Extracellular cysteine disulfide bond break at Cys122 disrupts PIP2-dependent Kir2.1 channel function and leads to arrhythmias in Andersen-Tawil Syndrome

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Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.The authors thank the Centro Nacional de Investigaciones Cardiovasculares (CNIC) Viral Vectors Unit for producing the adeno-associated virus serotype 9. Confocal experiments were conducted at the CNIC Microscopy and Dynamic Imaging Unit. The authors thank the CNIC Bioinformatics Unit for generating the in silico homology modeling simulations, F-function analysis, and helpful discussions. The authors also thank the Centro de Supercomputación de Galicia for the use of the Finis Terrae III supercomputer to perform molecular dynamics studies. The CNIC was supported by the Instituto de Salud Carlos III, the Ministerio de Ciencia, Innovación y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033). This work was supported by the National heart, Lung and Blood Institute under National Institutes of Health (NIH) grant R01HL163943; the La Caixa Banking Foundation project code HR18-00304 (grant LCF/PR/HR19/52160013); grants PI-FIS-2020, PI20/01220, PI-FIS-2023, and PI23/01039 from the Instituto de Salud Carlos III and cofunded by the Fondo Europeo de Desarrollo Regional (FEDER) and the European Union, respectively; grants PID2020-116935RB-I00 and BFU2016-75144-R funded by MICIU/AEI/10.13039/501100011033; the Fundación La Marató de TV3 (736/C/2020) amb el suport de la Fundació La Marató de TV3; the CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Cardiovasculares (grant CB16/11/00458); the European Union’s Horizon 2020 grant agreement GA-965286; and the Program S2022/BMD7229-CM ARCADIACM funded by the Comunidad de Madrid to J. Jalife; grant PID2021-126423OB-C22 (to M. Martín-Martínez) funded by MICIU/AEI/10.13039/501100011033; and European Regional Development Fund (ERDF) grant PID2022-137214OB-C22 (to M. Gutierrez-Rodríguez) funded by MICIU/AEI/10.13039/501100011033. The imaging studies were performed in the TRIMA@CNIC (Infraestructura de Imagen Traslacional Avanzada del CNIC) node of the ICTS ReDIB (Infraestructuras Científicas y Técnicas Singulares: Red Distribuida de Imagen Biomédica) grant ICTS-2018- 04-CNIC-16 funded by MICIU/AEI/10.13039/501100011033 and ERDF, and project EQC2018-005070-P funded by MICIU/AEI/10.13039/501100011033 and FEDER. A.I. Moreno-Manuel holds an formación profesional universitaria (FPU) contract (FPU20/01569) from the Ministerio de Universidades. J.M. Ruiz Robles holds an FPU contract (FPU22/03253) from the Ministerio de Universidades. L.K. Gutiérrez holds an FPI contract (PRE2018-083530) from the Ministerio de Economía y Competitividad de España cofunded by the Fondo Social Europeo, attached to project SEV-2015-0505-18-2. I. Martínez-Carrascoso holds a PFIS (Contratos predoctorales de formación en investigación en salud) contract (FI21/00243) funded by Instituto de Salud Carlos III and the Fondo Social Europeo Plus cofunded by the European Union. M.L. Vera-Pedrosa held contract PEJD-2019-PRE/BMD15982 funded by the Consejería de Educación e Investigación de la Comunidad de Madrid y Fondo Social Europeo.S

NIKA2: a mm camera for cluster cosmology

Galaxy clusters constitute a major cosmological probe. However, Planck 2015 results have shown a weak tension between CMB-derived and cluster-derived cosmological parameters. This tension might be due to poor knowledge of the cluster mass and observable relationship. As for now, arcmin resolution Sunyaev-Zeldovich (SZ) observations (e.g. SPT, ACT and Planck) only allowed detailed studies of the intra cluster medium for low redshift clusters (z < 0:2). For high redshift clusters ( z > 0:5) high resolution and high sensitivity SZ observations are needed. With both a wide field of view (6.5 arcmin) and a high angular resolution (17.7 and 11.2 arcsec at 150 and 260 GHz), the NIKA2 camera installed at the IRAM 30-m telescope (Pico Veleta, Spain) is particularly well adapted for these observations. The NIKA2 SZ observation program will map a large sample of clusters (50) at redshifts between 0.5 and 0.9. As a pilot study for NIKA2, several clusters of galaxies have been observed with the pathfinder, NIKA, at the IRAM 30-m telescope to cover the various configurations and observation conditions expected for NIKA2

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

La ganadería ante escenarios complejos.

