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1.
Development ; 148(15)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34323273

RESUMO

Vertebrate animals usually display robust growth trajectories during juvenile stages, and reversible suspension of this growth momentum by a single genetic determinant has not been reported. Here, we report a single genetic factor that is essential for juvenile growth in zebrafish. Using a forward genetic screen, we recovered a temperature-sensitive allele, pan (after Peter Pan), that suspends whole-organism growth at juvenile stages. Remarkably, even after growth is halted for a full 8-week period, pan mutants are able to resume a robust growth trajectory after release from the restrictive temperature, eventually growing into fertile adults without apparent adverse phenotypes. Positional cloning and complementation assays revealed that pan encodes a probable ATP-dependent RNA helicase (DEAD-Box Helicase 52; ddx52) that maintains the level of 47S precursor ribosomal RNA. Furthermore, genetic silencing of ddx52 and pharmacological inhibition of bulk RNA transcription similarly suspend the growth of flies, zebrafish and mice. Our findings reveal evidence that safe, reversible pauses of juvenile growth can be mediated by targeting the activity of a single gene, and that its pausing mechanism has high evolutionary conservation.


Assuntos
RNA Helicases/genética , RNA/genética , Peixe-Zebra/genética , Alelos , Animais , Feminino , Inativação Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Precursores de RNA/genética , Ribossomos/genética , Transcrição Gênica/genética
2.
Support Care Cancer ; 32(5): 285, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38607568

RESUMO

CONTEXT: Pain is a common experience in people living with cancer. Concerns around opioid prescribing have seen a move toward a multi-modality management approach, which includes interventional pain procedures. PURPOSE: In this paper we discuss the interventional pain procedures used to treat cancer pain at two major tertiary centers in Australia. METHODS AND RESULTS: This expert review provides practical insights on cancer pain management from healthcare providers in different specialties. These insights can be used to guide the management of a wide range of cancer pain types. CONCLUSIONS: Furthermore, this review identifies the need for a systematic and comprehensive approach to the management of cancer pain that is broader than that of a single specialty. With recent advances in pain management procedures, an interdisciplinary approach is essential in order to provide an up to date, patient tailored approach to pain management. This review will help inform the development of a cancer pain intervention registry.


Assuntos
Dor do Câncer , Neoplasias , Humanos , Dor do Câncer/etiologia , Dor do Câncer/terapia , Analgésicos Opioides/uso terapêutico , Padrões de Prática Médica , Dor/tratamento farmacológico , Dor/etiologia , Neoplasias/complicações
3.
BMC Health Serv Res ; 24(1): 232, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388905

RESUMO

BACKGROUND: The ongoing COVID-19 pandemic has impacted health systems globally and affected managing many chronic conditions, including cancer. This study aimed to explore the perceptions of multi-disciplinary cancer care providers on how cancer pain management was affected by the COVID-19 pandemic. METHODS: Participants were eligible if they were cancer care providers of any specialty and discipline from two tertiary hospitals in Australia. Data were collected using semi-structured interviews to explore cancer care providers' perspectives on cancer pain management within COVID-19. Thematic analysis of interview transcripts used an integrated approach that started with inductive coding before coding deductively against a behaviour framework called the COM-B Model, which proposes that 'capability', 'motivation' and 'opportunity' are requisites for any behaviour. RESULTS: Twenty-three providers participated. Five themes were developed and interpreted from the analysis of data, namely: "Telehealth enables remote access to cancer pain management but also created a digital divide", "Access to cancer pain management in the community is compromised due to the pandemic", "COVID-19 negatively impacts hospital resource allocation", "Patients were required to trade off cancer pain management against other health priorities" and "Hospital restrictions result in decreased social and psychological support for patients with cancer pain". CONCLUSIONS: The landscape of cancer pain management in the Australian health system underwent substantial shifts during the COVID-19 pandemic, with lasting impacts. Cancer care providers perceived the pandemic to have significant adverse effects on pain management across multiple levels, with repercussions for patients experiencing cancer-related pain. A more adaptive health system model needs to be established in the future to accommodate vulnerable cancer patients.


Assuntos
COVID-19 , Dor do Câncer , Neoplasias , Humanos , Dor do Câncer/terapia , Pandemias , COVID-19/epidemiologia , Austrália/epidemiologia , Dor , Pesquisa Qualitativa , Neoplasias/complicações , Neoplasias/terapia
4.
PLoS Genet ; 16(5): e1008823, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453789

RESUMO

The development of type 2 diabetes mellitus (T2DM) depends on interactions between genetic and environmental factors, and a better understanding of gene-diet interactions in T2DM will be useful for disease prediction and prevention. Ascorbic acid has been proposed to reduce the risk of T2DM. However, the links between ascorbic acid and metabolic consequences are not fully understood. Here, we report that glucose transporter 10 (GLUT10) maintains intracellular levels of ascorbic acid to promote adipogenesis, white adipose tissue (WAT) development and protect mice from high-fat diet (HFD)-induced metabolic dysregulation. We found genetic polymorphisms in SLC2A10 locus are suggestively associated with a T2DM intermediate phenotype in non-diabetic Han Taiwanese. Additionally, mice carrying an orthologous human Glut10G128E variant (Glut10G128E mice) with compromised GLUT10 function have reduced adipogenesis, reduced WAT development and increased susceptibility to HFD-induced metabolic dysregulation. We further demonstrate that GLUT10 is highly expressed in preadipocytes, where it regulates intracellular ascorbic acid levels and adipogenesis. In this context, GLUT10 increases ascorbic acid-dependent DNA demethylation and the expression of key adipogenic genes, Cebpa and Pparg. Together, our data show GLUT10 regulates adipogenesis via ascorbic acid-dependent DNA demethylation to benefit proper WAT development and protect mice against HFD-induced metabolic dysregulation. Our findings suggest that SLC2A10 may be an important HFD-associated susceptibility locus for T2DM.


Assuntos
Tecido Adiposo Branco/metabolismo , Ácido Ascórbico/metabolismo , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , Proteínas Facilitadoras de Transporte de Glucose/genética , Células 3T3-L1 , Adipogenia , Adulto , Idoso , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Metilação de DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação , PPAR gama/genética
5.
Ann Plast Surg ; 90(1 Suppl 1): S60-S67, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-37075295

RESUMO

BACKGROUND: Surgical site infection (SSI) after kidney transplantation can severely compromise graft function and prolong hospital stay. Organ/space SSI (osSSI) is a severe type of SSI associated with a significantly higher mortality rate. AIMS AND OBJECTIVES: This study aims to provide new strategies of managing (osSSI) after kidney transplant and other high-risk wound infections. METHOD: This is a single-center, retrospective study that analyzed the treatment outcomes of 4 patients who developed osSSI after kidney transplant at Shuang-Ho Hospital. The management strategy included real-time fluorescence imaging with MolecuLight, negative-pressure wound therapy (NPWT) with Si-Mesh, and incisional NPWT (iNPWT). RESULT: The average length of hospital stay was 18 days (range, 12-23 days). During hospitalization, all patients obtained high-quality debridement under real-time fluorescence image confirmation. The average duration of NPWT was 11.8 days (range, 7-17 days) and iNPWT was 7 days. All transplanted kidneys were preserved with normal function after 6 months of follow-up. CONCLUSIONS: Our strategies with real-time fluorescence imaging provide a novel and effective method that can be used in adjunct with the standard of care for managing osSSI after kidney transplantation. More studies are warranted to validate the efficacy of our approach.


Assuntos
Tratamento de Ferimentos com Pressão Negativa , Ferida Cirúrgica , Humanos , Infecção da Ferida Cirúrgica/terapia , Tratamento de Ferimentos com Pressão Negativa/métodos , Estudos Retrospectivos , Rim/diagnóstico por imagem
6.
Hum Factors ; : 187208231162453, 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36916743

RESUMO

OBJECTIVE: The current paper conducted two parallel studies to explore user experiences of well-being conversational agents (CAs) and identify important features for engagement. BACKGROUND: Students transitioning into university life take on greater responsibility, yet tend to sacrifice healthy behaviors to strive for academic and financial gain. Additionally, students faced an unprecedented pandemic, leading to remote courses and reduced access to healthcare services. One tool designed to improve healthcare accessibility is well-being CAs. CAs have addressed mental health support in the general population but have yet to address physical well-being support and accessibility to those in disadvantaged socio-economic backgrounds where healthcare access is further limited. METHOD: Study One comprised a thematic analysis of mental health applications featuring CAs from the public forum, Reddit. Study Two explored emerging usability themes of an SMS-based CA designed to improve accessibility to well-being services alongside a commercially available CA, Woebot. RESULTS: Study One identified several themes, including accessibility and availability, communication style, and anthropomorphism as important features. Study Two identified themes such as user response modality, perceived CA role, question specificity, and conversation flow control as critical for user engagement. CONCLUSION: Various themes emerged from individuals' experiences regarding CA features, functionality, and responses. The mixed experiences relevant to the communication and conversational styles between the CA and the user suggest varied motivations for using CAs for mental and physical well-being. APPLICATION: Practical recommendations to encourage continued use include providing dynamic response modalities, anthropomorphizing the chatbot, and calibrating expectations early.

7.
Int J Mol Sci ; 24(9)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37175754

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is a critical cofactor essential for various cellular processes. Abnormalities in NAD+ metabolism have also been associated with a number of metabolic disorders. The regulation and interconnection of NAD+ metabolic pathways are not yet completely understood. By employing an NAD+ intermediate-specific genetic system established in the model organism S. cerevisiae, we show that histone deacetylases (HDACs) Hst1 and Rpd3 link the regulation of the de novo NAD+ metabolism-mediating BNA genes with certain aspects of the phosphate (Pi)-sensing PHO pathway. Our genetic and gene expression studies suggest that the Bas1-Pho2 and Pho2-Pho4 transcription activator complexes play a role in this co-regulation. Our results suggest a model in which competition for Pho2 usage between the BNA-activating Bas1-Pho2 complex and the PHO-activating Pho2-Pho4 complex helps balance de novo activity with PHO activity in response to NAD+ or phosphate depletion. Interestingly, both the Bas1-Pho2 and Pho2-Pho4 complexes appear to also regulate the expression of the salvage-mediating PNC1 gene negatively. These results suggest a mechanism for the inverse regulation between the NAD+ salvage pathways and the de novo pathway observed in our genetic models. Our findings help provide a molecular basis for the complex interplay of two different aspects of cellular metabolism.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , NAD/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fosfatos/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Transativadores/metabolismo , Proteínas de Homeodomínio/metabolismo
8.
Int J Mol Sci ; 23(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36077467

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.


Assuntos
Metformina , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Glicina N-Metiltransferase/genética , Glicina N-Metiltransferase/metabolismo , Fígado/metabolismo , Metformina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteômica
9.
J Hum Genet ; 66(5): 475-489, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33106546

RESUMO

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.


Assuntos
Genes de Cadeia Pesada de Imunoglobulina , Estudo de Associação Genômica Ampla , Síndrome de Linfonodos Mucocutâneos/genética , Adulto , Alelos , Linfócitos B/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Seguimentos , Regulação da Expressão Gênica , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão/epidemiologia , Leucócitos/metabolismo , Desequilíbrio de Ligação , Modelos Genéticos , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Polimorfismo de Nucleotídeo Único , República da Coreia/epidemiologia , Taiwan/epidemiologia , Transcrição Gênica
10.
Environ Res ; 200: 111419, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34087193

RESUMO

Traffic-related fine particulate matter air pollution (tr-PM2.5) has been associated with adverse health outcomes such as cardiopulmonary morbidity and mortality, with in-vehicle tr-PM2.5 exposure contributing to total personal pollution exposure. Trip characteristics, including time of day, day of the week, and traffic congestion, are associated with in-vehicle PM2.5 exposures. We hypothesized that some commuter characteristics, such as whether commuters travel primarily during rush hour, would also be associated with increased tr-PM2.5 exposures. The commute data consisted of unscripted personal vehicle trips of 46 commuters in the Washington, D.C. metro area over 48-h, with a total of 320 trips. We identified commuter types using sparse K-means clustering, which identifies the hours throughout the day important for clustering commuters. Source-specific PM2.5 over 48 h was estimated using Positive Matrix Factorization. Linear regression was used to estimate differences in source-specific PM2.5 by commuter cluster. Two commuter clusters were identified using the clustering approach: rush hour commuters, who primarily travelled during rush hour, and sporadic commuters, who travelled throughout the day. The hours given the largest weights by sparse K-means were 7-8 a.m. and 6-7 p.m., corresponding to peak travel times. Integrated black carbon (BC) was higher for rush hour commuters (median = 3.1 µg/m3 (IQR = 1.5)) compared to sporadic commuters (2.0 µg/m3 (IQR = 1.9)). Mobile PM2.5, consisting primarily of tailpipe emissions and brake/tire wear, was also higher for rush hour commuters (2.9 µg/m3 (IQR = 1.6)) compared to sporadic commuters (2.1 µg/m3 (IQR = 2.4)), though this difference was not statistically significant in regression models. Estimated differences between commuter types for secondary/mixed PM2.5 and road salt PM2.5 were smaller. Further research may elucidate whether commuter characteristics are an efficient way to identify individuals with highest tr-PM2.5 exposures associated with commuting and to develop effective mitigation strategies.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Análise por Conglomerados , Exposição Ambiental/análise , Monitoramento Ambiental , Humanos , Material Particulado/análise , Emissões de Veículos/análise
11.
Int J Mol Sci ; 22(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34576011

RESUMO

Both the detrimental effect of prenatal exposure to di-(2-ethylhexyl)-phthalate (DEHP) and the beneficial effects of physical exercise on brain functions have been reported. The oxytocin pathway has been implicated in the onset of maternal behaviors. Epigenetic modification of the oxytocin receptor gene (OXTR) through DNA methylation has been associated with the pathogenesis of neuropsychiatric disorders. The purpose of this study was to investigate the effects of prenatal DEHP exposure on oxytocin-regulated maternal behaviors and to examine the protective effect of exercise. Pregnant rats (F0) were fed with vehicle or DEHP during gestation and the offspring females (F1) were assessed for their maternal behaviors by pup retrieval test at postpartum. The results showed that reduced pup retrieval activities without significant alteration of stress responses were observed in the prenatally DEHP-exposed females. Prenatal DEHP exposure decreased the expressions of oxytocin, Oxtr mRNA, and oxytocin receptor, and increased Oxtr methylation in the hypothalamus of postpartum female rats. There were no significant effects of exercise on behavioral, biochemical, and epigenetic measurements. These results suggest that prenatal DEHP exposure has a long-term adverse effect on maternal behaviors; Oxtr hyper-methylation may be a potential epigenetic mechanism for this alteration, which cannot be prevented by physical exercise during childhood.


Assuntos
Dietilexilftalato/toxicidade , Hipotálamo/efeitos dos fármacos , Comportamento Materno/efeitos dos fármacos , Condicionamento Físico Animal , Efeitos Tardios da Exposição Pré-Natal , Animais , Metilação de DNA , Feminino , Hipotálamo/metabolismo , Gravidez , Ratos Sprague-Dawley , Receptores de Ocitocina/genética
12.
Hum Mol Genet ; 27(2): 307-321, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29149261

RESUMO

Glucose transporter 10 (GLUT10) is a member of the GLUT family of membrane transporters, and mutations in this gene cause arterial tortuosity syndrome (ATS). However, the physiological role and regulation of GLUT10 in arteries remains unclear. To further understand its physiological roles in major arteries, we examined the regulatory mechanisms of GLUT10 in ASMCs and aortic tissues. Interestingly, we find that targeting of GLUT10 to mitochondria is increased in ASMCs under both stress and aging conditions, which enhances dehydroascorbic acid (DHA) uptake and maintains intracellular ascorbic acid (AA) levels. We further demonstrate that the targeting of GLUT10 to mitochondria is important to maintain redox homeostasis, mitochondrial structure and mitochondrial function in ASMCs. A missense mutation of GLUT10 (Glut10G128E) impairs mitochondrial targeting in ASMCs. Consequently, ASMCs isolated from Glut10G128E mice exhibit increased reactive oxygen species (ROS) levels, fragmented mitochondria and impaired mitochondrial function, as well as enhanced cell proliferation and migration. In vivo, mitochondrial structure is altered, and ROS levels are heightened in aortic tissues of Glut10G128E mice. Furthermore, increased number and disorganization of ASMCs, along with progressive arterial wall remodeling were observed in aortic tissues of Glut10G128E mice. These defects were coincident with elevated systolic blood pressure in aged Glut10G128E animals. Our results describe a novel mechanism that GLUT10 targeting to mitochondria under stress and aging condition has a critical role in maintaining AA levels, redox homeostasis and mitochondrial structure and function in ASMCs, which is likely to contribute to the maintenance of healthy vascular tissue.


Assuntos
Artérias/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Animais , Aorta/metabolismo , Transporte Biológico/genética , Linhagem Celular , Proteínas Facilitadoras de Transporte de Glucose/genética , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C3H , Mitocôndrias/metabolismo , Mutação , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Environ Res ; 187: 109644, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32422483

RESUMO

Exposure to traffic-related fine particulate matter air pollution (tr-PM2.5) has been associated with adverse health outcomes including preterm birth and low birthweight. In-vehicle exposure to tr-PM2.5 can contribute substantially to total tr-PM2.5 exposure. Because average commuting habits of women differ from men, a research gap is estimating in-vehicle tr-PM2.5 exposures for women commuters. For 46 women commuters in the Washington, D.C. metro area, we measured personal exposure to PM2.5 during all vehicle trips taken in a 48-h sampling period. We also measured 48-h integrated PM2.5 chemical constituents including black carbon and zinc. We identified trip times using vehicle monitors, specifically on-board diagnostics data loggers and dashboard cameras. For 386 trips, we estimated associations between PM2.5 exposure and trip characteristics using linear mixed models accounting for participant, day, and time of day. Additionally, we estimated associations between rush hour trip PM2.5 and 48-h integrated PM2.5 chemical constituents using linear models. Exposure to PM2.5 during trips was 1.9 µg/m3 (95% confidence interval (CI): 0.9, 2.9) higher than non-trip exposures and rush hour trip exposures were 3.2 µg/m3 (95% CI: 1.8, 4.6) higher than non-trip exposures on average. We did not find differences in PM2.5 exposure by trip length. Although concentrations of tr-PM2.5 chemical constituents were generally positively associated with rush hour trip PM2.5, associations were weak indicating that other settings contribute to total tr-PM2.5 exposure. Our study demonstrates the utility of combining vehicle monitors and personal PM2.5 monitors for estimating personal exposure to tr-PM2.5. Future work will investigate whether additional data collected by vehicle monitors, such as traffic and speed, can be leveraged to better understand tr-PM2.5 exposure among commuters.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Nascimento Prematuro , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Exposição Ambiental/análise , Monitoramento Ambiental , Feminino , Humanos , Recém-Nascido , Masculino , Material Particulado/análise , Gravidez , Emissões de Veículos/análise , Washington
14.
J Neurosci ; 37(9): 2485-2503, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28167673

RESUMO

Voltage-gated CaV2.1 channels comprise a pore-forming α1A subunit with auxiliary α2δ and ß subunits. CaV2.1 channels play an essential role in regulating synaptic signaling. Mutations in the human gene encoding the CaV2.1 subunit are associated with the cerebellar disease episodic ataxia type 2 (EA2). Several EA2-causing mutants exhibit impaired protein stability and exert dominant-negative suppression of CaV2.1 wild-type (WT) protein expression via aberrant proteasomal degradation. Here, we set out to delineate the protein degradation mechanism of human CaV2.1 subunit by identifying RNF138, an E3 ubiquitin ligase, as a novel CaV2.1-binding partner. In neurons, RNF138 and CaV2.1 coexist in the same protein complex and display notable subcellular colocalization at presynaptic and postsynaptic regions. Overexpression of RNF138 promotes polyubiquitination and accelerates protein turnover of CaV2.1. Disrupting endogenous RNF138 function with a mutant (RNF138-H36E) or shRNA infection significantly upregulates the CaV2.1 protein level and enhances CaV2.1 protein stability. Disrupting endogenous RNF138 function also effectively rescues the defective protein expression of EA2 mutants, as well as fully reversing EA2 mutant-induced excessive proteasomal degradation of CaV2.1 WT subunits. RNF138-H36E coexpression only partially restores the dominant-negative effect of EA2 mutants on CaV2.1 WT functional expression, which can be attributed to defective membrane trafficking of CaV2.1 WT in the presence of EA2 mutants. We propose that RNF138 plays a critical role in the homeostatic regulation of CaV2.1 protein level and functional expression and that RNF138 serves as the primary E3 ubiquitin ligase promoting EA2-associated aberrant degradation of human CaV2.1 subunits.SIGNIFICANCE STATEMENT Loss-of-function mutations in the human CaV2.1 subunit are linked to episodic ataxia type 2 (EA2), a dominantly inherited disease characterized by paroxysmal attacks of ataxia and nystagmus. EA2-causing mutants may exert dominant-negative effects on the CaV2.1 wild-type subunit via aberrant proteasomal degradation. The molecular nature of the CaV2.1 ubiquitin-proteasome degradation pathway is currently unknown. The present study reports the first identification of an E3 ubiquitin ligase for CaV2.1, RNF138. CaV2.1 protein stability is dynamically regulated by RNF138 and auxiliary α2δ and ß subunits. We provide a proof of concept that protecting the human CaV2.1 subunit from excessive proteasomal degradation with specific interruption of endogenous RNF138 function may partially contribute to the future development of a novel therapeutic strategy for EA2 patients.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Ataxia/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Canais de Cálcio Tipo N/genética , Linhagem Celular , Células Cultivadas , Córtex Cerebral/citologia , Cicloeximida/farmacologia , Células HEK293 , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Mutação/genética , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nistagmo Patológico/genética , Oócitos , Inibidores da Síntese de Proteínas/farmacologia , Proteólise/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética , Xenopus
15.
BMC Genomics ; 19(1): 578, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30068293

RESUMO

BACKGROUND: Satellite DNA is a rapidly diverging, largely repetitive DNA component of many eukaryotic genomes. Here we analyse the evolutionary dynamics of a satellite DNA repeat in the genomes of a group of Asian subtropical lady slipper orchids (Paphiopedilum subgenus Parvisepalum and representative species in the other subgenera/sections across the genus). A new satellite repeat in Paphiopedilum subgenus Parvisepalum, SatA, was identified and characterized using the RepeatExplorer pipeline in HiSeq Illumina reads from P. armeniacum (2n = 26). Reconstructed monomers were used to design a satellite-specific fluorescent in situ hybridization (FISH) probe. The data were also analysed within a phylogenetic framework built using the internal transcribed spacer (ITS) sequences of 45S nuclear ribosomal DNA. RESULTS: SatA comprises c. 14.5% of the P. armeniacum genome and is specific to subgenus Parvisepalum. It is composed of four primary monomers that range from 230 to 359 bp and contains multiple inverted repeat regions with hairpin-loop motifs. A new karyotype of P. vietnamense (2n = 28) is presented and shows that the chromosome number in subgenus Parvisepalum is not conserved at 2n = 26, as previously reported. The physical locations of SatA sequences were visualised on the chromosomes of all seven Paphiopedilum species of subgenus Parvisepalum (2n = 26-28), together with the 5S and 45S rDNA loci using FISH. The SatA repeats were predominantly localisedin the centromeric, peri-centromeric and sub-telocentric chromosome regions, but the exact distribution pattern was species-specific. CONCLUSIONS: We conclude that the newly discovered, highly abundant and rapidly evolving satellite sequence SatA is specific to Paphiopedilum subgenus Parvisepalum. SatA and rDNA chromosomal distributions are characteristic of species, and comparisons between species reveal that the distribution patterns generate a strong phylogenetic signal. We also conclude that the ancestral chromosome number of subgenus Parvisepalum and indeed of all Paphiopedilum could be either 2n = 26 or 28, if P. vietnamense is sister to all species in the subgenus as suggested by the ITS data.


