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1.
Nucleic Acids Res ; 49(10): 5760-5778, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34037780

RESUMO

Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.


Assuntos
Processamento Alternativo/genética , Carcinogênese/metabolismo , Desenvolvimento Embrionário/genética , Hematopoese/genética , Melanoma/metabolismo , Timócitos/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/genética , Carcinogênese/genética , Proliferação de Células/genética , Genômica , Células HEK293 , Humanos , Lectinas Tipo C/metabolismo , Linfopenia/genética , Linfopenia/metabolismo , Melanoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Timo/embriologia , Timo/metabolismo
2.
Cardiovasc Ultrasound ; 19(1): 5, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407517

RESUMO

BACKGROUND: It is unclear whether increased left ventricular (LV) thickness is associated with worse clinical outcomes in severe aortic stenosis (AS). The aim of this study was to determine the effect of increased LV wall thickness (LVWT) on major clinical outcomes in patients with severe AS. METHODS AND RESULTS: This study included 290 severe AS patients (mean age 69.4 ± 11.0 years; 136 females) between January 2008 and December 2018. For outcome assessment, the endpoint was defined as death from all causes, cardiovascular death, and the aortic valve replacement (AVR) surgery rate. During follow-up (48.7 ± 39.0 months), 157 patients had AVR, 43 patients died, and 28 patients died from cardiovascular causes. Patients with increased LVWT underwent AVR surgery much more than those without LVWT (60.0% vs. 39.0%, p < 0.001). Furthermore, in patients with increased LVWT, the all-cause and cardiovascular death rates were significantly lower in the AVR group than in the non-AVR group (8.8% vs. 27.3%, p < 0.001, 4.8%, vs. 21.0%, p < 0.001). Multivariate analysis revealed that increased LVWT, age, dyspnea, and AVR surgery were significantly correlated with cardiovascular death. CONCLUSIONS: In patients with severe AS, increased LVWT was associated with a higher AVR surgery rate and an increased rate of cardiovascular death independent of other well-known prognostic variates. Thus, these findings suggest that increased LVWT might be used as a potential prognostic factor in severe AS patients.


Assuntos
Estenose da Valva Aórtica/diagnóstico , Valva Aórtica/diagnóstico por imagem , Ecocardiografia/métodos , Implante de Prótese de Valva Cardíaca , Ventrículos do Coração/diagnóstico por imagem , Função Ventricular Esquerda/fisiologia , Idoso , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/cirurgia , Progressão da Doença , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
3.
Int J Mol Sci ; 22(9)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922276

RESUMO

Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1G227R and NEU1V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1G227R- and NEU1V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1G227R- and NEU1V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy-lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.


Assuntos
Astrócitos/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Mucolipidoses/patologia , Células-Tronco Neurais/patologia , Neuraminidase/metabolismo , Oligodendroglia/patologia , Teratoma/patologia , Astrócitos/metabolismo , Autofagia , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lisossomos , Mucolipidoses/genética , Mucolipidoses/metabolismo , Mutação , Células-Tronco Neurais/metabolismo , Neuraminidase/genética , Oligodendroglia/metabolismo , Fenótipo , Teratoma/genética , Teratoma/metabolismo
4.
Am Heart J ; 222: 121-130, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32028138

