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1.
Mol Cell Proteomics ; 22(8): 100600, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37343697

RESUMEN

High-density lipoprotein (HDL) levels are reduced in patients with coronavirus disease 2019 (COVID-19), and the extent of this reduction is associated with poor clinical outcomes. While lipoproteins are known to play a key role during the life cycle of the hepatitis C virus, their influence on coronavirus (CoV) infections is poorly understood. In this study, we utilize cross-linking mass spectrometry (XL-MS) to determine circulating protein interactors of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoprotein. XL-MS of plasma isolated from patients with COVID-19 uncovered HDL protein interaction networks, dominated by acute-phase serum amyloid proteins, whereby serum amyloid A2 was shown to bind to apolipoprotein (Apo) D. XL-MS on isolated HDL confirmed ApoD to interact with SARS-CoV-2 spike but not SARS-CoV-1 spike. Other direct interactions of SARS-CoV-2 spike upon HDL included ApoA1 and ApoC3. The interaction between ApoD and spike was further validated in cells using immunoprecipitation-MS, which uncovered a novel interaction between both ApoD and spike with membrane-associated progesterone receptor component 1. Mechanistically, XL-MS coupled with data-driven structural modeling determined that ApoD may interact within the receptor-binding domain of the spike. However, ApoD overexpression in multiple cell-based assays had no effect upon viral replication or infectivity. Thus, SARS-CoV-2 spike can bind to apolipoproteins on HDL, but these interactions do not appear to alter infectivity.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Lipoproteínas HDL/metabolismo , Unión Proteica , Espectrometría de Masas
2.
Respir Res ; 24(1): 60, 2023 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-36814234

RESUMEN

BACKGROUND: Inflammatory responses contribute to tissue damage in COVID-19 and community-acquired pneumonia (CAP). Although predictive values of different inflammatory biomarkers have been reported in both, similarities and differences of inflammatory profiles between these conditions remain uncertain. Therefore, we aimed to determine the similarities and differences of the inflammatory profiles between COVID-19 and CAP, and their association with clinical outcomes. METHODS: We report a prospective observational cohort study; conducted in a reference hospital in Latin America. Patients with confirmed COVID-19 pneumonia and CAP were included. Multiplex (Luminex) cytokine assays were used to measure the plasma concentration of 14 cytokines at hospital admission. After comparing similarities and differences in the inflammatory profile between COVID-19 and CAP patients, an unsupervised classification method (i.e., hierarchical clustering) was used to identify subpopulations within COVID-19 and CAP patients. RESULTS: A total of 160 patients were included, 62.5% were diagnosed with COVID-19 (100/160), and 37.5% with CAP (60/160). Using the hierarchical clustering, COVID-19 and CAP patients were divided based on its inflammatory profile: pauci, moderate, and hyper-inflammatory immune response. COVID-19 hyper-inflammatory subpopulation had the highest mortality. COVID-19 hyper-inflammatory subpopulation, compared to pauci-inflammatory, had higher levels of IL-10 (median [IQR] 61.4 [42.0-109.4] vs 13.0 [5.0-24.9], P: < 0.001), IL-6 (48.1 [22.3-82.6] vs 9.1 [0.1-30.4], P: < 0.001), among others. Hyper-inflammatory vs pauci-inflammatory CAP patients were characterized by elevation of IFN2 (48.8 [29.7-110.5] vs 3.0 [1.7-10.3], P: < 0.001), TNFα (36.3 [24.8-53.4] vs 13.1 [11.3-16.9], P: < 0.001), among others. Hyper-inflammatory subpopulations in COVID-19 and CAP compared to the corresponding pauci-inflammatory subpopulations had higher MCP-1. CONCLUSIONS: Our data highlights three distinct subpopulations in COVID-19 and CAP, with differences in inflammatory marker profiles and risks of adverse clinical outcomes. TRIAL REGISTRATION: This is a prospective study, therefore no health care intervention were applied to participants and trial registration is not applicable.


Asunto(s)
COVID-19 , Infecciones Comunitarias Adquiridas , Neumonía , Humanos , Estudios Prospectivos , COVID-19/complicaciones , Neumonía/diagnóstico , Citocinas , Hospitalización , Infecciones Comunitarias Adquiridas/diagnóstico
3.
J Clin Microbiol ; 60(4): e0228321, 2022 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-35321556

RESUMEN

Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold (CT) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.


Asunto(s)
COVID-19 , SARS-CoV-2 , Alelos , COVID-19/diagnóstico , Humanos , Reacción en Cadena de la Polimerasa , SARS-CoV-2/genética
4.
J Infect Dis ; 224(4): 595-605, 2021 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-34031695

RESUMEN

BACKGROUND: Convalescent plasma containing neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is under investigation for coronavirus disease 2019 (COVID-19) treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomized controlled trial that potentially influence treatment outcomes. METHODS: SARS-CoV-2 RNA in nasopharyngeal swabs collected pretreatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. RESULTS: Of 1274 subjects, 90% were PCR positive with viral loads 118-1.7 × 1011IU/mL. Median viral loads were 40-fold higher in those IgG seronegative (n = 354; 28%) compared to seropositives (n = 939; 72%). Frequencies of B.1.1.7 increased from <1% in November 2020 to 82% of subjects in January 2021. Seronegative individuals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8 × 106 and 2.0 × 105 IU/mL, respectively; P = 2 × 10-15). CONCLUSIONS: High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads, and antibody status define subgroups for analysis of treatment efficacy.


Asunto(s)
Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/terapia , SARS-CoV-2/inmunología , Carga Viral/inmunología , Anciano , Anticuerpos Neutralizantes/inmunología , COVID-19/virología , Enfermedad Crítica , Femenino , Humanos , Inmunización Pasiva , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , ARN Viral/inmunología , Pruebas Serológicas/métodos , Glicoproteína de la Espiga del Coronavirus/inmunología , Reino Unido , Sueroterapia para COVID-19
5.
JAMA ; 326(17): 1690-1702, 2021 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-34606578

RESUMEN

IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.


Asunto(s)
COVID-19/terapia , Sistema del Grupo Sanguíneo ABO , Adulto , Anciano , Enfermedad Crítica/terapia , Femenino , Mortalidad Hospitalaria , Humanos , Inmunización Pasiva , Tiempo de Internación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Respiración Artificial/estadística & datos numéricos , Insuficiencia del Tratamiento , Vasoconstrictores/uso terapéutico , Sueroterapia para COVID-19
7.
Shock ; 60(2): 172-180, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37405876

RESUMEN

ABSTRACT: Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function. The aim of this study was to elucidate whether P2YR-dependent hemostatic and inflammatory functions were altered in platelets isolated from sepsis patients, compared with patients with mild sterile inflammation. Platelets from patients undergoing elective cardiac surgery (20 patients, 3 female) or experiencing sepsis after community-acquired pneumonia (10 patients, 4 female) were obtained through the IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults (IMMERSE) Observational Clinical Trial. In vitro aggregation and chemotaxis assays were performed with platelets after stimulation with ADP and compared with platelets isolated from healthy control subjects (7 donors, 5 female). Cardiac surgery and sepsis both induced a robust inflammatory response with increases in circulating neutrophil counts with a trend toward decreased circulating platelet counts being observed. The ability of platelets to aggregate in response to ex vivo ADP stimulation was preserved in all groups. However, platelets isolated from patients with sepsis lost the ability to undergo chemotaxis toward N -formylmethionyl-leucyl-phenylalanine, and this suppression was evident at admission through to and including discharge from hospital. Our results suggest that P2Y 1 -dependent inflammatory function in platelets is lost in patients with sepsis resulting from community-acquired pneumonia. Further studies will need to be undertaken to determine whether this is due to localized recruitment to the lungs of a platelet responsive population or loss of function as a result of dysregulation of the immune response.


Asunto(s)
Hemostáticos , Neumonía , Sepsis , Adulto , Humanos , Femenino , Plaquetas/fisiología , Agregación Plaquetaria/fisiología , Hemostáticos/farmacología , Inflamación
8.
Elife ; 122023 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-36719070

RESUMEN

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of systemic FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.


Asunto(s)
Ayuno Intermitente , Regeneración Hepática , Ratones , Animales , Hígado , Ayuno , Hepatocitos , Proliferación Celular
9.
J Intensive Care Soc ; 23(3): 318-324, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36033245

RESUMEN

Sepsis is a common illness. Immune responses are considered major drivers of sepsis illness and outcomes. However, there are no proven immunomodulator therapies in sepsis. We hypothesised that in-depth characterisation of sepsis-specific immune trajectory may inform immunomodulation in sepsis-related critical illness. We describe the protocol of the IMMERSE study to address this hypothesis. We include critically ill sepsis patients without documented immune comorbidity and age-sex matched cardiac surgical patients as controls. We plan to perform an in-depth biological characterisation of innate and adaptive immune systems, platelet function, humoral components and transcriptional determinants of the immune system responses in sepsis. This will be done at pre-specified time points during their critical illness to generate an illness trajectory. The sample size for each biological assessment is different and is described in detail. In summary, the overall aim of the IMMERSE study is to increase the granularity of longitudinal immunology model of sepsis to inform future immunomodulation trials.