La calidad de las contribuciones, producto de la pluma de especialistas en los temas tratados, el presente es un libro que esperamos, basándonos en la importancia de los temas tratados, sea de utilidad y abone a la reflexión de los estudiosos de la ganadería mexicana y, por supuesto, en beneficio de las familias ganaderas y de los consumidores de sus productos.este libro refleja en muchos sentidos la situación de la ganadería mexicana, a la que se le están demandando mayor producción y productividad, que los procesos productivos tengan la menor huella ecológicposible, que los alimentos sean inocuos, que se abatan costos de producción y, cada vez aumentan las presiones de diversos grupos para, que se incluyan los protocolos de bienestar animal, solamente por citar algunos de los retos que tiene. Algunas de estas demandas son complementarias, otras se contraponen, lo que hace valiosos a los estudios que desde las ciencias sociales se realizan y, desde diversas ópticas, se hagan propuestas de política pública balanceadas que consideren lo mejor de cada enfoque, pero sin desechar por completo los antagónicos.Universidad Autónoma Chaping

Investigación en Matemáticas, Economía, Ciencias Sociales y Agronomía

Cada trabajo del libro incluye conclusiones para los interesados en las temáticas aludidas y en ellos nos enteramos de aspectos como los siguientes: - El mayor incremento del precio de los insumos como el maíz, sorgo y en menor medida desperdicio de pan, en relación con el menor crecimiento del precio del ganado en pie, dará como consecuencia un desabasto de carne bovina. - El agua es un recurso primordial en las zonas áridas y semiáridas de México, en tanto que su aporte limita la producción de la agricultura. En este estudio se observó que el precio real del agua es muy bajo en relación a otras zonas agrícolas del mundo. - Hoy en día en el país se consumen alrededor de 718 mil barriles diarios de gasolinas, un aproximado de 113.7 millones de litros, una cantidad tan grande que nuestro país se ve en la necesidad de importar cerca del 39 % de las gasolinas que consumimos. - Los jaliscienses radicados en Estados Unidos tienen una mayor capacidad de financiamiento del bienestar en la entidad, que el propio gobierno de ese estado. - México continuará basando sus finanzas públicas y su política de desarrollo económico en la extracción de combustibles fósiles (petróleo). Este modelo acelerará el deterioro y agotamiento de los recursos naturales. -La importancia de la agricultura orgánica radica en que retoma los tres ámbitos de la sustentabilidad; el ámbito ambiental, el económico y el social. - Es fundamental motivar la organización de los productores de haba para que ellos puedan captar una mayor proporción de los altos márgenes de precios que los consumidores están dispuestos a pagar. - Las condiciones del clima afectan a la producción agraria. Debido al fenómeno de cambio climático, es necesario contar con herramientas informáticas que proporcionen información climatológica para poder tomar medidas preventivas a favor de una mayor cantidad y calidad de producción. La herramienta de software permite la consulta del clima por localidades evitando la necesidad de contar con una estación meteorológica

Thermal transformations of sonicated pyrophyllite

Abstract The differences on the thermal behaviour (DTG -DTA) of three pyrophyllite samples measured before and after sonication have been studied. Sonication treatment produces substantial textural modifications but negligible changes in the structure of the material. These modifications produce important changes in the thermal behaviour of pyrophyllite samples. Thus, it produces a decrease of more than 100 jC in the dehydroxylation temperature as measured by DTG and DTA effects. In addition, the exothermic effect of mullite formation shifts to lower temperature (about 30 jC) in sonicated pyrophyllite. These modification in the thermal behaviour are related to the pronounced decrease in particle size. The dehydroxylation effect of kaolinite that accompanies two of the studied samples, overlaps with that of sonicated pyrophyllite; however, the exothermic effect at 975 jC of kaolinite remain unchanged with the treatment.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of Short QT Syndrome type 3.

AIMS Short QT Syndrome Type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. METHODS AND RESULTS We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. CONCLUSIONS The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.This work was supported by ‘La Caixa’ Foundation [project code LCF/PR/ HR19/52160013]; grant PI20/01220 of the public call ‘Proyectos de Investigación en Salud 2020’ [PI-FIS-2020] funded by Instituto de Salud Carlos III (ISCIII); MCIU grant BFU2016-75144-R and PID2020-116935RB-I00, and co-funded by Fondo Europeo de Desarrollo Regional (FEDER); and Fundació La Marató de TV3 [736/C/ 2020]. We also receive support from the European Union’s ‘Horizon 2020 Research and Innovation Framework Programme’ [grant agreement GA-965286]; the Dynamic Microscopy and Imaging Unit—ICTS-ReDib Grant ICTS-2018-04-CNIC-16 funded by MCIN/AEI/10.13039/ 501100011033 and ERDF ‘A way of making Europe’; project EQC2018-005070-P funded by MCIN/AEI/10.13039/501100011033 and FEDER ‘Una manera de hacer Europa’. CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence [grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033]. A.I.M.M. holds a FPU contract [FPU20/01569] from Ministerio de Universidades. L.K.G. holds a FPI contract [PRE2018-083530], Ministerio de Economía y Competitividad de España co-funded by Fondo Social Europeo ‘El Fondo Social Europeo invierte en tu futuro’, attached to Project SEV-2015-0505-18-2. I.M.C. holds a PFIS contract [FI21/00243] funded by Instituto de Salud Carlos III and Fondo Social Europeo Plus (FSE+), ‘co-funded by the European Union’. M.L.V.P. held contract PEJD-2019-PRE/BMD-15982 funded by Consejería de Educación e Investigación de la Comunidad de Madrid ‘El FSE invierte en tu futuro’S

