RESUMO
Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Anemia de Fanconi/genética , Formaldeído/toxicidade , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Anemia de Fanconi/sangue , Anemia de Fanconi/patologia , Formaldeído/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Instabilidade Genômica/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células K562 , Transcrição GênicaRESUMO
Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for "reader" proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Recently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine-binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias. The human genome encodes four YEATS domain proteins, including GAS41, a component of chromatin remodelers responsible for H2A.Z deposition onto chromatin; however, the importance of the GAS41 YEATS domain in human cancer remains largely unknown. Here we report that GAS41 is frequently amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell proliferation, survival, and transformation. Biochemical and crystal structural studies demonstrate that GAS41 binds to histone H3 acetylated on H3K27 and H3K14, a specificity that is distinct from that of AF9 or ENL. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) analyses in lung cancer cells reveal that GAS41 colocalizes with H3K27ac and H3K14ac on the promoters of actively transcribed genes. Depletion of GAS41 or disruption of the interaction between its YEATS domain and acetylated histones impairs the association of histone variant H2A.Z with chromatin and consequently suppresses cancer cell growth and survival both in vitro and in vivo. Overall, our study identifies GAS41 as a histone acetylation reader that promotes histone H2A.Z deposition in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Histonas/metabolismo , Neoplasias Pulmonares/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Amplificação de Genes , Genes cdc , Histonas/fisiologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologiaRESUMO
BACKGROUND: We designed a novel ankle foot orthosis (AFO), namely, ideal training AFO (IT-AFO), with motion feedback on the hemiparetic lower limb to improve ambulation in individuals with stroke-related hemiplegia. We, therefore sought to compare the kinematic parameters of gait between IT-AFO with and without dynamic control and conventional anterior-type AFO or no AFO. METHODS: Gait parameters were measured using the RehaWatch® system in seven individuals with hemiplegia (mean 51.14 years). The parameters were compared across four conditions: no AFO, conventional anterior AFO, IT-AFO without dynamic control, and IT-AFO with dynamic control, with three trials of a 10-m walk test for each. RESULTS: The dorsiflexion angle increased during the swing phase when the IT-AFO was worn, and it was larger with dynamic control. These data can confirm drop foot improvement; however, the difference between the parameters with- and without-AFO control conditions was not significant in the swing phase. The IT-AFO with or without dynamic control enhanced the loading response to a greater extent between the hemiparetic and unaffected lower limbs than conventional AFO or no AFO. The duration of the stance phase on the hemiparetic lower limb was also longer when using IT-AFO with and without dynamic control than that when using conventional AFO, which improved asymmetry. User comfort and satisfaction was greater with IT-AFO than with the other conditions. CONCLUSIONS: The IT-AFO with dynamic control improved gait pattern and weight shifting to the hemiparetic lower limb, reducing gait asymmetry. The difference with and without dynamic control of IT-AFO is not statistically significant, and it is limited by sample size. However, this study shows the potential of IT-AFO in applying positive motion feedback with gait training. TRIAL REGISTRATION: Taipei Medical University-Joint Institutional Review Board. N201510010 . Registered 12 February 2015. http://ohr.tmu.edu.tw/main.php .
Assuntos
Retroalimentação Sensorial , Órtoses do Pé , Transtornos Neurológicos da Marcha/reabilitação , Reabilitação do Acidente Vascular Cerebral/instrumentação , Adulto , Idoso , Idoso de 80 Anos ou mais , Articulação do Tornozelo/fisiologia , Fenômenos Biomecânicos , Retroalimentação Sensorial/fisiologia , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Desenho de Prótese/métodos , Acidente Vascular Cerebral/complicaçõesRESUMO
BACKGROUND: Bipolar disorder (BD), a type of psychiatric mood disorder, is manifested by chronic and recurrent mood fluctuations. This study aims to determine whether hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a risk factor for BD. METHODS: A total of 48,215 patients with newly diagnosed viral hepatitis from 2000 to 2010 were identified and frequency-matched with 192,860 people without hepatitis. Both groups were followed until diagnosis with BD, withdrawal from the national health insurance program, or the end of 2011. Patients with viral hepatitis were grouped into 3 cohorts: HBV infection, HCV infection, and HBV/HCV coinfection. The association between viral hepatitis and BD were examined using Cox proportional hazards regression models. RESULTS: The incidence of BD was higher in HBV/HCV coinfection than in the control group, with an adjusted hazard ratio of 2.16 (95% confidence interval 1.06-4.41) when adjusted for sex, age, and comorbidity. After further adjustment, we noted that an age more than 65 years and female may be associated with an increased risk of BD in patients with chronic hepatitis B and C. CONCLUSION: Viral hepatitis may be associated with increased risk of subsequent BD.
Assuntos
Transtorno Bipolar/complicações , Hepatite B/virologia , Hepatite C/complicações , Hepatite C/virologia , Adulto , Idoso , Transtorno Bipolar/epidemiologia , Comorbidade , Feminino , Hepatite B/complicações , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
Age-related hearing loss (ARHL) is postulated to affect dementia. Our study aims to investigate the relationship between ARHL and the prevalence, and 10-year incidence of dementia in the Taiwan National Health Insurance Research Database (NHIRD). We selected patients diagnosed with ARHL from the NHIRD. A comparison cohort comprising of patients without ARHL was frequency-matched by age, sex, and co-morbidities, and the occurrence of dementia was evaluated in both cohorts. The ARHL cohort consisted of 4108 patients with ARHL and the control cohort consisted of 4013 frequency-matched patients without ARHL. The incidence of dementia [hazard ratio (HR), 1.30; 95% confidence interval (CI 1.14-1.49); P = 0.002] was higher among ARHL patients. Cox models showed that being female (HR, 1.34; 95% CI 1.07-1.68), as well as having co-morbidities, including chronic liver disease and cirrhosis, rheumatoid arthritis, hypertension, diabetes mellitus, stroke, head injury, chronic kidney disease, coronary artery disease, alcohol abuse/dependence, and tobacco abuse/dependence (HR, 1.27; 95% CI 1.11-1.45), were independent risk factors for dementia in ARHL patients. We found ARHL may be one of the early characteristics of dementia, and patients with hearing loss were at a higher risk of subsequent dementia. Clinicians should be more sensitive to dementia symptoms within the first 2 years following ARHL diagnosis. Further clinical studies of the relationship between dementia and ARHL may be necessary.
Assuntos
Demência , Presbiacusia , Idoso , Estudos de Coortes , Comorbidade , Demência/diagnóstico , Demência/epidemiologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Presbiacusia/diagnóstico , Presbiacusia/epidemiologia , Prevalência , Modelos de Riscos Proporcionais , Fatores de Risco , Taiwan/epidemiologiaRESUMO
PURPOSE: To analyze the influence of spectral-domain optical coherence tomography (SD-OCT) features on visual acuity changes in patients with idiopathic epiretinal membranes (ERMs). METHODS: Seventy-nine eyes of 71 patients were included in this study. SD-OCT was performed for all patients; data were collected upon ERM diagnosis and at the final visit. The patients were divided into subgroups based on their SD-OCT features. The initial best corrected visual acuity (BCVA) and changes in BCVA for each subgroup were compared. A multivariate analysis was performed to assess the factors associated with changes in BCVA. RESULTS: During a mean follow-up period of 20.78 months, the mean change in logMAR visual acuity was 0.052 ± 0.089. Eyes with inner segment/outer segment (IS/OS) junction disruption and cystoid macular edema (CME) had a significantly lower mean initial BCVA than those without disruption and CME (P = 0.036 and P = 0.012, respectively). However, only eyes with CME had significant changes in BCVA (P = .034). Multivariate analysis revealed the presence of CME as the only factor that had a significant correlation with VA changes. CONCLUSIONS: In patients with idiopathic ERMs, the presence of CME and IS/OS disruption detected by OCT correlated with a poorer initial BCVA. Most patients' visual acuity remained stable during follow-up. The presence of CME with OCT represented a predictor of the progression of visual acuity. These results may provide valuable clinical information regarding the management of patients with idiopathic ERMs. We demonstrated that the presence of CME and IS/OS disruption detected with OCT correlated with a poorer BCVA in idiopathic ERMs. The visual acuity of most patients was stable during the follow-up period. The presence of CME in OCT represented a predictor of vision deterioration for patients with idiopathic ERMs.
Assuntos
Membrana Epirretiniana/diagnóstico , Edema Macular/diagnóstico , Segmento Interno das Células Fotorreceptoras da Retina/patologia , Segmento Externo das Células Fotorreceptoras da Retina/patologia , Acuidade Visual/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Membrana Epirretiniana/fisiopatologia , Feminino , Seguimentos , Humanos , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência ÓpticaRESUMO
OBJECTIVES: Bipolar disorder (BD) is a systemic inflammatory disease, and disrupted bone metabolism due to the inflammatory process can cause fracture. Despite evidence of an association between lower bone mineral density and an increased risk of fracture among patients with depression, schizophrenia, and anorexia nervosa, whether BD is a risk factor for subsequent fracture is unknown. To determine the association between BD and fracture and to examine the risk factors for fracture among patients with BD. METHODS: In this study, we enrolled patients diagnosed with BD from the Taiwan National Health Insurance Research Database. Patients newly diagnosed with BD (ICD-9-CM 296) from 2001 to 2008 were included in the BD cohort, and the date of the initial diagnosis of BD was used as the index date. The comparison cohort, comprising participants without BD, was frequency matched to the BD cohort by age, sex, and index year, and the occurrence of fracture was evaluated in both cohorts. RESULTS: The BD and comparison cohorts were comprised of 47,271 patients with BD and 1,89,084 frequency-matched participants without BD, respectively. The incidence of fracture was higher among patients with BD than among the controls. Cox models showed that BD was an independent risk factor for fracture irrespective of comorbidities [hazard ratio (HR) = 1.79, 95 % confidence interval (CI) = 1.73-1.84, p < .001]. CONCLUSION: Our study showed that patients with BD have a higher risk of subsequent fracture. Additional prospective clinical studies investigating the relationship between BD and fracture are warranted.