10.
Cardiovasc Res ; 118(2): 461-474, 2022 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-34755842

RESUMEN

AIMS: Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. METHODS AND RESULTS: We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. CONCLUSION: Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.


Asunto(s)
COVID-19/mortalidad , MicroARNs/sangre , SARS-CoV-2 , Adulto , Anciano , Biomarcadores , COVID-19/complicaciones , COVID-19/genética , Factores de Riesgo Cardiometabólico , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Gravedad del Paciente
11.
Elife ; 102021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33399538

RESUMEN

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.


Asunto(s)
Comunicación Paracrina , Hipófisis/fisiología , Células Madre/fisiología , Vía de Señalización Wnt , Animales , Diferenciación Celular , Proliferación Celular , Femenino , Masculino , Ratones
12.
Nat Commun ; 12(1): 3406, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099652

RESUMEN

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.


Asunto(s)
COVID-19/prevención & control , Cuidados Críticos/estadística & datos numéricos , Proteómica/métodos , ARN Viral/genética , SARS-CoV-2/genética , Adulto , Animales , Anticuerpos Neutralizantes/inmunología , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Proteína C-Reactiva/metabolismo , COVID-19/metabolismo , COVID-19/virología , Femenino , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , ARN Viral/sangre , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Componente Amiloide P Sérico/metabolismo , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Carga Viral/inmunología
13.
Cancer Cell ; 39(2): 257-275.e6, 2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33476581

RESUMEN

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.


Asunto(s)
COVID-19/inmunología , Neoplasias/inmunología , Neoplasias/virología , Síndrome Respiratorio Agudo Grave/inmunología , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/etiología , COVID-19/mortalidad , Femenino , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virología , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Nasofaringe/virología , Neoplasias/mortalidad , Neoplasias/terapia , Síndrome Respiratorio Agudo Grave/etiología , Síndrome Respiratorio Agudo Grave/mortalidad , Síndrome Respiratorio Agudo Grave/virología , Linfocitos T/virología , Esparcimiento de Virus , Adulto Joven
14.
Nat Med ; 26(11): 1701-1707, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32812012

RESUMEN

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-multisystem inflammatory syndrome in children (MIS-C)-which comprises multiorgan dysfunction and systemic inflammation2-13. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections14,15, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness1 and appears distinct from Kawasaki disease.


Asunto(s)
COVID-19/sangre , COVID-19/inmunología , Leucocitos/clasificación , Leucocitos/patología , SARS-CoV-2/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Adolescente , Edad de Inicio , Coagulación Sanguínea/fisiología , COVID-19/complicaciones , COVID-19/epidemiología , Cardiomiopatías/sangre , Cardiomiopatías/etiología , Cardiomiopatías/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Inmunofenotipificación , Inflamación/sangre , Inflamación/etiología , Inflamación/inmunología , Leucocitos/inmunología , Masculino , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología
15.
Nat Med ; 26(10): 1623-1635, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32807934

RESUMEN

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.


Asunto(s)
Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Infecciones por Coronavirus/inmunología , Citocinas/inmunología , Células Dendríticas/inmunología , Neumonía Viral/inmunología , Linfocitos T/inmunología , Anciano , Subgrupos de Linfocitos B/inmunología , Basófilos/inmunología , Betacoronavirus , COVID-19 , Estudios de Casos y Controles , Ciclo Celular , Quimiocina CXCL10/inmunología , Quimiocinas/inmunología , Estudios de Cohortes , Infecciones por Coronavirus/sangre , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Hospitalización , Humanos , Memoria Inmunológica , Inmunofenotipificación , Interleucina-10/inmunología , Interleucina-6/inmunología , Recuento de Leucocitos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Pronóstico , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Regulación hacia Arriba
18.
Games Health J ; 8(5): 332-338, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31216188

RESUMEN

Objective: The goal of this month-long controlled study was to compare the efficacy of a second antidepressant (sAD) medication with a prescribed regimen of Plants vs. Zombies™ (PvZ), a casual videogame, in reducing treatment-resistant depression symptoms (TRDS) and improving heart rate variability (HRV). Materials and Methods: Approximately ∼8 weeks after beginning antidepressant therapy, participants returned to psychiatrists for evaluation and complained of TRDS. The psychiatrist gave them a choice of self-selecting a sAD medication or playing a prescribed regimen of PvZ as part of a research study. Those who agreed were referred to researchers who then screened them for major depression, the criteria for inclusion. PvZ was prescribed four times per week for 30-45 minutes over 4 weeks. Self-reported data were collected at four different times utilizing the Patient Health Questionnaire-9. HRV, an indicator of autonomic nervous system (ANS) functioning, was also recorded each time. Results: The sAD group's TRDS significantly improved. Remarkably, the PvZ group's TRDS improved significantly beyond the control group at all measurement times except for time 1 or baseline. In addition, a single 30-minute session of playing PvZ was significantly more effective in acutely reducing TRDS when compared with the sAD group that surfed the NIHM website on depression. Changes in HRV parameters indicated increased parasympathetic engagement and ANS balance in the PvZ group compared with the sAD group. Discussion: The findings illustrate the potential of PvZ as an acute and chronic intervention for reducing TRDS. Health care practitioners such as physicians and recreational therapists can consider recommending a regimen of prescribed PvZ play as a method to ameliorate symptoms of depression for those clients who self-select this option. Finally, a psychophysiological method for measuring the efficacy of videogames in reducing TRDS and a means to quantify ANS changes during gameplay are presented.