Similar recovery of liver function after response to all‐oral HCV therapy in patients with cirrhosis with and without HIV coinfection

Among patients with cirrhosis, recovery of liver function after SVR to all‐oral direct‐acting antivirals (DAA ) in HIV /HCV coinfection could be different to that in HCV monoinfection. Because of this, we compared the changes in several markers of liver function between HCV ‐monoinfected and HIV /HCV ‐coinfected patients with cirrhosis who achieved SVR 12 to DAA combinations. In this retrospective cohort study, cirrhotics included in the HEPAVIR ‐DAA and GEHEP ‐MONO cohorts were selected if they had SVR 12 to all‐oral DAA s. Patients treated with atazanavir were excluded. Liver function improvement was defined as Child‐Pugh‐Turcotte (CPT ) decrease ≥1 and/or MELD decrease ≥2 between baseline and SVR 12. Liver function worsening was defined as a CPT increase ≥1 and/or MELD increase ≥2 and/or decompensations between baseline and SVR 12. We included 490 patients, 270 (55%) of them with HIV coinfection. Liver function improved in 50 (56%) HCV ‐infected individuals and in 82 (57%) HIV /HCV ‐coinfected patients (P = 0.835). Liver function worsened in 33 (15%) HCV ‐monoinfected patients and in 33 (13%) HIV /HCV ‐coinfected patients (P = 0.370). Factors independently related with liver function improvement were male gender [adjusted OR (AOR ) 2.1 (95% confidence interval, 95% CI : 1.03‐4.2), P = 0.040], bilirubin < 1.2 mg/dL (AOR 1.8 [95% CI : 1.004‐3.3], P = 0.49), and INR < 1.3 (AOR 2.4 [95% CI : 1.2‐5.0], P = 0.019) at baseline. After multivariate analysis, albumin < 3.5 g/dL was associated with liver function worsening (AOR 6.1 [95% CI : 3‐12.5], P < 0.001). Liver function worsening and improvement rates after responding to DAA are similar among HCV ‐monoinfected and HIV /HCV ‐coinfected cirrhotics. Gender, INR , bilirubin, and albumin levels were associated with liver function changes after response to DAA s.This study was partly supported by projects “PI15/01607” and “PI16/01443,” funded by Instituto de Salud Carlos III, integrated in the national I+D+i 2013‐2016, and cofunded by European Union (ERDF/ESF, “Investing in your future”) and by a grant from the Grupo para el Estudio de las Hepatitis Víricas (GEHEP) (grant GEHEP 001 2017). J.M. is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (grant number B‐0037). J.A.P. is recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa‐I3SNS). This work has been partially funded by the Spanish AIDS Research Network RD16/0025/0010 and RD16/0025/0034—ISCIII—FEDER.Peer reviewe

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats

SUMMARY We have modelled elaidyl-sulfamide (ES), a sulfamoyl analogue of oleoylethanolamide (OEA). ES is a lipid mediator of satiety that works through the peroxisome proliferator-activated receptor alpha (PPARα). We have characterised the pharmacological profile of ES (0.3–3 mg/kg body weight) by means of in silico molecular docking to the PPARα receptor, in vitro transcription through PPARα, and in vitro and in vivo administration to obese rats. ES interacts with the binding site of PPARα in a similar way as OEA does, is capable of activating PPARα and also reduces feeding in a dose-dependent manner when administered to food-deprived rats. When ES was given to obese male rats for 7 days, it reduced feeding and weight gain, lowered plasma cholesterol and reduced the plasmatic activity of transaminases, indicating a clear improvement of hepatic function. This pharmacological profile is associated with the modulation of both cholesterol and lipid metabolism regulatory genes, including the sterol response element-binding proteins SREBF1 and SREBF2, and their regulatory proteins INSIG1 and INSIG2, in liver and white adipose tissues. ES treatment induced the expression of thermogenic regulatory genes, including the uncoupling proteins UCP1, UCP2 and UCP3 in brown adipose tissue and UCP3 in white adipose tissue. However, its chronic administration resulted in hyperglycaemia and insulin resistance, which represent a constraint for its potential clinical development