellos

Benznidazole in cerebrospinal fluid: A case series of chagas disease meningoencephalitis in hiv-positive patients

Chagas disease reactivation in HIV-positive people is an opportunistic infection with 79 to 100% mortality. It commonly involves the central nervous system (CNS). Early treatment with trypanocidal drugs such as benznidazole (BNZ) is crucial for this severe manifestation of Trypanosoma cruzi infection. However, limited BNZ clinical pharmacology data are available, especially its concentration in the CNS. We report a series of HIV-positive patients undergoing treatment for T. cruzi meningoencephalitis, their clinical response, and cerebrospinal fluid (CSF) and plasma BNZ concentrations. Measurements were carried out using leftover samples originally obtained for routine medical care. A high-performance liquid chromatography/tandem mass spectrometry bioanalytical method designed for BNZ plasma measurements was adapted and validated for CSF samples. Six patients were enrolled in this study from 2015 to 2019. A total of 6 CSF and 19 plasma samples were obtained. Only three of the CSF samples had detectable BNZ levels, all under 1mg/ml. Fifteen plasma samples had detectable BNZ, and 13 were above 2mg/ml, which is the putative trypanocidal level. We observed BNZ concentrations in human CSF and plasma. CSF BNZ concentrations were low or not measurable in all patients, suggesting that the usual BNZ doses may be suboptimal in HIV-positive patients with T. cruzi meningoencephalitis. While drug-drug and drug-disease interactions may be in part responsible, the factors leading to low CSF BNZ levels remain to be studied in detail. These findings highlight the potential of therapeutic drug monitoring in BNZ treatment and suggest that the use of higher doses may be useful for Chagas disease CNS reactivations

Short- and Long-Term Prognosis of Patients With Takotsubo Syndrome Based on Different Triggers: Importance of the Physical Nature

Background Takotsubo syndrome (TTS) is an acute reversible heart condition initially believed to represent a benign pathology attributable to its self-limiting clinical course; however, little is known about its prognosis based on different triggers. This study compared short- and long-term outcomes between TTS based on different triggers, focusing on various physical triggering events. Methods and Results We analyzed patients with a definitive TTS diagnosis recruited for the Spanish National Registry on TTS (RETAKO [Registry on Takotsubo Syndrome]). Short- and long-term outcomes were compared between different groups according to triggering factors. A total of 939 patients were included. An emotional trigger was detected in 340 patients (36.2%), a physical trigger in 293 patients (31.2%), and none could be identified in 306 patients (32.6%). The main physical triggers observed were infections (30.7%), followed by surgical procedures (22.5%), physical activities (18.4%), episodes of severe hypoxia (18.4%), and neurological events (9.9%). TTS triggered by physical factors showed higher mortality in the short and long term, and within this group, patients whose physical trigger was hypoxia were those who had a worse prognosis, in addition to being triggered by physical factors, including age >70 years, diabetes mellitus, left ventricular eyection fraction <30% and shock on admission, and increased long-term mortality risk. Conclusions TTS triggered by physical factors could present a worse prognosis in terms of mortality. Under the TTS label, there could be as yet undiscovered very different clinical profiles, whose differentiation could lead to individual better management, and therefore the perception of TTS as having a benign prognosis should be generally ruled out

The IRYSS-COPD appropriateness study: objectives, methodology, and description of the prospective cohort

