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1.
PLoS Biol ; 22(1): e3002462, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38289969

RESUMO

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.


Assuntos
Esclerose Lateral Amiotrófica , Animais , Camundongos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Cisteína/genética , Mutação , Superóxido Dismutase/genética , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética
2.
Am J Respir Crit Care Med ; 208(5): 579-588, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37384378

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.


Assuntos
Fibrose Pulmonar Idiopática , Fonte de Informação , Humanos , Capacidade Vital , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão , Resultado do Tratamento , Progressão da Doença
3.
Annu Rev Med ; 72: 135-149, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33113336

RESUMO

Lung transplantation improves survival and quality of life in patients with advanced pulmonary disease. Over the past several decades, the volume of lung transplants has grown substantially, with increasing transplantation of older and acutely ill individuals facilitated by improved utilization and preservation of available donor organs. Other advances include improvements in the diagnosis and mechanistic understanding of frequent post-transplant complications, such as primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction (CLAD). CLAD occurs as a result of the host immune response to the allograft and is the principal factor limiting long-term survival after lung transplantation. Two distinct clinical phenotypes of CLAD have emerged, bronchiolitis obliterans syndrome and restrictive allograft syndrome, and this distinction has enabled further understanding of underlying immune mechanisms. Building on these advances, ongoing studies are exploring novel approaches to diagnose, prevent, and treat CLAD. Such studies are necessary to improve long-term outcomes for lung transplant recipients.


Assuntos
Pneumopatias/cirurgia , Transplante de Pulmão/métodos , Pulmão/cirurgia , Preservação de Órgãos/métodos , Disfunção Primária do Enxerto/epidemiologia , Saúde Global , Humanos , Incidência , Fatores de Risco
4.
BMC Pulm Med ; 23(1): 414, 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37904125

RESUMO

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition of somatic mutations that leads to an expanded blood cell clone, has been associated with development of a pro-inflammatory state. An enhanced or dysregulated inflammatory response may contribute to rejection after lung transplantation, however the prevalence of CHIP in lung recipients and influence of CHIP on allograft outcomes is unknown. METHODS: We analyzed whole-exome sequencing data in 279 lung recipients to detect CHIP, defined by pre-specified somatic mutations in 74 genes known to promote clonal expansion of hematopoietic stem cells. We compared the burden of acute rejection (AR) over the first post-transplant year in lung recipients with vs. without CHIP using multivariable ordinal regression. Multivariate Cox proportional hazards models were used to assess the association between CHIP and CLAD-free survival. An exploratory analysis evaluated the association between the number of CHIP-associated variants and chronic lung allograft dysfunction (CLAD)-free survival. RESULTS: We detected 64 CHIP-associated mutations in 45 individuals (15.7%), most commonly in TET2 (10.8%), DNMT3A (9.2%), and U2AF1 (9.2%). Patients with CHIP tended to be older but did not significantly differ from patients without CHIP in terms of race or native lung disease. Patients with CHIP did not have a higher incidence of AR over the first post-transplant year (p = 0.45) or a significantly increased risk of death or CLAD (adjusted HR 1.25, 95% CI 0.88-1.78). We did observe a significant association between the number of CHIP variants and CLAD-free survival, specifically patients with 2 or more CHIP-associated variants had an increased risk for death or CLAD (adjusted HR 3.79, 95% CI 1.98-7.27). CONCLUSIONS: Lung recipients have a higher prevalence of CHIP and a larger variety of genes with CHIP-associated mutations compared with previous reports for the general population. CHIP did not increase the risk of AR, CLAD, or death in lung recipients.


Assuntos
Hematopoiese Clonal , Transplante de Pulmão , Humanos , Transplantados , Prevalência , Pulmão , Transplante de Pulmão/efeitos adversos
5.
Respir Res ; 21(1): 304, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213478

RESUMO

BACKGROUND: Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients. METHODS: This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis. RESULTS: The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p = 0.03 respectively), and ET-1 predicted future 6MWD (p = 0.02). ET-1 (p = 0.01) and cGMP/NT-proBNP ratio (p = 0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p = 0.03) and PAH patients on ERA therapy (p = 0.01). CONCLUSIONS: ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.