Asunto(s)
Antidepresivos/normas , Trastorno Depresivo Resistente al Tratamiento/terapia , Juegos de Video/normas , Adulto , Antidepresivos/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/psicología , Femenino , Determinación de la Frecuencia Cardíaca/métodos , Humanos , Masculino , Persona de Mediana Edad , Psicometría/instrumentación , Psicometría/métodos , Encuestas y Cuestionarios , Juegos de Video/psicología
19.
Genetics ; 176(2): 1307-22, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17409086

RESUMEN

Rab proteins are small GTPases that play important roles in transport of vesicle cargo and recruitment, association of motor and other proteins with vesicles, and docking and fusion of vesicles at defined locations. In vertebrates, >75 Rab genes have been identified, some of which have been intensively studied for their roles in endosome and synaptic vesicle trafficking. Recent studies of the functions of certain Rab proteins have revealed specific roles in mediating developmental signal transduction. We have begun a systematic genetic study of the 33 Rab genes in Drosophila. Most of the fly proteins are clearly related to specific vertebrate proteins. We report here the creation of a set of transgenic fly lines that allow spatially and temporally regulated expression of Drosophila Rab proteins. We generated fluorescent protein-tagged wild-type, dominant-negative, and constitutively active forms of 31 Drosophila Rab proteins. We describe Drosophila Rab expression patterns during embryogenesis, the subcellular localization of some Rab proteins, and comparisons of the localization of wild-type, dominant-negative, and constitutively active forms of selected Rab proteins. The high evolutionary conservation and low redundancy of Drosophila Rab proteins make these transgenic lines a useful tool kit for investigating Rab functions in vivo.


Asunto(s)
Proteínas de Drosophila/genética , Drosophila/genética , Proteínas de Unión al GTP rab/genética , Animales , ADN/genética , ADN/aislamiento & purificación , Familia de Multigenes , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes/metabolismo , Transfección
20.
Lab Chip ; 6(8): 1012-9, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16874371

RESUMEN

We have developed an automated system based on microelectromechanical systems (MEMS) injectors for reliable mass-injection of Drosophila embryos. Targeted applications are high-throughput RNA interference (RNAi) screens. Our injection needles are made of silicon nitride. The liquid to be injected is stored in an integrated 500 nl reservoir, and an externally applied air pressure pulse precisely controls the injected volume. A steady-state water flow rate per applied pressure of 1.2 nl s(-1) bar(-1) was measured for a needle with channel width, height and length of 6.1 microm, 2.3 microm and 350 microm, respectively. A typical volume of 60 pl per embryo can be reliably and rapidly delivered within tens of milliseconds. Theoretical predictions of flow rates match measured values within +/-10%. Embryos are attached to a glass slide surface and covered with oil. Packages with the injector chip and the embryo slide are mounted on motorized xyz-stages. Two cameras allow the user to quickly align the needle tip to alignment marks on the glass slide. Our system then automatically screens the glass slide for embryos and reliably detects and injects more than 98% of all embryos. Survival rates after deionized (DI) water injection of 80% and higher were achieved. A first RNAi experiment was successfully performed with double-stranded RNA (dsRNA) corresponding to the segment polarity gene armadillo at a concentration of 0.01 microM. Almost 80% of the injected embryos expressed an expected strong loss-of-function phenotype. Our system can replace current manual injection technologies and will support systematic identification of Drosophila gene functions.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Técnicas Analíticas Microfluídicas , Microinyecciones , Interferencia de ARN , ARN Bicatenario , ARN Interferente Pequeño , Animales , Proteínas del Dominio Armadillo/biosíntesis , Proteínas del Dominio Armadillo/genética , Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/genética , Drosophila melanogaster , Embrión no Mamífero/metabolismo , ARN Bicatenario/genética , ARN Interferente Pequeño/genética , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética
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