<p>Abstract</p> <p>Background</p> <p>Patients with chronic obstructive pulmonary disease (COPD) often experience exacerbations of the disease that require hospitalization. Current guidelines offer little guidance for identifying patients whose clinical situation is appropriate for admission to the hospital, and properly developed and validated severity scores for COPD exacerbations are lacking. To address these important gaps in clinical care, we created the IRYSS-COPD Appropriateness Study.</p> <p>Methods/Design</p> <p>The RAND/UCLA Appropriateness Methodology was used to identify appropriate and inappropriate scenarios for hospital admission for patients experiencing COPD exacerbations. These scenarios were then applied to a prospective cohort of patients attending the emergency departments (ED) of 16 participating hospitals. Information was recorded during the time the patient was evaluated in the ED, at the time a decision was made to admit the patient to the hospital or discharge home, and during follow-up after admission or discharge home. While complete data were generally available at the time of ED admission, data were often missing at the time of decision making. Predefined assumptions were used to impute much of the missing data.</p> <p>Discussion</p> <p>The IRYSS-COPD Appropriateness Study will validate the appropriateness criteria developed by the RAND/UCLA Appropriateness Methodology and thus better delineate the requirements for admission or discharge of patients experiencing exacerbations of COPD. The study will also provide a better understanding of the determinants of outcomes of COPD exacerbations, and evaluate the equity and variability in access and outcomes in these patients.</p

Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project

Background: Prenatal exposure to air pollutants has been suggested as a possible etiologic factor for the occurrence of autism spectrum disorder. Objectives: We aimed to assess whether prenatal air pollution exposure is associated with childhood autistic traits in the general population. Methods: Ours was a collaborative study of four European population-based birth/child cohorts—CATSS (Sweden), Generation R (the Netherlands), GASPII (Italy), and INMA (Spain). Nitrogen oxides (NO2, NOx) and particulate matter (PM) with diameters of ≤ 2.5 μm (PM2.5), ≤ 10 μm (PM10), and between 2.5 and 10 μm (PMcoarse), and PM2.5 absorbance were estimated for birth addresses by land-use regression models based on monitoring campaigns performed between 2008 and 2011. Levels were extrapolated back in time to exact pregnancy periods. We quantitatively assessed autistic traits when the child was between 4 and 10 years of age. Children were classified with autistic traits within the borderline/clinical range and within the clinical range using validated cut-offs. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. Results: A total of 8,079 children were included. Prenatal air pollution exposure was not associated with autistic traits within the borderline/clinical range (odds ratio = 0.94; 95% CI: 0.81, 1.10 per each 10-μg/m3 increase in NO2 pregnancy levels). Similar results were observed in the different cohorts, for the other pollutants, and in assessments of children with autistic traits within the clinical range or children with autistic traits as a quantitative score. Conclusions: Prenatal exposure to NO2 and PM was not associated with autistic traits in children from 4 to 10 years of age in four European population-based birth/child cohort studies.Funding was provided as follows: ESCAPE Project— European Community’s Seventh Framework Program (FP7/2007-2011-GA#211250). CATSS, Sweden— Swedish Research Council for Health, Working Life and Welfare (FORTE), Swedish Research Council (VR) Formas, in partner hip with FORTE and VINNOVA (cross-disciplinary research program concerning children’s and young people’s mental health); VR through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant 340-2013-5867; HKH Kronprinsessan Lovisas förening för barnasjukvård; and the Strategic Research Program in Epidemiology at Karolinska Institutet. Generation R, the Netherlands—The Generation R Study is conducted by the Erasmus University Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam; the Municipal Health Service Rotterdam area, Rotterdam; the Rotterdam Homecare foundation, Rotterdam; and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. The general design of the Generation R Study is made possible by financial support from the Erasmus University Medical Center, Rotterdam; the Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Netherlands Organization for Scientific Research (NWO); and the Ministry of Health, Welfare and Sport. The Netherlands Organisation for Applied Scientific Research (TNO) received funding from the Netherlands Ministry of Infrastructure and the Environment to support exposure assessment. GASPII, Italy—grant from the Italian Ministry of Health (ex art.12, 2001). INMA, Spain— grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041 FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/01007, 11/02591, CP11/00178, FIS-PI041436, FIS-PI081151, FIS-PI06/0867, FIS-PS09/00090), PI13/1944, PI13_02032, PI14/0891, PI14/1687, MS13/00054, UE (FP7-ENV-2011 cod 282957, and HEALTH.2010.2.4.5-1); Generalitat de Catalunya-CIRIT 1999SGR 00241; La Fundació La Marató de TV3 (090430); Conselleria de Sanitat Generalitat Valenciana; Department of Health of the Basque Government (2005111093 and 2009111069); and Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). A.G.’s work was supported by a research grant from the European Community’s 7th Framework Programme (FP7/2008–2013-GA#212652). A full roster of the INMA project investigators can be found online (http://www. proyectoinma.org/presentacion-inma/listado-investigadores/ en_listado-investigadores.html)