RESUMO

BACKGROUND: The PLEIO (comParison of ticagreLor and clopidogrEl on mIcrocirculation in patients with acute cOronary syndrome) study showed that 6 months of ticagrelor therapy significantly improved microvascular dysfunction in acute coronary syndrome (ACS) patients with stent implantation compared to clopidogrel. Improved microvascular function may affect myocardial blood flow (MBF). We compared the effects of ticagrelor and clopidogrel on MBF over a 6-month follow-up period among patients diagnosed with ACS treated with percutaneous coronary intervention (PCI). METHODS: In the PLEIO trial, 120 participants were randomized to receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily after at least 6 months. 13 N-ammonia positron emission tomography (PET) imaging was performed in 94 patients to measure MBF at the 6-month follow-up visit. RESULTS: On a per-patient level, MBF (1.88 ±â€¯0.52 versus 1.67 ±â€¯0.64 mL/min per gram, P = .01) was significantly higher with ticagrelor compared with clopidogrel in the hyperemic state, but not under resting state (0.75 ±â€¯0.24 versus 0.75 ±â€¯0.19 mL/min per gram, P = .84). On a culprit-vessel analysis, the resting MBF was similar (0.69 ±â€¯0.20 versus 0.70 ±â€¯0.21, P = .89) between the two groups. However, the hyperemic MBF and myocardial flow reserve in the ticagrelor group were significantly higher compared with clopidogrel (1.75 ±â€¯0.46 versus 1.52 ±â€¯0.59, P = .03 and 2.71 ±â€¯0.89 versus 2.20 ±â€¯0.81, P = .02, respectively). These differences were not observed in non-culprit vessels. CONCLUSIONS: Maintenance treatment of ticagrelor increased the hyperemic MBF and myocardial flow reserve compared with clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02618733.


Assuntos
Síndrome Coronariana Aguda/terapia , Clopidogrel/uso terapêutico , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Tomografia por Emissão de Pósitrons/métodos , Ticagrelor/uso terapêutico , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/fisiopatologia , Amônia , Angiografia Coronária , Circulação Coronária/fisiologia , Vasos Coronários/diagnóstico por imagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Prospectivos , Fatores de Tempo
5.
Stem Cells ; 36(10): 1525-1534, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29873154

RESUMO

The importance of alternative splicing (AS) events in pluripotency regulation has been highlighted by the determination of different roles and contributions of different splice isoforms of pluripotency-related genes and by the identification of distinct pluripotency-related splicing factors. In particular, epithelial splicing regulatory protein 1 (ESRP1) has been characterized as an essential splicing factor required for the regulation of human pluripotency and differentiation. Nevertheless, a detailed molecular characterization of ESRP1 (mRNA splice variants 1-6) in human pluripotency is lacking. In this study, we determined that ESRP1 splice variants are differentially expressed in undifferentiated and differentiated human pluripotent stem cells (PSCs). Undifferentiated human PSCs predominantly expressed the ESRP1 v1, v4, and v5, and their expression was downregulated upon differentiation. Ectopic expression of ESRP1 v1, v4, or v5 enhanced the pluripotent reprogramming of human fibroblasts and restored the ESRP1 knockdown-mediated reduction of reprogramming efficiency. Notably, undifferentiated human PSCs expressed the cell surface protein CD44 variant 3 (CD44 v3), and isoform switching from CD44 v3 to CD44 variant 6 (CD44 v6) occurred upon differentiation. Importantly, the human PSC-specific ESRP1 variants influenced CD44 v3 expression. CD44 knockdown or inhibition of binding of CD44 with its major ligand, hyaluronan, significantly induced the loss of human PSC pluripotency and the reduction of reprogramming efficiency. Our results demonstrate that the effect of ESRP1 and CD44 on human PSC pluripotency is isoform-dependent and that ESRP1-induced CD44 v3 is functionally associated with human PSC pluripotency control. Stem Cells 2018;36:1525-1534.


Assuntos
Receptores de Hialuronatos/metabolismo , Células-Tronco Pluripotentes/metabolismo , Proteínas de Ligação a RNA/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Humanos
6.
Cardiovasc Ultrasound ; 17(1): 2, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755201

