Continuity of spectrum and approximate point spectrum on operator matrices

AbstractLet X and Y be given Banach spaces. For A∈B(X), B∈B(Y) and C∈B(Y,X), let MC be the operator defined on X⊕Y by MC=[AC0B]. In this paper we give conditions for continuity of τ at MC through continuity of τ at A and B, where τ can be equal to the spectrum or approximate point spectrum

Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP

Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk.We thank Miguel Sánchez for text editing. We thank Erika R. Geisbrecht, Kenneth Irvine, and Ariberto Fassati for kindly providing reagents. This study was supported by grants from the Spanish Ministry of Science and Innovation (MICIIN)/Agencia Estatal de Investigación (AEI)/European Regional Development Fund (ARDF/FEDER) “A way to make Europe” (PID2020-118658RB-I00, SAF2017-83130-R, IGP-SO grant MINSEV1512-07-2016, CSD2009-0016 and BFU2016-81912-REDC), Comunidad Autónoma de Madrid (Tec4Bio-CM, S2018/NMT¬4443), Fundació La Marató de TV3 (201936-30-31), “La Caixa” Foundation (HR20-00075) and AECC (PROYE20089DELP) all to M.A.d.P. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 641639. M.G.G. and L.S. are sponsored by FPU fellowships (FPU15/03776 and FPU18/05394, respectively). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MICIIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence CEX2020-001041-S

Age validation in Octopus vulgaris beaks across full ontogenetic range. Beaks as recorders of live-events in octopuses

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Graph based study of allergen cross-reactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study.

The study of cross-reactivity in allergy is key to both understanding. the allergic response of many patients and providing them with a rational treatment In the present study, protein microarrays and a co-sensitization graph approach were used in conjunction with an allergen microarray immunoassay. This enabled us to include a wide number of proteins and a large number of patients, and to study sensitization profiles among members of the LTP family. Fourteen LTPs from the most frequent plant food-induced allergies in the geographical area studied were printed into a microarray specifically designed for this research. 212 patients with fruit allergy and 117 food-tolerant pollen allergic subjects were recruited from seven regions of Spain with different pollen profiles, and their sera were tested with allergen microarray. This approach has proven itself to be a good tool to study cross-reactivity between members of LTP family, and could become a useful strategy to analyze other families of allergens

Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress.

INTRODUCTION The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease. METHODS We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells. RESULTS Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines. CONCLUSION We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.This work was supported by grants from Ministerio de Ciencia e Innovación (MCIN) from Spain [SAF2016-78711R and PID202-11794 to EM-N and FJC]; Comunidad de Madrid [B2017/BMD-3727 to EMN and FJC]; Comunidad de Madrid (REACT-UE, ANTICIPA-CM Ref. PR38/21-24) to E.M-N and HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679 to FJC the European Union’s Horizon 2020 research and innovation program [ERC-2016- Consolidator Grant 725091 to DS]; MCIN/AEI/10.13039/ 501100011033 [PID2019-108157RB to DS]; la Caixa Foundation (ID 100010434) [LCF/BQ/PR20/11770008 to SW]; Instituto de Salud Carlos III (ISCIII) [PI18/00348 to VE]; ISCIII [PI21/01641 to RT-R]; Spanish National Research and Development Plan, ISCIII and FEDER [PI17/02303 and PI20/01837 to SR-P]; Proyecto Desarrollo Tecnológico [DTS19/00111 to SR-P], AEI/MICIU EXPLORA Project [BIO2017-91272-EXP to SR-P]; Programa Estratégico Instituto de Biologıa y Gene ́ ́ tica Molecular (IBGM), Junta de Castilla y León (CCVC8485) [PID2019-104218RB-I00 to DB]; NIH [DK088199 to RB] and Universidad Complutense de Madrid (UCM 920631) [CT42/ 18-CT43/18 and EB15/21 to BM-A].S

Clinical characteristics of patients hospitalized with COVID-19 in Spain: Results from the SEMI-COVID-19 Registry

Background: Spain has been one of the countries most affected by the COVID-19 pandemic. Objective: To create a registry of patients with COVID-19 hospitalized in Spain, in order to improve our knowledge of the clinical, diagnostic, therapeutic, and prognostic aspects of this disease. Methods: A multicentre retrospective cohort study, including consecutive patients hospitalized with confirmed COVID-19 throughout Spain. Epidemiological and clinical data, additional tests at admission and at seven days, treatments administered, and progress at 30 days of hospitalization were collected from electronic medical records. Results: Up to June 30th 2020, 15,111 patients from 150 hospitals were included. Their median age was 69.4 years (range: 18-102 years) and 57.2% were male. Prevalences of hypertension, dyslipidemia, and diabetes mellitus were 50.9%, 39.7%, and 19.4%, respectively. The most frequent symptoms were fever (84.2%) and cough (73.5%). High values of ferritin (73.5%), lactate dehydrogenase (73.9%), and D-dimer (63.8%), as well as lymphopenia (52.8%), were frequent. The most used antiviral drugs were hydroxychloroquine (85.6%) and lopinavir/ritonavir (61.4%); 33.1% developed respiratory distress. Overall mortality rate was 21.0%, with a marked increase with age (50-59 years: 4.7%, 60-69 years: 10.5%, 70-79 years: 26.9%, ≥ 80 years: 46.0%). Conclusions: The SEMI-COVID-19 Network provides data on the clinical characteristics of patients with COVID-19 hospitalized in Spain. Patients with COVID-19 hospitalized in Spain are mostly severe cases, as one in three patients developed respiratory distress and one in five patients died. These findings confirm a close relationship between advanced age and mortality.Antecedentes: España ha sido uno de los países más afectados por la pandemia de COVID-19.Objetivo: Crear un registro de pacientes hospitalizados en España por COVID-19 para mejorar nuestro conocimiento sobre los aspectos clínicos, diagnósticos, terapéuticos y pronósticos de esta enfermedad. Métodos: Estudio de cohorte retrospectiva, multicéntrico, que incluye pacientes consecutivos hospitalizados con COVID-19 confirmada en toda España. Se obtuvieron los datos epidemiológicos y clínicos, las pruebas complementarias al ingreso y a los 7 días de la admisión, los tratamientos administrados y la evolución a los 30 días de hospitalización de las historias clínicas electrónicas. Resultados: Hasta el 30 de junio de 2020 se incluyeron 15.111 pacientes de 150 hospitales. Su mediana de edad fue 69,4 años (rango: 18-102 años) y el 57,2% eran hombres. Las prevalencias de hipertensión, dislipemia y diabetes mellitus fueron 50,9%, 39,7% y 19,4%, respectivamente.Los síntomas más frecuentes fueron fiebre (84,2%) y tos (73,5%). Fueron frecuentes los valores elevados de ferritina (73,5%), lactato deshidrogenasa (73,9%) y dímero D (63,8%), así como lalinfopenia (52,8%). Los fármacos antivirales más utilizados fueron la hidroxicloroquina (85,6%)y el lopinavir/ritonavir (61,4%). El 33,1% desarrolló distrés respiratorio. La tasa de mortalidad global fue del 21,0%, con un marcado incremento con la edad (50-59 años: 4,7%; 60-69 años:10,5%; 70-79 años: 26,9%; ≥ 80 años: 46%).Conclusiones: El Registro SEMI-COVID-19 proporciona información sobre las características clínicas de los pacientes con COVID-19 hospitalizados en España. Los pacientes con COVID-19 hospitalizados en España son en su mayoría casos graves, ya que uno de cada 3 pacientes desarrolló distrés respiratorio y uno de cada 5 pacientes falleció. Nuestros datos confirman una estrecha relación entre la edad avanzada y la mortalidadLa Sociedad Española de Medicina Interna (SEMI) es la patrocinadora de este estudio

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

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