Assuntos
DNA Satélite/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hibridização in Situ Fluorescente/métodos , Orchidaceae/genética , Análise de Sequência de DNA/métodos , Mapeamento Cromossômico , DNA de Plantas/genética , DNA Ribossômico/genética , Evolução Molecular , Filogenia , RNA Ribossômico/genética , Especificidade da Espécie
16.
Int J Mol Sci ; 19(12)2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487393

RESUMO

Mutations in the skeletal muscle-specific CLC-1 chloride channel are associated with the human hereditary disease myotonia congenita. The molecular pathophysiology underlying some of the disease-causing mutations can be ascribed to defective human CLC-1 protein biosynthesis. CLC-1 protein folding is assisted by several molecular chaperones and co-chaperones, including FK506-binding protein 8 (FKBP8). FKBP8 is generally considered an endoplasmic reticulum- and mitochondrion-resident membrane protein, but is not thought to contribute to protein quality control at the cell surface. Herein, we aim to test the hypothesis that FKBP8 may regulate CLC-1 protein at the plasma membrane. Surface biotinylation and subcellular fractionation analyses reveal that a portion of FKBP8 is present at the plasma membrane, and that co-expression with CLC-1 enhances surface localization of FKBP8. Immunoblotting analyses of plasma membrane proteins purified from skeletal muscle further confirm surface localization of FKBP8. Importantly, FKBP8 promotes CLC-1 protein stability at the plasma membrane. Together, our data underscore the importance of FKBP8 in the peripheral quality control of CLC-1 channel.


Assuntos
Membrana Celular/metabolismo , Canais de Cloreto/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Complexo de Golgi/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Músculo Esquelético/metabolismo , Estabilidade Proteica
17.
Hu Li Za Zhi ; 65(6): 87-94, 2018 Dec.
Artigo em Zh | MEDLINE | ID: mdl-30488416

RESUMO

BACKGROUND & PROBLEMS: When patients with breast cancer undergo radical mastectomy, seromas are often caused due to the large area of excised breast tissue and the resulting cavity that fills with blood and water. Therefore, strong adhesive elastic tape and large amounts of gauze are needed to compress the wound. Our clinical experience shows that repeatedly removing dressings during dressing changes significantly increases the risk of unexpected skin defects. However, the increased duration of hospital stays required for these patients with skin defects exposes them to high risk environments, which may result in nosocomial infections and even longer hospitalization durations. PURPOSE: This project aimed to decrease the incidence of unexpected skin defects in patients after mastectomy to below 15%. RESOLUTION: After a review of the literature, we implemented this project to: (1) build up a standard operating procedure for post-mastectomy wound compression; (2) use narrow girdles instead of strong adhesive elastic tape; (3) use soft elastic bandages to replace the single layer of gauze for wound compression; (4) use a skin examination form as a continuous monitoring tool. We expected that these measurements would effectively decrease the incidence of unexpected skin defects in post-mastectomy patients. RESULTS: After implementing this project, the incidence of unexpected skin defects in post-mastectomy patients decreased from 100% to 13% and the time required by clinical nursing staff to perform wound dressing care decreased from 25 mins to 15 mins per care instance. CONCLUSIONS: We hope that this project helps effectively improve postoperative wound care quality in post-mastectomy patients and decreases the time spent by clinical nursing staff on wound dressing care.


Assuntos
Neoplasias da Mama/cirurgia , Mastectomia/enfermagem , Enfermagem em Pós-Anestésico , Dermatopatias/prevenção & controle , Feminino , Humanos , Incidência , Mastectomia/efeitos adversos , Pesquisa em Avaliação de Enfermagem , Melhoria de Qualidade , Dermatopatias/epidemiologia , Gerenciamento do Tempo
18.
N Engl J Med ; 370(2): 119-28, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24369049

RESUMO

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).


Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/genética , Carboxiliases/genética , Lítio/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/etnologia , China , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
19.
Circ Res ; 116(5): 876-83, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25605650

RESUMO

RATIONALE: Kawasaki disease (KD), an acute febrile vasculitis, is the most common cause of acquired heart disease in childhood; however, diagnosing KD can be difficult. OBJECTIVE: To identify unique proteomic biomarkers that can be used to facilitate earlier diagnosis of KD. METHODS AND RESULTS: We enrolled 214 children with fever and clinical features suggestive of KD. Of those, only 100 were diagnosed with KD. Their plasma samples were globally analyzed for cytokines, chemokines, and cell adhesion molecules using an unbiased, large-scale, quantitative protein array. This study was conducted in 3 stages: discovery, replication, and blinded validation. During the discovery phase (n [KD]=37; n [control]=20), the expression of interleukin-17F, sCD40L, E-selectin, CCL23 (myeloid progenitor inhibitory factor 1), and CXCL10 (IFN-γ-inducible protein 10 [IP-10]) were upregulated during the acute phase in patients with KD when compared with that in the controls. A notable increase was observed in the IP-10 levels (KD, 3037 ± 226.7 pg/mL; control, 672 ± 130.4 pg/mL; P=4.1 × 10(-11)). Receiver-operating characteristic analysis of the combined discovery and replication data (n [KD]=77; n [control]=77) showed that the IP-10 level had high area under the curve values (0.94 [95% confidence interval, 0.9055-0.9778]; sensitivity, 100%; and specificity, 77%). With 1318 pg/mL as the optimal cutoff, the blinded validation study confirmed that the IP-10 levels were a good predictor of KD. With intravenous immunoglobulin treatment, the IP-10 levels returned to normal. The downstream receptor of IP-10, CXCR3, was activated in the T cells of patients with acute KD. CONCLUSIONS: IP-10 may be used as a biomarker to facilitate KD diagnosis, and it may provide clues about the pathogenesis of KD.


Assuntos
Quimiocina CXCL10/sangue , Síndrome de Linfonodos Mucocutâneos/sangue , Biomarcadores/sangue , Moléculas de Adesão Celular/sangue , Quimiocina CXCL10/fisiologia , Quimiocinas/sangue , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Febre/etiologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Recém-Nascido , Inflamação , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Síndrome de Linfonodos Mucocutâneos/terapia , Curva ROC , Receptores CXCR3/metabolismo , Método Simples-Cego , Linfócitos T/metabolismo
20.
J Cell Sci ; 127(Pt 1): 85-100, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24213532

RESUMO

Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-associated multi-domain SCUBE protein family. We previously demonstrated that SCUBE2 is a novel breast-tumor suppressor and could be a useful prognostic marker. However, the role of SCUBE2 in breast-cancer cell migration and invasion and how it is regulated during the epithelial-mesenchymal transition (EMT) remain undefined. In this study, we showed that ectopic SCUBE2 overexpression could enhance the formation of E-cadherin-containing adherens junctions by ß-catenin-SOX-mediated induction of forkhead box A1 (a positive regulator of E-cadherin) and upregulation of E-cadherin, which in turn led to epithelial transition and inhibited migration and invasion of aggressive MDA-MB-231 breast-carcinoma cells. SCUBE2 expression was repressed together with that of E-cadherin in TGF-ß-induced EMT; direct expression of SCUBE2 alone was sufficient to inhibit the TGF-ß-induced EMT. Furthermore, quantitative DNA methylation, methylation-specific PCR, and chromatin immunoprecipitation analyses revealed that SCUBE2 expression was inactivated by DNA hypermethylation at the CpG islands by recruiting and binding DNA methyltransferase 1 during TGF-ß-induced EMT. Together, our results suggest that SCUBE2 plays a key role in suppressing breast-carcinoma-cell mobility and invasiveness by increasing the formation of the epithelial E-cadherin-containing adherens junctions to promote epithelial differentiation and drive the reversal of EMT.


Assuntos
Junções Aderentes/metabolismo , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Proteínas Adaptadoras de Transdução de Sinal , Junções Aderentes/efeitos dos fármacos , Caderinas/genética , Caderinas/metabolismo , Proteínas de Ligação ao Cálcio , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Genes Reporter , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Luciferases/genética , Luciferases/metabolismo , Proteínas de Membrana/metabolismo , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOX/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/farmacologia , beta Catenina/genética , beta Catenina/metabolismo
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