Assuntos
Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Administração Oral , Idoso , Biomarcadores/sangue , Endotelina-1/sangue , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Estudos Prospectivos , Resultado do Tratamento
6.
Biophys J ; 116(8): 1386-1393, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30979553

RESUMO

In mammalian ventricular cardiomyocytes, invaginations of the surface membrane form the transverse tubular system (T-system), which consists of transverse tubules (TTs) that align with sarcomeres and Z-lines as well as longitudinal tubules (LTs) that are present between Z-lines in some species. In many cardiac disease etiologies, the T-system is perturbed, which is believed to promote spatially heterogeneous, dyssynchronous Ca2+ release and inefficient contraction. In general, T-system characterization approaches have been directed primarily at isolated cells and do not detect subcellular T-system heterogeneity. Here, we present MatchedMyo, a matched-filter-based algorithm for subcellular T-system characterization in isolated cardiomyocytes and millimeter-scale myocardial sections. The algorithm utilizes "filters" representative of TTs, LTs, and T-system absence. Application of the algorithm to cardiomyocytes isolated from rat disease models of myocardial infarction (MI), dilated cardiomyopathy induced via aortic banding, and sham surgery confirmed and quantified heterogeneous T-system structure and remodeling. Cardiomyocytes from post-MI hearts exhibited increasing T-system disarray as proximity to the infarct increased. We found significant (p < 0.05, Welch's t-test) increases in LT density within cardiomyocytes proximal to the infarct (12 ± 3%, data reported as mean ± SD, n = 3) versus sham (4 ± 2%, n = 5), but not distal to the infarct (7 ± 1%, n = 3). The algorithm also detected decreases in TTs within 5° of the myocyte minor axis for isolated aortic banding (36 ± 9%, n = 3) and MI cardiomyocytes located intermediate (37 ± 4%, n = 3) and proximal (34 ± 4%, n = 3) to the infarct versus sham (57 ± 12%, n = 5). Application of bootstrapping to rabbit MI tissue revealed distal sections comprised 18.9 ± 1.0% TTs, whereas proximal sections comprised 10.1 ± 0.8% TTs (p < 0.05), a 46.6% decrease. The matched-filter approach therefore provides a robust and scalable technique for T-system characterization from isolated cells through millimeter-scale myocardial sections.


Assuntos
Algoritmos , Processamento de Imagem Assistida por Computador/métodos , Espaço Intracelular/metabolismo , Miócitos Cardíacos/citologia , Animais , Ventrículos do Coração/citologia , Ventrículos do Coração/diagnóstico por imagem , Ratos
7.
Planta ; 246(5): 879-898, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28699116

RESUMO

MAIN CONCLUSION: Molecular and microscopic analyses reveal enormous non-cultivable endophytic bacteria in grapevine field shoots with functional significance. Diverse bacteria enter tissue cultures through surface-sterilized tissues and survive surreptitiously with varying taxonomic realignments. The study was envisaged to assess the extent of endophytic bacterial association with field shoot tissues of grapevine and the likelihood of introduction of such internally colonizing bacteria in vitro adopting molecular techniques targeting the non-cultivable bacterial community. PowerFood®-kit derived DNA from surface-sterilized field shoot tips of grapevine Flame Seedless was employed in a preliminary bacterial class-specific PCR screening proving positive for major prokaryotic taxa including Archaea. Taxonomic and functional diversity were analyzed through whole metagenome profiling (WMG) which revealed predominantly phylum Actinobacteria, Proteobacteria, and minor shares of Firmicutes, Bacteroidetes, and Deinococcus-Thermus with varying functional roles ascribable to the whole bacterial community. Field shoot tip tissues and callus derived from stem segments were further employed in 16S rRNA V3-V4 amplicon taxonomic profiling. This revealed elevated taxonomic diversity in field shoots over WMG, predominantly Proteobacteria succeeded by Actinobacteria, Firmicutes, Bacteroidetes, and 15 other phyla including several candidate phyla (135 families, 179 genera). Callus stocks also displayed broad bacterial diversity (16 phyla; 96 families; 141 genera) bearing resemblance to field tissues with Proteobacterial dominance but a reduction in its share, enrichment of Actinobacteria and Firmicutes, disappearance of some field-associated phyla and detection of a few additional taxonomic groups over field community. Similar results were documented during 16S V3-V4 amplicon taxonomic profiling on Thompson Seedless field shoot tip and callus tissues. Video microscopy on tissue homogenates corroborated enormous endophytic bacteria. This study elucidates a vast diversity of cultivation-recalcitrant endophytic bacteria prevailing in grapevine field shoots, their in vitro introduction, and unsuspecting sustenance with possible silent participation in tissue culture processes.


Assuntos
Bactérias/genética , Metagenômica , Vitis/microbiologia , Bactérias/classificação , Bactérias/isolamento & purificação , Biodiversidade , Endófitos , Brotos de Planta/microbiologia , Reação em Cadeia da Polimerase , Técnicas de Cultura de Tecidos
8.
Am J Respir Cell Mol Biol ; 52(6): 663-73, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25611885

RESUMO

Significant advances in the treatment of pulmonary arterial hypertension (PAH) over the last two decades have led to the introduction of multiple classes of oral therapy, but the disease remains devastating for many patients. Disease progression, in spite of oral monotherapy, is a major problem, and alternative therapy, such as infusion of prostacyclins, is cumbersome and carries considerable potential morbidity. Use of combination oral therapy, including drugs from both the endothelin receptor antagonist and phosphodiesterase-5 inhibitor classes, has increased, and there is some evidence to support this approach. Given the multiple options now available in pulmonary hypertension (PH) therapy, biomarkers to guide treatment decisions could be helpful. Here, we review the evidence for and against the clinical use of molecular biomarkers relevant to PH pathogenesis, emphasizing assayable markers that may also inform more rational selection of agents that influence pathways targeted by treatment. We emphasize the interactive nature of changes in mediators and messengers, such as endothelin-1, prostacyclin, brain natriuretic peptide (which has demonstrated biomarker utility), nitric oxide derivatives, and cyclic guanosine monophosphate, which play important roles in processes central to progression of PAH, such as vascular remodeling, vasoconstriction, and maladaptive right ventricular changes, and are relevant to its therapy. Accordingly, we propose that the identification and use of a molecular biomarker panel that assays these molecules in parallel and serially might, if validated, better inform unique patient phenotypes, prognosis, and the rational selection and titration of combination oral and other therapy in individual patients with PH/PAH.


Assuntos
Hipertensão Pulmonar/sangue , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Fator Natriurético Atrial/sangue , Biomarcadores/sangue , AMP Cíclico/sangue , GMP Cíclico/sangue , Endotelina-1/sangue , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Óxido Nítrico/sangue , S-Nitrosotióis/sangue , Resultado do Tratamento
9.
ACS Appl Mater Interfaces ; 16(3): 3542-3551, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38215005

RESUMO

The transition metal phosphide (TMP)-based functional electrocatalysts are very promising for the development of electrochemical energy conversion and storage devices including rechargeable metal-air batteries and water electrolyzer. Tuning the electrocatalytic activity of TMPs is one of the vital steps to achieve the desired performance of these energy devices. Herein, we demonstrate the modulation of the bifunctional oxygen electrocatalytic activity of nitrogen-doped carbon-encapsulated CoP (CoP@NC) nanostructures by surface tailoring with ultralow amount (0.56 atomic %) of Ru nanoparticles (2.5 nm). The CoP at the core and the Ru nanoparticles on the shell have a facile charge transfer interaction with the encapsulating NC. The strong coupling of Ru with CoP@NC boosts the electrocatalytic performance toward oxygen reduction (ORR), oxygen evolution (OER), and hydrogen evolution (HER) reactions. The surface-tailored catalyst requires only 35 mV to deliver the benchmark current density of 10 mA·cm-2 for HER. A small potential gap of 620 mV between ORR and OER is achieved, making the catalyst highly suitable for the development of rechargeable zinc-air batteries (ZABs). The homemade ZAB delivers a specific capacity of 780 mA·hgZn-1 and peak power density of 175 mW·cm-2 with a very small voltaic efficiency loss (1.1%) after 300 cycles. The two-electrode water splitting cell (CoP@NC-Ru||CoP@NC-Ru) delivers remarkably low cell voltage of 1.47 V at the benchmark current density. Stable current density of 25 mA·cm-2 for 25 h without any significant change is achieved. Theoretical studies support the charge transfer interaction-induced enhanced electrocatalytic activity of the surface-tailored nanostructure.

10.
BMJ Open Respir Res ; 11(1)2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38242716

RESUMO

BACKGROUND: Chronic cough is common, negatively affects quality of life and has limited treatment options. Inhibition of purinergic signalling is a promising therapeutic approach but is associated with taste-related adverse effects. Little is known about treatment preferences from the perspective of patients with chronic cough, such as trade-offs between efficacy and side effect. METHODS: Patients with chronic cough completed an online discrete choice experiment survey in which they answered a series of questions requiring a choice between two constructed treatment options characterised by varying attribute levels. Selection of cough and taste-related attributes was informed by qualitative interviews and clinical trial data. Logit-based models were used to analyse resulting choice data. RESULTS: The discrete choice experiment survey was completed by 472 participants with chronic cough. Among study attributes, frequency of intense cough attacks was the most important to participants, followed by taste change, frequency of night-time coughing and frequency of daytime coughing. To accept the least preferred taste disturbance of a bitter, metallic, chalky or oily taste change, participants required either: (1) elimination of night-time cough along with a slight reduction in daytime cough; (2) elimination of daytime cough along with a pronounced reduction in night-time or (3) reduction in intense cough attacks from 7 to 2 times per week. Two distinct preference patterns were identified, each placing different importance on efficacy versus side effect trade-offs. CONCLUSIONS: Participants with chronic cough were willing to accept some taste disturbances in exchange for improved efficacy of chronic cough treatments. Knowledge of patient preferences can facilitate shared decision-making.


Assuntos
Comportamento de Escolha , Tosse Crônica , Humanos , Preferência do Paciente , Qualidade de Vida , Tosse/terapia
11.
Appl Environ Microbiol ; 79(1): 381-4, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23087040

RESUMO

Evaluating different swabbing materials for spore recovery efficiency (RE) from steel surfaces, we recorded the maximum RE (71%) of 10(7) Bacillus subtilis spores with Tulips cotton buds, followed by Johnson's cotton buds and standard Hi-Media cotton, polyester, nylon, and foam (23%) swabs. Among cotton swabs, instant water-absorbing capacity or the hydrophilicity index appeared to be the major indicator of RE, as determined by testing three more brands. Tulips swabs worked efficiently across diverse nonporous surfaces and on different Bacillus spp., registering 65 to 77% RE.


Assuntos
Bacillus subtilis/isolamento & purificação , Técnicas Bacteriológicas/métodos , Microbiologia Ambiental , Manejo de Espécimes/métodos , Esporos/isolamento & purificação , Gossypium , Interações Hidrofóbicas e Hidrofílicas , Nylons , Poliésteres , Aço
12.
Chest ; 164(1): 159-168, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36681147

RESUMO

BACKGROUND: Frailty, measured as a single construct, is associated variably with poor outcomes before and after lung transplantation. The usefulness of a comprehensive frailty assessment before transplantation is unknown. RESEARCH QUESTION: How are multiple frailty constructs, including phenotypic and cumulative deficit models, muscle mass, exercise tolerance, and social vulnerabilities, measured before transplantation, associated with short-term outcomes after lung transplantation? STUDY DESIGN AND METHODS: We conducted a retrospective cohort study of 515 lung recipients who underwent frailty assessments before transplantation, including the short physical performance battery (SPPB), transplant-specific frailty index (FI), 6-min walk distance (6MWD), thoracic sarcopenia, and social vulnerability indexes. We tested the association between frailty measures before transplantation and outcomes after transplantation using logistic regression to model 1-year survival and zero-inflated negative binomial regression to model hospital-free days (HFDs) in the first 90 days after transplantation. Adjustment covariates included age, sex, native lung disease, transplantation type, lung allocation score, BMI, and primary graft dysfunction. RESULTS: Before transplantation, 51.3% of patients were frail by FI (FI ≥ 0.25) and no patients were frail by SPPB. In multivariate adjusted models that also included FI, SPPB, and 6MWD, greater frailty by FI, but not SPPB, was associated with fewer HFDs (-0.006 per 0.01 unit worsening; 95% CI, -0.01 to -0.002 per 0.01 unit worsening) among discharged patients. Greater SPPB deficits were associated with decreased odds of 1-year survival (OR, 0.51 per 1 unit worsening; 95% CI, 0.28-0.93 per 1 unit worsening). Correlation among frailty measurements overall was poor. No association was found between thoracic sarcopenia, 6MWD, or social vulnerability assessments and short-term outcomes after lung transplantation. INTERPRETATION: Both phenotypic and cumulative deficit models measured before transplantation are associated with short-term outcomes after lung transplantation. Cumulative deficit measures of frailty may be more relevant in the first 90 days after transplantation, whereas phenotypic frailty may have a stronger association with 1-year survival.


Assuntos
Fragilidade , Transplante de Pulmão , Sarcopenia , Humanos , Fragilidade/complicações , Estudos Retrospectivos , Sarcopenia/epidemiologia , Sarcopenia/complicações , Pulmão
13.
Comput Biol Med ; 146: 105579, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35588677

RESUMO

Ventricular arrhythmias are the leading cause of mortality in patients with ischemic heart diseases, such as myocardial infarction (MI). Computational simulation of cardiac electrophysiology provides insights into these arrhythmias and their treatment. However, only sparse information is available on crucial model parameters, for instance, the anisotropic intracellular electrical conductivities. Here, we introduced an approach to estimate these conductivities in normal and MI hearts. We processed and analyzed images from confocal microscopy of left ventricular tissue of a rabbit MI model to generate 3D reconstructions. We derived tissue features including the volume fraction of myocytes (Vmyo), gap junctions-containing voxels (Vgj), and fibrosis (Vfibrosis). We generated models of the intracellular space and intercellular coupling. Applying numerical methods for solving Poisson's equation for stationary electrical currents, we calculated normal (σmyo,n), longitudinal (σmyo,l), and transverse (σmyo,t) intracellular conductivities. Using linear regression analysis, we assessed relationships of conductivities to tissue features. Vgj and Vmyo were reduced in MI vs. control, but Vfibrosis was increased. Both σmyo,l and σmyo,n were lower in MI than in control. Differences of σmyo,t between control and MI were not significant. We found strong positive relationships of σmyo,l with Vmyo and Vgj, and a strong negative relationship with Vfibrosis. The relationships of σmyo,n with these tissue features were similar but less pronounced. Our study provides quantitative insights into the intracellular conductivities in the normal and MI heart. We suggest that our study establishes a framework for the estimation of intracellular electrical conductivities of myocardium with various pathologies.


Assuntos
Coração , Infarto do Miocárdio , Animais , Arritmias Cardíacas/patologia , Fibrose , Coração/fisiologia , Humanos , Microscopia Confocal , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio/patologia , Coelhos
14.
Ann Am Thorac Soc ; 19(6): 981-990, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35073248

RESUMO

Rationale: Lung transplant offers the potential to extend life for patients with idiopathic pulmonary fibrosis (IPF); yet, this therapeutic modality is only available to a small proportion of patients. Objectives: To identify clinical characteristics and social determinants of health that differentially associate with lung transplant compared with death in patients with IPF. Methods: We evaluated data from the Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were enrolled between June 2014 and October 2018. Patients who were listed for lung transplant were not eligible to enroll in the registry, but patients could be listed for transplant after enrollment. We performed a multivariable time-to-event analysis incorporating competing risks methodology to examine differential associations between prespecified covariates and the risk of lung transplant versus death. Covariates included factors related to lung transplant eligibility, clinical characteristics of IPF, and social determinants of health. Covariates were modeled as time independent or time dependent as appropriate. Results: Among 955 patients with IPF, event rates of lung transplant and death were 7.4% and 16.3%, respectively, at 2 years. Covariates with the strongest differential association were age, median zip code income, and enrollment at a center with a lung transplant program. Lung transplant was less likely (hazard ratio [HR], 0.13 [95% confidence interval (CI), 0.06-0.28] per 5-yr increase) and death more likely (HR, 1.41 [95% CI, 1.22-1.64] per 5-yr increase) among those older than 70 years of age. Higher median zip code income was associated with lung transplant (HR, 1.22 [95% CI, 1.13-1.31] per $10,000 increase) but not death (HR, 0.99 [95% CI, 0.94-1.04] per $10,000 increase). Enrollment at a center with a lung transplant program was associated with lung transplant (HR, 4.31 [95% CI, 1.76-10.54]) but not death (HR, 0.99 [95% CI, 0.69-1.43]). Oxygen use with activity was associated with both lung transplant and death, but more strongly with lung transplant. A higher number of comorbidities was associated with an increased likelihood of death but not lung transplant. Conclusions: For patients in the Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry, median zip code income and access to a lung transplant center differentially impact the risk of lung transplant compared with death, regardless of disease severity measures or other transplant eligibility factors. Interventions are needed to mitigate inequalities in lung transplantation based on socioeconomic status. Clinical trial registered with www.clinicaltrials.gov (NCT01915511).


Assuntos
Fibrose Pulmonar Idiopática , Transplante de Pulmão , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/cirurgia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros
15.
Front Physiol ; 12: 730933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675817

RESUMO

With an estimated 64.3 million cases worldwide, heart failure (HF) imposes an enormous burden on healthcare systems. Sudden death from arrhythmia is the major cause of mortality in HF patients. Computational modeling of the failing heart provides insights into mechanisms of arrhythmogenesis, risk stratification of patients, and clinical treatment. However, the lack of a clinically informed approach to model cardiac tissues in HF hinders progress in developing patient-specific strategies. Here, we provide a microscopy-based foundation for modeling conduction in HF tissues. We acquired 2D images of left ventricular tissues from HF patients (n = 16) and donors (n = 5). The composition and heterogeneity of fibrosis were quantified at a sub-micrometer resolution over an area of 1 mm2. From the images, we constructed computational bidomain models of tissue electrophysiology. We computed local upstroke velocities of the membrane voltage and anisotropic conduction velocities (CV). The non-myocyte volume fraction was higher in HF than donors (39.68 ± 14.23 vs. 22.09 ± 2.72%, p < 0.01), and higher in ischemic (IC) than nonischemic (NIC) cardiomyopathy (47.2 ± 16.18 vs. 32.16 ± 6.55%, p < 0.05). The heterogeneity of fibrosis within each subject was highest for IC (27.1 ± 6.03%) and lowest for donors (7.47 ± 1.37%) with NIC (15.69 ± 5.76%) in between. K-means clustering of this heterogeneity discriminated IC and NIC with an accuracy of 81.25%. The heterogeneity in CV increased from donor to NIC to IC tissues. CV decreased with increasing fibrosis for longitudinal (R 2 = 0.28, p < 0.05) and transverse conduction (R 2 = 0.46, p < 0.01). The tilt angle of the CV vectors increased 2.1° for longitudinal and 0.91° for transverse conduction per 1% increase in fibrosis. Our study suggests that conduction fundamentally differs in the two etiologies due to the characteristics of fibrosis. Our study highlights the importance of the etiology-specific modeling of HF tissues and integration of medical history into electrophysiology models for personalized risk stratification and treatment planning.

16.
BMJ Open ; 11(10): e050571, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607865

RESUMO

OBJECTIVE: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma. DESIGN: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease. SETTING: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020. PARTICIPANTS: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed. PRIMARY OUTCOME MEASURE: Factors associated with all-cause mortality at 28 days after enrolment. RESULTS: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death. CONCLUSION: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death. TRIAL REGISTRATION NUMBER: CTRI/2020/04/024775.


Assuntos
COVID-19 , Adulto , COVID-19/terapia , Humanos , Imunização Passiva , Índia/epidemiologia , Pessoa de Meia-Idade , SARS-CoV-2 , Soroterapia para COVID-19
17.
Data Brief ; 29: 105244, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32099876

RESUMO

One factor at a time approach was employed for the optimization of media components, physical factors and additional additives for lignin peroxidase (LiP) production under submerged fermentation by the endophytic fungus Endomelanconiopsis sp. The optimized conditions derived were: carbon source (dextrose 10 g/L), nitrogen source (ammonium tartarate 0.027 g/L), veratryl alcohol (1 mM), MnSO4 (0.5 g/L), inoculum concentration (3 mycelial plugs), pH (5), temperature (30 °C) and Tween 80 (1.5%). A 40 fold increase of enzyme activity was observed after the single parameter optimization. The lignin peroxidase (LiP) production to the level of 345.26 ± 0.52 IU/mL indicates that the fungus has the commercial potential for LiP.

18.
Ann Am Thorac Soc ; 17(3): 253-263, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31860801

RESUMO

Bronchiolar abnormalities are common and can occur in conditions that affect either the large airways or the more distal parenchyma. In this review, we focus on the diagnosis and management of primary bronchiolar disorders, or conditions in which bronchiolitis is the predominant pathologic process, including constrictive bronchiolitis, follicular bronchiolitis, acute bronchiolitis, respiratory bronchiolitis, and diffuse panbronchiolitis. Due to the nature of abnormalities in the small airway, clinical and physiological changes in bronchiolitis can be subtle, making diagnosis challenging. Primary bronchiolar disorders frequently present with progressive dyspnea and cough that can be out of proportion to imaging and physiologic studies. Pulmonary function tests may be normal, impaired in an obstructive, restrictive, or mixed pattern, or have an isolated decrease in diffusion capacity. High-resolution computed tomography scan is an important diagnostic tool that may demonstrate one or more of the following three patterns: 1) solid centrilobular nodules, often with linear branching opacities (i.e., "tree-in-bud" pattern); 2) ill-defined ground glass centrilobular nodules; and 3) mosaic attenuation on inspiratory images that is accentuated on expiratory images, consistent with geographic air trapping. Bronchiolitis is often missed on standard transbronchial lung biopsies, as the areas of small airway involvement can be patchy. Fortunately, many patients can be diagnosed with a combination of clinical suspicion, inspiratory and expiratory high-resolution computed tomography scans, and pulmonary function testing. Joint consultation of clinicians with both radiologists and pathologists (in cases where histopathology is pursued) is critical to appropriately assess the clinical-radiographic-pathologic context in each individual patient.


Assuntos
Broncopatias/diagnóstico , Broncopatias/terapia , Biópsia , Brônquios/patologia , Brônquios/fisiopatologia , Broncopatias/patologia , Broncopatias/fisiopatologia , Diagnóstico Diferencial , Humanos , Testes de Função Respiratória , Tomografia Computadorizada por Raios X
19.
Sci Total Environ ; 731: 139074, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32417476

RESUMO

The environment of a high altitude brackish water lake presents an unprecedented reservoir for the microbial community with adaptability towards surviving stressful conditions. Pangong lake is a high altitude brackish water lake of the Himalayas situated in the eastern part of Ladakh (Indian Tibet), at the height of 4250 m above the sea level. Shotgun metagenomics sequencing of Pangong Lake sediments was performed to examine the taxonomic diversity and functional adaptations of the resident psychrophilic and psychrotolerant microbial communities of the lake (September; a temperature of ±10 °C). Proteobacteria was the most prominent phylum, and Methylophaga, Halomonas, and Marinobacter were mainly abundant at the genus level. Enzyme pathways responsible for methane metabolism, nitrogen metabolism, sulfur reduction, benzoate, and xylene degradation appeared to be complete in the metagenomic dataset. Stress response genes responsible for adaption to pH, cold, salt tolerance, osmotic stress, and oxidative stress were also found in abundance in the metagenome. We compared the Pangong lake metagenome sample to sediments and water samples from three different aquatic habitats, namely saline lake, freshwater lakes and marine ecosystem using MG-RAST server against RefSeq and Subsystem databases. The Pangong lake microbial community contains six unique genera. Regression analysis using metagenome samples suggested that Pangong lake was most closely related to the Trophic South Pacific Ocean (R2 = 0.971) and Socompa lake ecosystem (R2 = 0.991) at phylum and functional level II, respectively. Our study signifies that the functional metabolic potentiality of Pangong lake is strongly influenced by the taxonomic structure and environmental conditions. We are reporting the metagenome of the sediment sample of the Pangong lake, which unveils the microbial diversity and their functional potential.


Assuntos
Lagos , Metagenoma , Bactérias/genética , Sedimentos Geológicos , Metagenômica , Oceano Pacífico , Filogenia , Tibet
20.
Nat Struct Mol Biol ; 11(10): 992-1000, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15361857

RESUMO

Nonsense-mediated mRNA decay (NMD) in mammalian cells targets cap-binding protein 80 (CBP80)-bound mRNA during or after a pioneer round of translation. It is unknown whether eukaryotic translation initiation factor 4G (eIF4G) functions in the pioneer round. We show that baculovirus-produced CBP80 and CBP20 independently interact with eIF4GI. The interactions between eIF4G and the heterodimer CBP80/20 suggest that eIF4G has a function in the pioneer initiation complex rather than merely a presence during remodeling to the steady-state complex. First, NMD is inhibited upon eIF4G cleavage by HIV-2 or poliovirus 2A protease. Second, eIF4GI coimmunopurifies with pre-mRNA, indicating that it associates with transcripts before the pioneer round. Third, eIF4G immunopurifies with Upf NMD factors and eIF4AIII, which are constituents of the pioneer translation initiation complex. We propose a model in which eIF4G serves to connect CBP80/20 with other initiation factors during the pioneer round of translation.


Assuntos
Biossíntese de Proteínas/fisiologia , Animais , Sequência de Bases , Células COS , Primers do DNA , Ligação Proteica , RNA Mensageiro/metabolismo
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