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1.
PLoS One ; 16(4): e0249477, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33836031

RESUMO

BACKGROUND: The search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells. METHODS: Bronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry. RESULTS: The bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, γδ T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p = 0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants. CONCLUSION: This observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.

2.
J Cardiovasc Dev Dis ; 8(3)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801433

RESUMO

Among the three transforming growth factor beta (TGFß) ligands, TGFß2 is essential for heart development and is produced by multiple cell types, including myocardium. Heterozygous mutations in TGFB2 in patients of connective tissue disorders result in congenital heart defects and adult valve malformations, including mitral valve prolapse (MVP) with or without regurgitation. Tgfb2 germline knockout fetuses exhibit multiple cardiac defects but the role of myocardial-TGFß2 in heart development is yet to be elucidated. Here, myocardial Tgfb2 conditional knockout (CKO) embryos were generated by crossing Tgfb2flox mice with Tgfb2+/-; cTntCre mice. Tgfb2flox/- embryos were normal, viable. Cell fate mapping was done using dual-fluorescent mT/mG+/- mice. Cre-mediated Tgfb2 deletion was assessed by genomic PCR. RNAscope in situ hybridization was used to detect the loss of myocardial Tgfb2 expression. Histological, morphometric, immunohistochemical, and in situ hybridization analyses of CKOs and littermate controls at different stages of heart development (E12.5-E18.5) were used to determine the role of myocardium-derived TGFß2 in atrioventricular (AV) cushion remodeling and myocardial development. CKOs exhibit a thin ventricular myocardium, AV cushion remodeling defects and developed incomplete AV septation defects. The loss of myocardial Tgfb2 resulted in impaired cushion maturation and dysregulated cell death. Phosphorylated SMAD2, a surrogate for TGFß signaling, was "paradoxically" increased in both AV cushion mesenchyme and ventricular myocardium in the CKOs. Our results indicate that TGFß2 produced by cardiomyocytes acting as cells autonomously on myocardium and via paracrine signaling on AV cushions are required for heart development.

3.
J Biol Chem ; : 100554, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33744290

RESUMO

The structural study of icosahedral viruses has a long and impactful history in both crystallographic methodology and molecular biology. The evolution of the Protein Data Bank has paralleled and supported these studies providing readily accessible formats dealing with novel features associated with viral particle symmetries and subunit interactions. This overview describes the growth in size and complexity of icosahedral viruses from the first early studies of small RNA plant viruses and human picorna viruses up to the larger and more complex bacterial phage, insect and human disease viruses such as Zika, hepatitis B, Adeno and Polyoma virus. The analysis of icosahedral viral capsid protein domain folds has shown striking similarities, with the beta jelly roll motif observed across multiple evolutionarily divergent species. The icosahedral symmetry of viruses drove the development of non-crystallographic symmetry averaging as a powerful phasing method, and the constraints of maintaining this symmetry resulted in the concept of quasi-equivalence in viral structures. Symmetry also played an important early role in demonstrating the power of cryo-electron microscopy as an alternative to crystallography in generating atomic resolution structures of these viruses. The Protein Data Bank has been a critical resource for assembling and disseminating these structures to a wide community, and the virus particle explorer (VIPER) was developed to enable users to easily generate and view complete viral capsid structures from their asymmetric building blocks. Finally, we share a personal perspective on the early use of computer graphics to communicate the intricacies, interactions and beauty of these virus structures.

4.
Viruses ; 13(3)2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652918

RESUMO

The human complement system is an important part of the innate immune system. Its effector pathways largely mediate virus neutralization. Vesicular stomatitis virus (VSV) activates the classical pathway of the complement, leading to virus neutralization by lysis. Two host-derived membrane-associated regulators of complement activation (RCA), CD55 and CD46, which are incorporated into the VSV envelope during egress, confer protection by delaying/resisting complement-mediated neutralization. We showed previously that CD55 is more effective than CD46 in the inhibition of neutralization. In this study, we identified that, at the protein level, VSV infection resulted in the down-regulation of CD46 but not CD55. The mRNA of both the RCAs was significantly down-regulated by VSV, but it was delayed in the case of CD55. The immunoblot analysis of the levels of RCAs in the progeny virion harvested at three specific time intervals, points to an equal ratio of its distribution relative to viral proteins. Besides reconfirming the dominant role of CD55 over CD46 in shielding VSV from complement, our results also highlight the importance of the subtle modulation in the expression pattern of RCAs in a system naturally expressing them.