RESUMO

BACKGROUND: Aortic dilatation is a major risk factor for aortic dissection. The aim of the present study was to assess the relationship between left ventricular (LV) geometry and maximal ascending aorta (MAA). METHODS: We reviewed data from patients who were diagnosed with acute type A aortic dissection and who underwent surgical management from December 2002 to March 2016 at Dong-A University Hospital. Among 151 patients with non-Marfan aortic dissection in the study, 50 who had echocardiography preoperatively were investigated and MAA diameter was analyzed by LV geometric patterns. RESULTS: Patients' mean age was 59.6 ± 13.5 years and 38.0% were male. The mean MAA diameter was 52.9 ± 8.5 mm. MAA diameter was significantly correlated with LV mass index (r = 0.62, P < 0.001). On analysis by LV geometry, MAA diameter showed a significant difference between the 4 groups (P = 0.02), and the eccentric and concentric hypertrophy groups showed significantly larger MAA diameter than the other two groups. CONCLUSION: MAA diameter was associated with LV mass index and was significantly different between LV geometry types. In this study, not only concentric hypertrophy but also eccentric LV hypertrophy was related to larger MAA in type A aortic dissection patients.


Assuntos
Aorta/diagnóstico por imagem , Aneurisma da Aorta Torácica/diagnóstico , Dissecção Aórtica/diagnóstico , Ecocardiografia Doppler/métodos , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Dissecção Aórtica/etiologia , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/fisiopatologia , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
7.
Echocardiography ; 36(6): 1035-1040, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31148208

RESUMO

BACKGROUND: It is unclear whether asymmetry itself plays a role in developing eccentric aortic regurgitation (AR) in patients with tricuspid aortic valve (TAV). The aim of this study was to determine whether an asymmetric aortic valve structure may have association with the development of eccentric AR in patients with TAV. METHODS: Of the 164 410 patients who underwent echocardiography between January 2006 and January 2018 at Dong-A University Hospital, 306 (mean age 69.9 ± 12.6 years; 62% men) eccentric AR were identified. After excluding patients with bicuspid and prolapsed AV, 104 patients who had eccentric AR with TAV were enrolled for the study. Comprehensive echocardiographic AV cusp measurements were compared to those of 104 age- and gender-matched control patients with central AR. RESULTS: In the eccentric and central AR groups, 66 (63.5%) and 48 patients (46.2%) had asymmetric AV, respectively. Mean cusp height was significantly larger in the eccentric AR group than in the central AR group (1.8 ± 0.3 cm vs 1.7 ± 0.2 cm, P = 0002). Furthermore, the mean cusp area and average asymmetry index of the cusp area were also significantly larger in the eccentric AR group than in the central AR group (2.6 ± 0.8 cm2 vs 2.3 ± 0.6 cm2 , P = 0.001, and 7.1 ± 4.5% vs 4.9 ± 2.5%, P < 0.001, respectively). CONCLUSION: AV asymmetry indices of eccentric AR were significantly larger than those of patients with central AR. These data suggest that the presence of asymmetric AV might have association with the development of eccentric AR in patients with TAV.


Assuntos
Insuficiência da Valva Aórtica/diagnóstico por imagem , Valva Aórtica/anormalidades , Ecocardiografia/métodos , Valva Tricúspide/diagnóstico por imagem , Idoso , Feminino , Humanos , Masculino
8.
Echocardiography ; 35(11): 1782-1787, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30225938

RESUMO

AIMS: The early diastolic mitral annular velocity (e') and mitral E/e' criteria for clinically evaluating diastolic dysfunction in patients with atrial fibrillation (AF) are almost the same as in patients with sinus rhythm. In this study, we aimed to investigate whether e' is useful to assess diastolic function in AF patients. METHODS: Thirty patients who underwent successful electric cardioversion (EC) due to persistent AF and who maintained sinus rhythm for 1 month after EC were enrolled in this study. Transthoracic echocardiography was performed on all patients before and 1 month after EC. Standard diastolic parameters, the global longitudinal strain (GLS), and left ventricular (LV) twist were measured. RESULTS: Conventional Doppler parameters measured before EC were not significantly different from 1 month after EC. However, the lateral and septal e' were significantly decreased 1 month after EC (from 12.8 ± 2.5 to 9.8 ± 2.3 cm/s and from 9.5 ± 1.9 to 7.1 ± 1.5 cm/s, respectively, P < 0.001). Likewise, the lateral and septal E/e' were also significantly increased 1 month after EC (P < 0.001). The GLS was significantly improved from -15.9 ± 2.2% to -19.4 ± 2.4% after EC (P < 0.001), as was the LV twist (from 5.8 ± 1.7° to 9.1 ± 2.4°, P < 0.001). CONCLUSION: We demonstrated that e' was significantly higher in AF compared with during sinus rhythm in the same patients. Thus, in AF patients, diastolic dysfunction should be suspected even when e' values are normal.


Assuntos
Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Ecocardiografia Transesofagiana/métodos , Cardioversão Elétrica/métodos , Valva Mitral/diagnóstico por imagem , Valva Mitral/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
J Biol Chem ; 291(12): 6169-81, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-26797131

RESUMO

Nuclear speckles are subnuclear storage sites containing pre-mRNA splicing machinery. Proteins assembled in nuclear speckles are known to modulate transcription and pre-mRNA processing. We have previously identified nuclear speckle-related protein 70 (NSrp70) as a novel serine/arginine (SR)-related protein that co-localizes with classical SR proteins such as serine/arginine-rich splicing factor 1 (SRSF1 or ASF/SF2) and SRSF2 (SC35). NSrp70 mediates alternative splice site selection, targeting several pre-mRNAs, including CD44 exon v5. Here we demonstrated that NSrp70 interacts physically with two SR proteins, SRSF1 and SRSF2, and reverses their splicing activity in terms of CD44 exon v5 as exon exclusion. The NSrp70 RS-like region was subdivided into three areas. Deletion of the first arginine/serine-rich-like region (RS1) completely abrogated binding to the SR proteins and to target mRNA and also failed to induce splicing of CD44 exon v5, suggesting that RS1 is critical for NSrp70 functioning. Interestingly, RS1 deletion also resulted in the loss of NSrp70 and SR protein speckle positioning, implying a potential scaffolding role for NSrp70 in nuclear speckles. NSrp70 contains an N-terminal coiled-coil domain that is critical not only for self-oligomerization but also for splicing activity. Consistently, deletion of the coiled-coil domain resulted in indefinite formation of nuclear speckles. Collectively, these results demonstrate that NSrp70 acts as a new molecular counterpart for alternative splicing of target RNA, counteracting SRSF1 and SRSF2 splicing activity.


Assuntos
Processamento Alternativo , Proteínas Nucleares/metabolismo , Ribonucleoproteínas/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Células HEK293 , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Proteínas Nucleares/química , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Multimerização Proteica , Estrutura Quaternária de Proteína , Precursores de RNA/metabolismo
10.
Am J Emerg Med ; 35(8): 1210.e1-1210.e4, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28438445

RESUMO

Pneumothorax can cause a variety of electrocardiographic changes. ST segment elevation, which is mainly observed in myocardial infarction, can also be induced by pneumothorax. The mechanism is presumed to be a decrease in cardiac output, due to increased intra-thoracic pressure. We encountered a patient with ST segment elevation with minimal pneumothorax. Coronary angiography with ergonovine provocation test and echocardiogram had normal findings. The ST segment elevation was normalized by decreasing the amount of pneumothorax. We reviewed the literature and present possible mechanisms for this condition.


Assuntos
Eletrocardiografia , Pneumotórax/fisiopatologia , Radiografia Torácica/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Adulto , Dor no Peito , Humanos , Masculino , Pneumotórax/complicações , Pneumotórax/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Resultado do Tratamento
11.
Proteomics ; 15(13): 2220-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25736782