Long-term ocean and resource dynamics in a hotspot of climate change

Unidad de excelencia María de Maeztu CEX2019-000940-MThe abundance, distribution, and size of marine species are linked to temperature and nutrient regimes and are profoundly affected by humans through exploitation and climate change. Yet little is known about long-term historical links between ocean environmental changes and resource abundance to provide context for current and potential future trends and inform conservation and management. We synthesize >4000 years of climate and marine ecosystem dynamics in a Northwest Atlantic region currently undergoing rapid changes, the Gulf of Maine and Scotian Shelf. This period spans the late Holocene cooling and recent warming and includes both Indigenous and European influence. We compare environmental records from instrumental, sedimentary, coral, and mollusk archives with ecological records from fossils, archaeological, historical, and modern data, and integrate future model projections of environmental and ecosystem changes. This multidisciplinary synthesis provides insight into multiple reference points and shifting baselines of environmental and ecosystem conditions, and projects a near-future departure from natural climate variability in 2028 for the Scotian Shelf and 2034 for the Gulf of Maine. Our work helps advancing integrative end-to-end modeling to improve the predictive capacity of ecosystem forecasts with climate change. Our results can be used to adjust marine conservation strategies and network planning and adapt ecosystem-based management with climate change

A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B

Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. a-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation coupled to molecular mechanics with generalized Born and surface area method energy decomposition on RNAP II. They were performed with a clinical drug that shares chemical similarities to a-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of a-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by a-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal a-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to a-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-a-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with a-amanitin was able to guarantee 100 % survival. Polymyxin B protects RNAP II from inactivation leading to an effective prevention of organ damage and increasing survival in a-amanitin-treated animals. The present use of clinically relevant concentrations of an already human-use-approved drug prompts the use of polymyxin B as an antidote for A. phalloides poisoning in humans.Juliana Garcia, Vera Marisa Costa, Ricardo Dinis-Oliveira and Ricardo Silvestre thank FCT-Foundation for Science and Technology-for their PhD grant (SFRH/BD/74979/2010), Post-doc grants (SFRH/BPD/63746/2009 and SFRH/BPD/110001/2015) and Investigator grants (IF/01147/2013) and (IF/00021/2014), respectively. This work was supported by the Fundacao para a Ciencia e Tecnologia (FCT) - project PTDC/DTPFTO/4973/2014 - and the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundacao para a Ciencia e Tecnologia) through project Pest-C/EQB/LA0006/2013

The inventory of geological heritage of the state of São Paulo, Brazil: Methodological basis, results and perspectives

An inventory of geological sites based on solid and clear criteria is a first step for any geoconservation strategy. This paper describes the method used in the geoheritage inventory of the State of São Paulo, Brazil, and presents its main results. This inventory developed by the geoscientific community aimed to identify geosites with scientific value in the whole state, using a systematic approach. All 142 geosites representative of 11 geological frameworks were characterised and quantitatively evaluated according to their scientific value and risk of degradation, in order to establish priorities for their future management. An online database of the inventory is under construction, which will be available to be easily consulted and updated by the geoscientific community. All data were made available to the State Geological Institute as the backbone for the implementation of a future state geoconservation strategy.The authors acknowledge the Science Without Borders Programme, Process 075/2012, which supported this study and the São Paulo Research Foundation (FAPESP), Process 2011/17261-6. We also thanks C. Mazoca for his help with maps and figures.info:eu-repo/semantics/acceptedVersio

Varicellovirus UL49.5 Proteins Differentially Affect the Function of the Transporter Associated with Antigen Processing, TAP

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms