Anomalous ballistic scaling in the tensionless or inviscid Kardar-Parisi-Zhang equation

The one-dimensional Kardar-Parisi-Zhang (KPZ) equation is becoming an overarching paradigm for the scaling of nonequilibrium, spatially extended, classical and quantum systems with strong correlations. Recent analytical solutions have uncovered a rich structure regarding its scaling exponents and fluctuation statistics. However, the zero surface tension or zero viscosity case eludes such analytical solutions and has remained ill-understood. Using numerical simulations, we elucidate a well-defined universality class for this case that differs from that of the viscous case, featuring intrinsically anomalous kinetic roughening (despite previous expectations for systems with local interactions and time-dependent noise) and ballistic dynamics. The latter may be relevant to recent quantum spin chain experiments which measure KPZ and ballistic relaxation under different conditions. We identify the ensuing set of scaling exponents in previous discrete interface growth models related with isotropic percolation, and show it to describe the fluctuations of additional continuum systems related with the noisy Korteweg-de Vries equation. Along this process, we additionally elucidate the universality class of the related inviscid stochastic Burgers equation.This work has been partially supported by Ministerio de Ciencia, Innovación y Universidades (Spain), Agencia Estatal de Investigación (AEI, Spain), and Fondo Europeo de Desarrollo Regional (FEDER, EU) through Grants No. PGC2018-094763-B-I00 and No. PID2019-106339GB-I00, and by Comunidad de Madrid (Spain) under the Multiannual Agreements with UC3M in the line of Excellence of University Professors (No. EPUC3M14 and No. EPUC3M23), in the context of the V Plan Regional de Investigación Científica e Innovación Tecnológica (PRICIT). E.R.-F. acknowledges financial support through Contract No. 2022/018 under the EPUC3M23 line

Extracorporeal membrane oxigenation in COVID-19 patients: Results of the ECMO-COVID Registry of the Spanish Society of Cardiovascular and Endovascular Surgery

Oxigenación con membrana extracorpórea; COVID-19; Insuficiencia cardiacaExtracorporeal membrane oxygenation; COVID-19; Heart failureOxigenació amb membrana extracorpòria; COVID-19; Insuficiència cardíacaIntroducción y objetivos La oxigenación con membrana extracorpórea (ECMO) ha resultado ser una opción terapéutica en los pacientes con insuficiencia respiratoria o cardiaca severa por COVID-19. Las indicaciones y manejo de estos pacientes están aún por determinar. Nuestro objetivo es evaluar los resultados de la terapia ECMO en pacientes con COVID-19 incluidos en un registro prospectivo e intentar optimizar los resultados. Métodos En marzo de 2020 se inició un registro multicéntrico anónimo prospectivo de pacientes con COVID-19 tratados mediante ECMO veno-arterial (V-A) o veno-venosa (V-V). Se registraron las variables clínicas, analíticas y respiratorias preimplante, datos de implante y evolución de la terapia. El evento primario fue la mortalidad hospitalaria de cualquier causa y los eventos secundarios fueron la recuperación funcional y el evento combinado de recuperación funcional y mortalidad de cualquier causa a partir de los 3 meses de seguimiento tras el alta. Resultados Se analizó a un total de 365 pacientes procedentes de 25 hospitales, 347 V-V y 18 V-A (edad media de 52,7 y 49,4 años, respectivamente). Los pacientes con ECMO V-V fueron más obesos, presentaban menos fracaso orgánico diferente al pulmonar y precisaron menos terapia inotrópica previa al implante. El 33,3% y el 34,9% de los pacientes con ECMO V-A y V-V, respectivamente, fueron dados de alta del hospital (p = NS) y la mortalidad fue similar, del 56,2% y 50,9% de los casos respectivamente, la inmensa mayoría durante la ECMO y sobre todo por fracaso multiorgánico. El 14,0% (51 pacientes) permanecían ingresados. El seguimiento medio fue de 196 ± 101,7 días. En el análisis multivariante, resultaron protectores de evento primario en pacientes con ECMO V-V el peso corporal (OR 0,967; IC 95%: 0,95-0,99; p = 0,004) y la procedencia del propio hospital (OR 0,48; IC 95%: 0,27-0,88; p = 0,018), mientras que la edad (OR 1,063; IC 95%: 1,005-1,12; p = 0,032), la hipertensión arterial (3,593; IC 95%: 1,06-12,19; p = 0,04) y las complicaciones en ECMO globales (2,44; IC 95%: 0,27-0,88; p = 0,019), digestivas (OR 4,23, IC 95%: 1,27-14,07; p = 0,019) y neurológicas (OR 4,66; IC 95%: 1,39-15,62; p = 0,013) fueron predictores independientes de mortalidad. El único predictor independiente de aparición de los eventos secundarios resultó el momento de seguimiento del paciente. Conclusiones La terapia con ECMO permite supervivencias hospitalarias hasta del 50% en pacientes con COVID-19 grave. La edad, la hipertensión arterial y las complicaciones en ECMO son los predictores de mortalidad hospitalaria en pacientes con ECMO V-V. Un mayor peso corporal y la procedencia del propio hospital son factores protectores. La recuperación funcional solo se ve influida por el tiempo de seguimiento transcurrido tras el alta. La estandarización de los criterios de implante y manejo del paciente con COVID grave mejoraría los resultados y la futura investigación clínica.Background and aim: COVID-19 patients with severe heart or respiratory failure are potential candidates for extracorporeal membrane oxygenation (ECMO). Indications and management of these patients are unclear. Our aim is to describe the results of a prospective registry of COVID-19 patients treated with ECMO. Methods: An anonymous prospective registry of COVID-19 patients treated with veno-arterial (V-A) or veno-venous (V-V) ECMO was created on march 2020. Clinical, analytical and respiratory preimplantation variables, implantation data and post-implantation course data were recorded. The primary endpoint was all cause in-hospital mortality. Secondary events were functional recovery and the combined endpoint of mortality and functional recovery in patients followed at least 3 months after discharge. Results: Three hundred and sixty-six patients from 25 hospitals were analyzed, 347 V-V ECMO and 18 V-A ECMO patients (mean age 52.7 and 49.5 years respectively). Patients with V-V ECMO were more obese, had less frequently organ damage other than respiratory failure and needed less inotropic support; Thirty three percent of V-A ECMO and 34.9% of V-A ECMO were discharged (P = NS). Hospital mortality was non-significantly different, 56.2% versus 50.9% respectively, mainly during ECMO therapy and mostly due to multiorgan failure. Other 51 patients (14%) remained admitted. Mean follow-up was 196 ± 101.7 days (95%CI: 170.8-221.6). After logistic regression, body weight (OR 0.967, 95%CI: 0.95-0.99, P = 0.004) and ECMO implantation in the own centre (OR 0.48, 95%CI: 0.27-0.88, P = 0.018) were protective for hospital mortality. Age (OR 1.063, 95%CI: 1.005-1.12, P = 0.032), arterial hypertension (3.593, 95%CI: 1.06-12.19, P = 0.04) and global (2.44, 95%CI: 0.27-0.88, P = 0.019), digestive (OR 4,23, 95%CI: 1.27-14.07, P = 0.019) and neurological (OR 4.66, 95%CI: 1.39-15.62, P = 0.013) complications during ECMO therapy were independent predictors of primary endpoint occurrence. Only the post-discharge day at follow-up was independent predictor of both secondary endpoints occurrence. Conclusions: Hospital survival of severely ill COVID-19 patients treated with ECMO is near 50%. Age, arterial hypertension and ECMO complications are predictors of hospital mortality, and body weight and implantation in the own centre are protective. Functional recovery is only predicted by the follow-up time after discharge. A more homogeneous management of these patients is warranted for clinical results and future research optimization

Acetylome in Human Fibroblasts From Parkinson's Disease Patients

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. The pathogenesis of this disease is associated with gene and environmental factors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of familial and sporadic PD. Moreover, posttranslational modifications, including protein acetylation, are involved in the molecular mechanism of PD. Acetylation of lysine proteins is a dynamic process that is modulated in PD. In this descriptive study, we characterized the acetylated proteins and peptides in primary fibroblasts from idiopathic PD (IPD) and genetic PD harboring G2019S or R1441G LRRK2 mutations. Identified acetylated peptides are modulated between individuals' groups. Although acetylated nuclear proteins are the most represented in cells, they are hypoacetylated in IPD. Results display that the level of hyperacetylated and hypoacetylated peptides are, respectively, enhanced in genetic PD and in IPD cells

Loss of KEAP1 causes an accumulation of nondegradative organelles

KEAP1 is a cytoplasmic protein that functions as an adaptor for the Cullin-3-based ubiquitin E3 ligase system, which regulates the degradation of many proteins, including NFE2L2/NRF2 and p62/SQSTM1. Loss of KEAP1 leads to an accumulation of protein ubiquitin aggregates and defective autophagy. To better understand the role of KEAP1 in the degradation machinery, we investigated whether Keap1 deficiency affects the endosome-lysosomal pathway. We used KEAP1-deficient mouse embryonic fibroblasts (MEFs) and combined Western blot analysis and fluorescence microscopy with fluorometric and pulse chase assays to analyze the levels of lysosomal-endosomal proteins, lysosomal function, and autophagy activity. We found that the loss of keap1 downregulated the protein levels and activity of the cathepsin D enzyme. Moreover, KEAP1 deficiency caused lysosomal alterations accompanied by an accumulation of autophagosomes. Our study demonstrates that KEAP1 deficiency increases nondegradative lysosomes and identifies a new role for KEAP1 in lysosomal function that may have therapeutic implications

Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation

Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome. The online version contains supplementary material available at 10.1186/s13046-022-02497-w

Oxigenación con membrana extracorpórea en el paciente COVID-19: resultados del Registro Español ECMO-COVID de la Sociedad Española de Cirugía Cardiovascular y Endovascular (SECCE)

Background and aim: COVID-19 patients with severe heart or respiratory failure are potential candidates for extracorporeal membrane oxygenation (ECMO). Indications and management of these patients are unclear. Our aim is to describe the results of a prospective registry of COVID-19 patients treated with ECMO. Methods: An anonymous prospective registry of COVID-19 patients treated with veno-arterial (V-A) or veno-venous (V-V) ECMO was created on march 2020. Clinical, analytical and respiratory preimplantation variables, implantation data and post-implantation course data were recorded. The primary endpoint was all cause in-hospital mortality. Secondary events were functional recovery and the combined endpoint of mortality and functional recovery in patients followed at least 3 months after discharge. Results: Three hundred and sixty-six patients from 25 hospitals were analyzed, 347 V-V ECMO and 18 V-A ECMO patients (mean age 52.7 and 49.5 years respectively). Patients with V-V ECMO were more obese, had less frequently organ damage other than respiratory failure and needed less inotropic support; Thirty three percent of V-A ECMO and 34.9% of V-A ECMO were discharged (P = NS). Hospital mortality was non-significantly different, 56.2% versus 50.9% respectively, mainly during ECMO therapy and mostly due to multiorgan failure. Other 51 patients (14%) remained admitted. Mean follow-up was 196 +/- 101.7 days (95%CI: 170.8-221.6). After logistic regression, body weight (OR 0.967, 95%CI: 0.95-0.99, P = 0.004) and ECMO implantation in the own centre (OR 0.48, 95%CI: 0.27-0.88, P = 0.018) were protective for hospital mortality. Age (OR 1.063, 95%CI: 1.005-1.12, P = 0.032), arterial hypertension (3.593, 95%CI: 1.06-12.19, P = 0.04) and global (2.44, 95%CI: 0.27-0.88, P = 0.019), digestive (OR 4,23, 95%CI: 1.27-14.07, P = 0.019) and neurological (OR 4.66, 95%CI: 1.39-15.62, P = 0.013) complications during ECMO therapy were independent predictors of primary endpoint occurrence. Only the post-discharge day at follow-up was independent predictor of both secondary endpoints occurrence. Conclusions: Hospital survival of severely ill COVID-19 patients treated with ECMO is near 50%. Age, arterial hypertension and ECMO complications are predictors of hospital mortality, and body weight and implantation in the own centre are protective. Functional recovery is only predicted by the follow-up time after discharge. A more homogeneous management of these patients is warranted for clinical results and future research optimization. (C) 2022 Sociedad Espanola de Cirugia Cardiovascular y Endovascular. Published by Elsevier Espana, S.L.U

Presentación de "Science for policy"

Datos técnicos: 187 minutos, color, español. Ficha técnica: Gabinete de Presidencia CSIC y Departamento de Comunicación. Emitido en directo el 28 jun 2023El Consejo Superior de Investigaciones Científicas (CSIC) presenta este miércoles, 28 de junio, en su sede central en Madrid, los informes Ciencia para las Políticas Públicas (Science For Policy). Elaborados por equipos de investigadores del CSIC, tienen el objetivo de servir de puente entre los centros de investigación y los decisores políticos para contribuir a la definición de políticas públicas basadas en la evidencia científica.Peer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

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

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure