Relative telomere length impact on mortality of COVID-19: Sex differences

Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality. RTL was measured in patients hospitalized because of COVID-19. We used Kaplan-Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). Six hundred and eight patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted hazard ratio [HR] (aHR) = 3.33; 95% confidence interval [CI] = 1.05-10.00; p = 0.040) and at 90 days (aHR = 3.57; 95%CI = 1.23-11.11; p = 0.019). Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population.This study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant number COV20/1144 [MPY224/20] to AFR/MAJS) and Fundación Universidad Alfonso X el Sabio (FUAX) – Santander (1.013.005). MAJS is Miguel Servet researcher supported and funded by ISCIII (grant number: CP17CIII/00007). The study was also supported by the Centro de Investigación Biomédica en Red (CIBER) en Enfermedades Infecciosas (CB21/13/00044). We also acknowledge the Spanish Coalition to Unlock Research on Host Genetics on COVID‐19 (SCOURGE).S

Variations of biochemical and hematic parameters following Taoist qigong practice

Qigong is an ancient Chinese psychosomatic discipline which employs specially designed body movements to achieve mind-body integration, preserve health, and pursue longevity. The Taoist school of qigong, one of the main traditions within this Chinese discipline, has a particular approach that emphasizes naturalness for the achievement of those goals. Albeit diverse methods of qigong have already been shown to display significant psychobiological effects, Taoist qigong has been scarcely investigated to date. Thus, this research was carried out with the aim of shedding light on the effects of Taoist qigong on biochemical and hematic parameters measured shortly after practice. Forty five naive subjects participated in the study, twenty-eight in the experimental group and the rest in the control group. Experimental subjects underwent a qigong training program consisting of three half-hour guided sessions per week, for the period of one month. Blood samples for the quantification of biochemical and hematic parameters were drawn from all subjects the day before the experiment commenced and one hour after the last session of practice concluded. Analysis of covariance (ANCOVA) was performed as statistical analyses. Our results showed that after completing the qigong program, experimental subjects displayed lower levels of serum albumin, as well as lower values of Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC), when compared to control. These findings, therefore, reveal that the practice of Taoist qigong for a short period of one month exerted a peculiar biochemical and hematimetric influence, which suggests interesting psychobiological and clinical implications.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages. In this study, we characterize 21 GM-CSF autoantibodies from PAP patients and find that somatic mutations critically determine their specificity for the self-antigen. Individual antibodies only partially neutralize GM-CSF activity using an in vitro bioassay, depending on the experimental conditions, while, when injected in mice together with human GM- CSF, they lead to the accumulation of a large pool of circulating GM-CSF that remains partially bioavailable. In contrast, a combination of three non-cross-competing antibodies completely neutralizes GM-CSF activity in vitro by sequestering the cytokine in high-molecular-weight complexes, and in vivo promotes the rapid degradation of GM-CSF-containing immune complexes in an Fc-dependent manner. Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies

Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus

Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes severe respiratory disease with a high mortality rate. There is no licensed vaccine or antiviral for MERS. Here we isolated for the first time, to our knowledge, a potent MERS-CoV–neutralizing antibody from memory B cells of an infected individual. This antibody binds to a novel site on the viral Spike protein, neutralizes by interfering with the binding to the cellular receptor CD26, and is highly effective both in prophylaxis and in therapy in a relevant mouse model. This antibody can be developed for prophylaxis, for postexposure prophylaxis, or for the treatment of severe MERS-CoV infections

Plasma miRNA profile at COVID-19 onset predicts severity status and mortality

BACKGROUND: MicroRNAs (miRNAs) have a crucial role in regulating immune response against infectious diseases, showing changes early in disease onset and before the detection of the pathogen. Thus, we aimed to analyze the plasma miRNA profile at COVID-19 onset to identify miRNAs as early prognostic biomarkers of severity and survival. METHODS AND RESULTS: Plasma miRNome of 96 COVID-19 patients that developed asymptomatic/mild, moderate and severe disease was sequenced together with a group of healthy controls. Plasma immune-related biomarkers were also assessed. COVID-19 patients showed 200 significant differentially expressed (SDE) miRNAs concerning healthy controls, with upregulated putative targets of SARS-CoV-2, and inflammatory miRNAs. Among COVID-19 patients, 75 SDE miRNAs were observed in asymptomatic/mild compared to symptomatic patients, which were involved in platelet aggregation and cytokine pathways, among others. Moreover, 137 SDE miRNAs were identified between severe and moderate patients, where miRNAs targeting the SARS CoV-2 genome were the most strongly disrupted. Finally, we constructed a mortality predictive risk score (miRNA-MRS) with ten miRNAs. Patients with higher values had a higher risk of 90-days mortality (hazard ratio = 4.60; p-value < 0.001). Besides, the discriminant power of miRNA-MRS was significantly higher than the observed for age and gender (AUROC = 0.970 vs. 0.881; p = 0.042). CONCLUSIONS: SARS-CoV-2 infection deeply disturbs the plasma miRNome from an early stage of COVID-19, making miRNAs highly valuable as early predictors of severity and mortality

A New Pathway for Protein Haptenation by beta-Lactams

"This is the peer reviewed version of the following article: Pérez-Ruíz, Raúl, Emilio Lence, Inmaculada Andreu, Daniel Limones-Herrero, Concepción González-Bello, Miguel A. Miranda, and M. Consuelo Jiménez. 2017. A New Pathway for Protein Haptenation by &#946;-Lactams. Chemistry - A European Journal 23 (56). Wiley: 13986 94. doi:10.1002/chem.201702643, which has been published in final form at https://doi.org/10.1002/chem.201702643. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] The covalent binding of beta-lactams to proteins upon photochemical activation has been demonstrated by using an integrated approach that combines photochemical, proteomic and computational studies, selecting human serum albumin (HSA) as a target protein and ezetimibe (1) as a probe. The results have revealed a novel protein haptenation pathway for this family of drugs that is an alternative to the known nucleophilic ring opening of beta-lactams by the free amino group of lysine residues. Thus, photochemical ring splitting of the beta-lactam ring, following a formal retro-Staudinger reaction, gives a highly reactive ketene intermediate that is trapped by the neighbouring lysine residues, leading to an amide adduct. For the investigated 1/HSA system, covalent modification of residues Lys414 and Lys525, which are located in sub-domains IIIA and IIIB, respectively, occurs. The observed photobinding may constitute the key step in the sequence of events leading to photoallergy. Docking and molecular dynamics simulation studies provide an insight into the molecular basis of the selectivity of 1 for these HSA sub-domains and the covalent modification mechanism. Computational studies also reveal positive cooperative binding of sub-domain IIIB that explains the experimentally observed modification of Lys414, which is located in a barely accessible pocket (sub-domain IIIA).Financial support from Ministerio de Economia, Industria y Competitividad (CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2013-42899-R, SAF2016-75638-R), Instituto de Salud Carlos III (RD12/0013/0009 and RD16/0006/0030), Generalitat Valenciana (PROMETEOII/2013/005), Xunta de Galicia (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and European Union (European Regional Development Fund -ERDF) is gratefully acknowledged. E.L. thanks the Xunta de Galicia for a postdoctoral fellowship. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER.Pérez-Ruiz, R.; Lence, E.; Andreu Ros, MI.; Limones Herrero, D.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2017). A New Pathway for Protein Haptenation by beta-Lactams. Chemistry - A European Journal. 23(56):13986-13994. https://doi.org/10.1002/chem.201702643S13986139942356Van Boeckel, T. P., Gandra, S., Ashok, A., Caudron, Q., Grenfell, B. T., Levin, S. A., & Laxminarayan, R. (2014). Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. The Lancet Infectious Diseases, 14(8), 742-750. doi:10.1016/s1473-3099(14)70780-7Elander, R. P. (2003). Industrial production of β-lactam antibiotics. 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Metabolic Profiling at COVID-19 Onset Shows Disease Severity and Sex-Specific Dysregulation

Background: metabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression. Material and methods: we performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation. Results: After data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis. Conclusions: This technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.This study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant number COV20/1144 (MPY224/20) to AF-R/MJ-S). The study was also funded by CIBER - Consorcio Centro de Investigación Biomédica en Red - (CB 2021; CB21/13/00044), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea - NextGenerationEU. AF-R and MJ-S are Miguel Servet researchers supported and funded by ISCIII (grant numbers: CP14CIII/00010 to AFR and CP17CIII/00007 to MJ-S). Universidad Alfonso X el Sabio, grant number 1.013.005S

Are Reduced Levels of Coagulation Proteins Upon Admission Linked to COVID-19 Severity and Mortality?

Background: The link between coagulation system disorders and COVID-19 has not yet been fully elucidated. Aim: Evaluating the association of non-previously reported coagulation proteins with COVID-19 severity and mortality. Design: Cross-sectional study of 134 COVID-19 patients recruited at admission and classified according to the highest COVID-19 severity reached (asymptomatic/mild, moderate, or severe) and 16 healthy control individuals. Methods: Coagulation proteins levels (antithrombin, prothrombin, factor_XI, factor_XII, and factor_XIII) and CRP were measured in plasma by the ProcartaPlex Panel (Invitrogen) multiplex immunoassay upon diagnosis. Results: We found higher levels of antithrombin, prothrombin, factor XI, factor XII, and factor XIII in asymptomatic/mild and moderate COVID-19 patients compared to healthy individuals. Interestingly, decreased levels of antithrombin and factors XI, XII, and XIII were observed in those patients who eventually developed severe illness. Additionally, survival models showed us that patients with lower levels of these coagulation proteins had an increased risk of death. Conclusion: COVID-19 provokes early increments of some specific coagulation proteins in most patients. However, lower levels of these proteins at diagnosis might "paradoxically" imply a higher risk of progression to severe disease and COVID-19-related mortality.This study was supported by grants from Instituto de Salud Carlos III [ISCIII; Grant Number COV20/1144 (MPY224/20) to AF-R/MJ-S]. AF-R, MJ-S, and MR are Miguel Servet researchers supported and funded by ISCIII (Grant Numbers: CP14CIII/00010 to AF-R, CP17CIII/00007 to MJ-S, and CP19CIII/00002 to MR).S