5.
Arch Virol ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33683475

RESUMO

Virus maturation is found in all animal viruses and dsDNA bacteriophages that have been studied. It is a programmed process, cued by cellular environmental factors, that transitions a noninfectious, initial assembly product (provirus) to an infectious particle (virion). Nudaurelia capensis omega virus (NωV) is an ssRNA insect virus with T=4 quasi-symmetry. Over the last 20 years, NωV virus-like particles (VLPs) have been an attractive model for the detailed study of maturation. The novel feature of the system is the progressive transition from procapsid to capsid controlled by pH. Homogeneous populations of maturation intermediates can be readily produced at arbitrary intervals by adjusting the pH between 7.6 and 5.0. These intermediates were investigated using biochemical and biophysical methods to create a stop-frame transition series of this complex process. The studies reviewed here characterized the large-scale subunit reorganization during maturation (the particle changes size from 48 nm to 41 nm) as well as the mechanism of a maturation cleavage, a time-resolved study of cleavage site formation, and specific roles of quasi-equivalent subunits in the release of membrane lytic peptides required for cellular entry.

6.
Med Ultrason ; 23(1): 124-125, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33621284

RESUMO

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7.
Nucleic Acids Res ; 49(D1): D809-D816, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33313778

RESUMO

VIrus Particle ExploreR data base (VIPERdb) (http://viperdb.scripps.edu) is a curated repository of virus capsid structures and a database of structure-derived data along with various virus specific information. VIPERdb has been continuously improved for over 20 years and contains a number of virus structure analysis tools. The release of VIPERdb v3.0 contains new structure-based data analytics tools like Multiple Structure-based and Sequence Alignment (MSSA) to identify hot-spot residues within a selected group of structures and an anomaly detection application to analyze and curate the structure-derived data within individual virus families. At the time of this writing, there are 931 virus structures from 62 different virus families in the database. Significantly, the new release also contains a standalone database called 'Virus World database' (VWdb) that comprises all the characterized viruses (∼181 000) known to date, gathered from ICTVdb and NCBI, and their capsid protein sequences, organized according to their virus taxonomy with links to known structures in VIPERdb and PDB. Moreover, the new release of VIPERdb includes a service-oriented data engine to handle all the data access requests and provides an interface for futuristic data analytics using machine leaning applications.


Assuntos
Capsídeo/química , Ciência de Dados , Bases de Dados como Assunto , Vírus/química , Curadoria de Dados , Alinhamento de Sequência
8.
J Antimicrob Chemother ; 76(3): 582-586, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33374006

RESUMO

BACKGROUND: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. OBJECTIVES: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. METHODS: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. RESULTS: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). CONCLUSIONS: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

9.
Afr Health Sci ; 20(2): 955-959, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33163064

RESUMO

Background: Low education levels and language barriers present challenges in obtaining informed consent for clinical research. Objective: To describe and correlate the association between the level of education and the participant's preferred language of consent. Design: Descriptive-analytical cross-sectional study. Participants: Adults being consented for participation in tuberculosis(TB) research studies in an East African community with varying levels of education. Procedures: We analyzed data on demographic and educational characteristics collected from adults being consented for participation in TB studies .Only participants who could understand and speak Luganda (the main local language) or English (the official language of Uganda) were included in this analysis. Results: A total of 523 participants were consented between April 2015 and December 2017 and included in this analysis; 250 below Senior four (< 11yrs of education), 114 senior four (at 11yrs of education),73 senior five-senior six (12-13yrs of education) and 86 beyond senior six (> 13yrs of education). We noted that the preference for English rises with the rising levels of education and peaked at beyond senior six (83%Vs17%,OR=49,95%CI:22.8-106.3,p<0.001).Participants below senior four preferred Luganda Vs senior four and above(OR=16.9,95%CI:9.9-28.8,p<0.001). Conclusion: Rising education levels of participants were associated with preference for English language usage during initial consent for clinical research studies.

10.
Front Immunol ; 11: 573583, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133089

RESUMO

Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible "hijacking" of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus-complement interactions.

11.
Biomed J ; 43(5): 462-463, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33032964
12.
Proc Natl Acad Sci U S A ; 117(44): 27598-27607, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33060297

RESUMO

Human rhinoviruses (RVs) are positive-strand RNA viruses that cause respiratory tract disease in children and adults. Here we show that the innate immune signaling protein STING is required for efficient replication of members of two distinct RV species, RV-A and RV-C. The host factor activity of STING was identified in a genome-wide RNA interference (RNAi) screen and confirmed in primary human small airway epithelial cells. Replication of RV-A serotypes was strictly dependent on STING, whereas RV-B serotypes were notably less dependent. Subgenomic RV-A and RV-C RNA replicons failed to amplify in the absence of STING, revealing it to be required for a step in RNA replication. STING was expressed on phosphatidylinositol 4-phosphate (PI4P)-enriched membranes and was enriched in RV-A16 compared with RV-B14 replication organelles isolated in isopycnic gradients. The host factor activity of STING was species-specific, as murine STING (mSTING) did not rescue RV-A16 replication in STING-deficient cells. This species specificity mapped primarily to the cytoplasmic, ligand-binding domain of STING. Mouse-adaptive mutations in the RV-A16 2C protein allowed for robust replication in cells expressing mSTING, suggesting a role for 2C in recruiting STING to RV-A replication organelles. Palmitoylation of STING was not required for RV-A16 replication, nor was the C-terminal tail of STING that mediates IRF3 signaling. Despite co-opting STING to promote its replication, interferon signaling in response to STING agonists remained intact in RV-A16 infected cells. These data demonstrate a surprising requirement for a key host mediator of innate immunity to DNA viruses in the life cycle of a small pathogenic RNA virus.

14.
Genes Genomics ; 42(8): 957-969, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32648234

RESUMO

BACKGROUND: Brassinosteroids (BRs) are a class of phytohormones with important roles in regulating physiological and developmental processes. Small RNAs, including small interfering RNAs and microRNAs (miRNAs), are non-protein coding RNAs that regulate gene expression at the transcriptional and post-transcriptional levels. However, the roles of small RNAs in BR response have not been studied well. OBJECTIVE: In this study, we aimed to identify BR-responsive small RNA clusters and miRNAs in Arabidopsis. In addition, the effect of BR-responsive small RNAs on their transcripts and target genes were examined. METHODS: Small RNA libraries were constructed from control and epibrassinolide-treated seedlings expressing wild-type BRI1-Flag protein under its native promoter in the bri1-5 mutant. After sequencing the small RNA libraries, differentially expressed small RNA clusters were identified by examining the expression levels of small RNAs in 100-nt bins of the Arabidopsis genome. To identify the BR-responsive miRNAs, the expression levels of all the annotated mature miRNAs, registered in miRBase, were analyzed. Previously published RNA-seq data were utilized to monitor the BR-responsive expression patterns of differentially expressed small RNA clusters and miRNA target genes. RESULTS: In results, 38 BR-responsive small RNA clusters, including 30 down-regulated and eight up-regulated clusters, were identified. These differentially expressed small RNA clusters were from miRNA loci, transposons, protein-coding genes, pseudogenes and others. Of these, a transgene, BRI1, accumulates small RNAs, which are not found in the wild type. Small RNAs in this transgene are up-regulated by BRs while BRI1 mRNA is down-regulated by BRs. By analyzing the expression patterns of mature miRNAs, we have identified BR-repressed miR398a-5p and BR-induced miR156g. Although miR398a-5p is down-regulated by BRs, its predicted targets were not responsive to BRs. However, SPL3, a target of BR-inducible miR156g, is down-regulated by BRs. CONCLUSION: BR-responsive small RNAs and miRNAs identified in this study will provide an insight into the role of small RNAs in BR responses in plants. Especially, we suggest that miR156g/SPL3 module might play a role in BR-mediated growth and development in Arabidopsis.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32615331

RESUMO

STUDY OBJECTIVE: Determine near-optimal dose, safety, and efficacy of nerindocianine in pelvic ureter detection with near-infrared fluorescence imaging in women undergoing minimally invasive pelvic surgery with 3 Food and Drug Administration-cleared imaging systems. DESIGN: Open label, phase 1/2a study. SETTING: University of Alabama at Birmingham. PATIENTS: Forty-one female subjects undergoing minimally invasive gynecologic surgery. INTERVENTIONS: Subjects received a single dose of nerindocianine sodium, starting at 0.06-mg/kg body weight and increased/decreased until the near-optimal dose was determined (part A). Examine the degree of concordance between endoscopic and robotic devices (part B). MEASUREMENTS AND MAIN RESULTS: In part A, composite scores were collected every 10 minutes for 30 minutes and then every 15 minutes through 90 minutes using a scale measuring the anatomy/laterality of ureter visualization. In part B (paired imaging system efficacy), 2 cohorts of 8 subjects each received the near-optimal dose. Composite scores for visualization of the ureter were collected at 10 and 30 minutes postinfusion with the Firefly Imaging System and either the PINPOINT or 1588 AIM endoscope. Composite scores were compared to examine the degree of concordance between devices. Part A comprised 25 total subjects enrolled in dosing groups 1, 2, and 3 (0.06-, 0.12-, and 0.045-mg/kg, respectively). Median time to first ureter visualization was 10 minutes (all groups). The nerindocianine 0.06-mg/kg and 0.12-mg/kg groups had longer length of time of visualization than the 0.045-mg/kg group, resulting in the selection of 0.06 mg/kg as the near-optimal dose. Part B enrolled 16 total subjects in 2 groups dosed at 0.06 mg/kg. Efficacy analysis showed no statistically significant difference in composite scores with Firefly versus PINPOINT or 1588 AIM. CONCLUSION: Nerindocianine was well tolerated with visualization of the ureter demonstrated in 88.9% of the subjects through 90 minutes postdosing. No meaningful visualization differences were observed among the Food and Drug Administration-cleared surgical imaging systems used.

16.
Sci Rep ; 10(1): 10151, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576865

RESUMO

We present evidence of inverse Hall-Petch behavior for a single-phase high entropy alloy (CoCrFeMnNi) in ultra-high vacuum and show that it is associated with low friction coefficients (~0.3). Grain size measurements by STEM validate a recently proposed dynamic amorphization model that accurately predicts grain size-dependent shear strength in the inverse Hall-Petch regime. Wear rates in the initially soft (coarse grained) material were shown to be remarkably low (~10-6 mm3/N-m), the lowest for any HEA tested in an inert environment where oxidation and the formation of mixed metal-oxide films is mitigated. The combined high wear resistance and low friction are linked to the formation of an ultra-nanocrystalline near-surface layer. The dynamic amorphization model was also used to predict an average high angle grain boundary energy (0.87 J/m2). This value was used to explain cavitation-induced nanoporosity found in the highly deformed surface layer, a phenomenon that has been linked to superplasticity.

17.
Immunity ; 52(5): 842-855.e6, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32353250

RESUMO

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet+ and T-bet- memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet- and T-bet+ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet- and T-bet+ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet+ MBCs could be subdivided into recirculating T-betlo MBCs and spleen-resident T-bethi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.


Assuntos
Especificidade de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Memória Imunológica/imunologia , Especificidade de Órgãos/imunologia , Proteínas com Domínio T/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Anticorpos Anti-HIV/imunologia , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
18.
Int J MS Care ; 22(2): 85-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32410903

RESUMO

Stimulation of the immune response after vaccination can occasionally result in adverse effects, including demyelination of the central nervous system. The most common presentation of postvaccination demyelination is acute disseminated encephalomyelitis, but cases of optic neuritis, transverse myelitis, and multiple sclerosis relapses have been reported. More recently, an increasing number of postvaccination neuromyelitis optica spectrum disorder (NMOSD) cases have surfaced in the literature, especially in patients with aquaporin-4 antibodies. In this article, we report an unusual case of myelin oligodendrocyte glycoprotein antibody-related NMOSD after the receipt of multiple vaccines in a first-trimester pregnant woman from Africa. We review the reported cases of postvaccination demyelination in the past decade, with a focus on the relationship between NMOSD and vaccination in patients with aquaporin-4 or myelin oligodendrocyte glycoprotein antibodies. Finally, we discuss the clinical relevance of the present case and similar reported cases as it relates to patient care in the neuroimmunology clinic and identify potential areas for future research.

19.
J Cardiovasc Dev Dis ; 7(2)2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32456345

RESUMO

Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3-/- fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3-/- fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3-/- fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFß3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFß3 was required for collagen matrix reorganization. Biochemical studies indicated the 'paradoxically' increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFß3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFß signaling pathways.

20.
J Am Heart Assoc ; 9(3): e015012, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32013706

RESUMO

Background Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological substrate with SCD varies between black and white individuals. Methods and Results Participants from the ARIC (Atherosclerosis Risk in Communities) study with analyzable ECGs (n=14 408; age, 54±6 years; 74% white) were included. Electrophysiological substrate was characterized by ECG metrics. Two competing outcomes were adjudicated: SCD and non-SCD. Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine-Gray competing risk models, adjusted for prevalent cardiovascular disease, risk factors, and incident nonfatal cardiovascular disease. At the baseline visit, adjusted for age, sex, and study center, blacks had larger spatial ventricular gradient magnitude (0.30 mV; 95% CI, 0.25-0.34 mV), sum absolute QRST integral (18.4 mV*ms; 95% CI, 13.7-23.0 mV*ms), and Cornell voltage (0.30 mV; 95% CI, 0.25-0.35 mV) than whites. Over a median follow-up of 24.4 years, SCD incidence was higher in blacks (2.86 per 1000 person-years; 95% CI, 2.50-3.28 per 1000 person-years) than whites (1.37 per 1000 person-years; 95% CI, 1.22-1.53 per 1000 person-years). Blacks with hypertension had the highest rate of SCD: 4.26 (95% CI, 3.66-4.96) per 1000 person-years. Race did not modify an association of ECG variables with SCD, except QRS-T angle. Spatial QRS-T angle was associated with SCD in whites (hazard ratio, 1.38; 95% CI, 1.25-1.53) and hypertension-free blacks (hazard ratio, 1.52; 95% CI, 1.09-2.12), but not in blacks with hypertension (hazard ratio, 1.15; 95% CI, 0.99-1.32) (P-interaction=0.004). Conclusions Race did not modify associations of electrophysiological substrate with SCD and non-SCD. Electrophysiological substrate does not explain racial disparities in SCD rate.

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