RESUMO

Recent studies have suggested that REX1 (reduced expression 1) plays an important role in pluripotency, proliferation, and differentiation. However, the molecular mechanisms involved in REX1-dependent regulation of diverse cellular processes remain unclear. To elucidate the regulatory functions of REX1 in human embryonic stem cells (hESCs), comparative proteomic analysis was performed on REX1 RNAi specifically silenced hESCs. Analysis of the proteome via nano-LC-MS/MS identified 140 differentially expressed proteins (DEPs) displaying a >2-fold difference in expression level between control and REX1 knockdown (KD) hESCs, which were then compared with transcriptome data and validated by quantitative real-time RT-PCR and Western blotting. These DEPs were analyzed by GO, pathway, and functional clustering analyses to determine the molecular functions of the proteins and pathways regulated by REX1. The REX1 KD-mediated DEPs mapped to major biological processes involved in the regulation of ribosome-mediated translation and mitochondrial function. Functional network analysis revealed a highly interconnected network among these DEPs and indicated that these interconnected proteins are predominantly involved in translation and the regulation of mitochondrial organization. These findings regarding REX1-mediated regulatory network have revealed the contributions of REX1 to maintaining the status of hESCs and have improved our understanding of the molecular events that underlie the fundamental properties of hESCs.


Assuntos
Células-Tronco Embrionárias Humanas/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteômica , Western Blotting , Humanos , Fatores de Transcrição Kruppel-Like/genética , Interferência de RNA
12.
Echocardiography ; 32(7): 1094-100, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25363252

RESUMO

INTRODUCTION: Although left atrium (LA) has played an important role in diastole, ischemic insult of atrium in acute myocardial infarction (AMI) has not been clearly evaluated. METHODS: We hypothesized that LA function would be further decreased in AMI patients with a culprit lesion in the left circumflex branch (LCX). This was an observational cohort study in a single university hospital. Echocardiography was performed to evaluate left ventricular diastolic function, LA volume, and LA function. Systolic (LAS ) and late diastolic (LAA ) LA strain were measured using speckle tracking echocardiography. RESULTS: Sixty-eight AMI patients treated with emergent or urgent percutaneous coronary intervention were enrolled. Global LAS strain was significantly lower in patients with a culprit lesion in the LCX than culprit lesions in other vessels (left anterior descending, 27.3 ± 6.8%; left circumflex, 20.1 ± 8.9%; right coronary artery, 23.3 ± 6.5%; P = 0.007). LA volume index did not differ significantly (P = 0.093). Other clinical and conventional echocardiographic parameters, including Doppler measurements, did not differ significantly. CONCLUSIONS: Global LAS strain was lower in AMI patients with a culprit lesion in the LCX than those with culprit lesions in other vessels, without any significant difference in LA volume index. The lower global LAS strain might suggest decreased LA function resulting from ischemic insult by AMI with culprit lesions in the LCX.


Assuntos
Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Doença Aguda , Estudos de Coortes , Feminino , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
13.
bioRxiv ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38826407

RESUMO

The expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.

14.
J Epidemiol ; 23(4): 270-4, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23629647

RESUMO

BACKGROUND: We evaluated the recent prevalence of serologic markers of hepatitis A virus (HAV) in South Korea. METHODS: The study data were the results of 60 126 anti-HAV (total) tests and 30 786 anti-HAV IgM tests that were performed during April 2009 through March 2010 by the Eone Reference Laboratory at the request of 1935 institutions throughout Korea. RESULTS: The overall positivity rate was 51.06% on the anti-HAV (total) test and 11.20% on the anti-HAV IgM test. As compared with the other age groups the rate of anti-HAV (total) positivity was significantly lower (P < 0.001), and the rate of anti-HAV IgM positivity was significantly higher (P < 0.001), among Koreans aged 11 to 40 years. The seroprevalence of anti-HAV IgM significantly differed according to region but not by referral date. CONCLUSIONS: This was the largest nationwide study in South Korea by 1 laboratory, and it provides useful recent baseline data on hepatitis A in Asia. The findings suggest that active immunization of younger Koreans should be made a priority.


Assuntos
Anticorpos Anti-Hepatite A/sangue , Vírus da Hepatite A/isolamento & purificação , Hepatite A/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Vírus da Hepatite A/imunologia , Humanos , Imunoglobulina M/sangue , Lactente , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Soroepidemiológicos , Adulto Jovem
15.
Nucleic Acids Res ; 39(10): 4300-14, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21296756

RESUMO

Nuclear speckles are known to be the storage sites of mRNA splicing regulators. We report here the identification and characterization of a novel speckle protein, referred to as NSrp70, based on its subcellular localization and apparent molecular weight. This protein was first identified as CCDC55 by the National Institutes of Health Mammalian Gene Collection, although its function has not been assigned. NSrp70 was colocalized and physically interacted with SC35 and ASF/SF2 in speckles. NSrp70 has a putative RNA recognition motif, the RS-like region, and two coiled-coil domains, suggesting a role in RNA processing. Accordingly, using CD44, Tra2ß1 and Fas constructs as splicing reporter minigenes, we found that NSrp70 modulated alternative splice site selection in vivo. The C-terminal 10 amino acids (531-540), including (536)RD(537), were identified as a novel nuclear localization signal, and the region spanning 290-471 amino acids was critical for speckle localization and binding to SC35 and ASF/SF2. The N-terminal region (107-161) was essential for the pre-mRNA splicing activity. Finally, we found that knockout of NSrp70 gene in mice led to a lack of progeny, including fetal embryos. Collectively, we demonstrate that NSrp70 is a novel splicing regulator and essentially required early stage of embryonic development.


Assuntos
Processamento Alternativo , Proteínas Nucleares/metabolismo , Precursores de RNA/metabolismo , RNA Mensageiro/metabolismo , Animais , Linhagem Celular , Estruturas do Núcleo Celular/química , Genes Letais , Humanos , Camundongos , Camundongos Knockout , Proteínas Nucleares/análise , Proteínas Nucleares/química , Proteínas Nucleares/genética , Fenótipo , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-Arginina
16.
Materials (Basel) ; 16(5)2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36902917

RESUMO

IN738LC is a conventional-cast Ni-based superalloy intended for power generation and aerospace applications. Typically, ultrasonic shot peening (USP) and laser shock peening (LSP) are utilized to enhance cracking, creep, and fatigue resistance. In this study, the optimal process parameters for USP and LSP were established by observing the microstructure and measuring the microhardness of the near-surface region of IN738LC alloys. The LSP impact region (modification depth) was approximately 2500 µm, which was much higher than the USP impact depth of 600 µm. The observation of the microstructural modification and resulting strengthening mechanism revealed that the build-up of dislocations upon peening with plastic deformation was crucial for alloy strengthening in both methods. In contrast, significant strengthening via γ' shearing was observed only in the USP-treated alloys.

17.
medRxiv ; 2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37425708

RESUMO

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

18.
J Environ Biol ; 33(5): 969-75, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23734467

RESUMO

We installed seaweed reef for restoration of barron ground coast. We hollowed out a U-shaped groove in a cross-shaped artificial seaweed reef and covered it with a zinc sheet (U-bar) to transplant Ecklonia cava growing on Dellenia wood by hand, installing the U-bar on the artificial seaweed reef, fixing it with concrete. Thus seaweed can be attached easily, with pre-installed stainless bolts and nuts. The length of Ecklonia cava leaf transplanted to the cross-shaped reef was 7.2 cm in February 2005 reached its maximum size, 35.9 cm (n = 30) by July. Thereafter, it decreased to 18.9 cm in October due to shedding. The leaf weight after the experiment was 24.8 from the initial 0.4 cm (n = 30). Regression analysis showed Y = 0.7875X-4.6488 (R2 = 0.7225) for blade length and Y = 0.0025X2.6733 (R2 = 0.8711) for leaf weight. The high values of the R2 values for the two measurements were highly reliable, with the reliability of the linear regression function higher than that of the functions of 2 variables. The artificial seaweed forest constructed in the barren ground was highly comparable with natural seaweed forest in terms of growth, indicating that the artificial seaweed construction can be done in an easy, efficient and economically viable way. This further indicates that the technology developed by the present study can be extensively used for the project for artificial seaweed forest construction.


Assuntos
Recuperação e Remediação Ambiental/métodos , Phaeophyceae/crescimento & desenvolvimento , Alga Marinha/crescimento & desenvolvimento , Biomassa , Folhas de Planta/crescimento & desenvolvimento , Análise de Regressão , República da Coreia
19.
Children (Basel) ; 9(10)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36291468

RESUMO

(1) Background: Contrary to a tenet of the funnel-shaped pediatric larynx with the cricoid level being narrowest, recent studies show the glottis and subglottis as the narrowest levels. To locate the functionally narrowest level of the larynx, we reported normal laryngeal dimensions and their croup-related changes in young children. (2) Methods: We reviewed normal plain neck radiographs recorded for the evaluation of minor trauma or foreign bodies in 504 children aged ≤4 years who visited the emergency department from 2016 through 2021. Using computed tomography-based localization of the glottis, we radiographically defined the subglottis and cricoid. At these levels, we measured diameters and calculated cross-sectional areas (CSAs) on the radiographs. The values were compared to the equivalent values of a 1:1 age-matched population with croup. (3) Results: In the study population (n = 401), the narrowest diameter and CSA were observed in the glottis. In detail, the mean anteroposterior/transverse diameters were 9.8/3.4 mm at the glottis, 8.5/5.6 mm at the subglottis, and 7.4/6.8 mm at the cricoid (p < 0.001), respectively. In the same order, the mean CSAs were 26.5, 38.1, and 40.5 mm2 (p < 0.001). All dimensions were narrower in the croup population (p < 0.001). We found croup-related narrowing, namely reductions in the transverse diameter and CSA that were more severe closer to the glottis (p < 0.001), without differences per level in the anteroposterior diameter. (4) Conclusions: This study confirms the glottis as the narrowest level of the larynx in young children. In addition, level-based differences in croup-related narrowing suggest some point between the glottis and subglottis as the functionally narrowest level.

20.
Medicine (Baltimore) ; 101(14): e29128, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35446295

RESUMO

ABSTRACT: Acute variceal bleeding, a crucial complication of liver cirrhosis requires high energy expenditures but gastrointestinal bleeding limits enteral feeding in the acute stage. We investigated the safety and efficacy of ω-3 fatty acid-enriched parenteral nutrition in acute variceal bleeding patients.In this retrospective study, a total of 208 cirrhotic patients with acute variceal bleeding who underwent parenteral nutrition in the absence of enteral nutrition were enrolled. Among the patients, 86 patients received ω-3 fatty-acid-enriched parenteral nutrition. The primary endpoint was to evaluate the duration of hospital stay and the presence of clinical complications of liver cirrhosis.The mean age of the patients enrolled was 54.9 years-old and 185 patients (88.9%) were male. The cause of liver cirrhosis, Child-Pugh score and comorbidities were statistically not different. Patients with ω-3 enriched parenteral nutrition had a significantly lower systolic blood pressure and total bilirubin levels. The difference in the in-hospital mortality (P = .813) or rate of complications (P = .880) was not statistically significant. The duration of hospital stay was significantly shorter in the patients who underwent ω-3 fatty acid-enriched parenteral nutrition (10.7 ±â€Š7.3 vs 7.9 ±â€Š4.2 days, P = .001).In liver cirrhosis patients with acute variceal bleeding, ω-3 fatty acid-enriched parenteral nutrition significantly decreased the length of hospital stay. Further prospective studies to consolidate these findings are warranted.


Assuntos
Varizes Esofágicas e Gástricas , Ácidos Graxos Ômega-3 , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/terapia , Feminino , Hemorragia Gastrointestinal/complicações , Hemorragia Gastrointestinal/terapia , Humanos , Tempo de Internação , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Nutrição Parenteral/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos
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