Assuntos
Transtorno Bipolar/epidemiologia , Fraturas Ósseas/epidemiologia , Adulto , Idoso , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Incidência , Classificação Internacional de Doenças , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7.
Assuntos
Regulação Neoplásica da Expressão Gênica , Fator de Transcrição Ikaros , Lenalidomida , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-myc , Fator de Transcrição 4 , Transcriptoma , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Lenalidomida/uso terapêutico , Lenalidomida/farmacologia , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo , Linfócitos B/metabolismo , Linfócitos B/imunologia , Prognóstico , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Variações do Número de Cópias de DNARESUMO
Activating transcription factor 2 (ATF2) belongs to the basic leucine zipper family of transcription factors. ATF2 regulates target gene expression by binding to the cyclic AMP-response element as a homodimer or a heterodimer with c-Jun. Cytoplasmic localization of ATF2 was observed in melanoma, brain tissue from patients with Alzheimer disease, prostate cancer specimens, and ionizing radiation-treated prostate cancer cells, suggesting that alteration of ATF2 subcellular localization may be involved in the pathogenesis of these diseases. We previously demonstrated that ATF2 is a nucleocytoplasmic shuttling protein, and it contains two nuclear localization signals in the basic region and one nuclear export signal (NES) in the leucine zipper domain (named LZ-NES). In the present study, we demonstrate that a hydrophobic stretch in the N terminus, (1)MKFKLHV(7), also functions as an NES (termed N-NES) in a chromosome region maintenance 1 (CRM1)-dependent manner. Mutation of both N-NES and LZ-NES results in a predominant nuclear localization, whereas mutation of each individual NES only partially increases the nuclear localization. These results suggest that cytoplasmic localization of ATF2 requires function of at least one of the NESs. Further, mutation of N-NES enhances the transcriptional activity of ATF2, suggesting that the novel NES negatively regulates the transcriptional potential of ATF2. Thus, ATF2 subcellular localization is probably modulated by multiple mechanisms, and further understanding of the regulation of ATF2 subcellular localization under various pathological conditions will provide insight into the pathophysiological role of ATF2 in human diseases.
Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sinais de Exportação Nuclear , Transcrição Gênica , Fator 2 Ativador da Transcrição/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células COS , Chlorocebus aethiops , Feminino , Humanos , Zíper de Leucina , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Mutação , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Estrutura Terciária de Proteína , Transporte Proteico/genéticaRESUMO
This study presents a novel flexible strain sensor for real-time strain sensing. The material for strain sensing is single-walled carbon nanonets, grown using the alcohol catalytic chemical vapor deposition method, that were encapsulated between two layers of Parylene-C, with a polyimide layer as the sensing surface. All of the micro-fabrication was compatible with the standard IC process. Experimental results indicated that the gauge factor of the proposed strain sensor was larger than 4.5, approximately 2.0 times greater than those of commercial gauges. The results also demonstrated that the gauge factor is small when the growth time of SWCNNs is lengthier, and the gauge factor is large when the line width of the serpentine pattern of SWCNNs is small.
RESUMO
The aims of this study were (1) to compare the effect of robot-assisted gait orthosis (RAGO) plus conventional physiotherapy with the effect of conventional therapy alone on functional outcomes, including balance, walking ability, muscle strength, daily activity, and cognition, in chronic stroke patients, and (2) to determine the association of adjustable parameters of RAGO on functional outcomes. Adjustable parameters of RAGO included guidance force, treadmill speed, and body-weight support. This retrospective cohort study enrolled 32 patients with chronic stroke. Of these, 16 patients received RAGO plus conventional physiotherapy (RAGO group), and 16 patients received conventional physiotherapy alone (control group). Balance was assessed using the Berg Balance Scale, walking ability using the Functional Ambulation Category, muscle strength using the Motricity Index, daily activity using the Barthel Index, and cognition using the Mini-Mental State Examination. The scores were assessed before and after training. The Mini-Mental State Examination and the Berg Balance Scale increased significantly in both groups, whereas improvements in the Motricity Index and the Barthel Index were only observed in the RAGO group after intervention. During RAGO training, reducing guidance force and body-weight support assistance was associated with improvements in the Barthel Index, whereas higher treadmill walking speed was associated with improvements in the Berg Balance Scale. Our study found that RAGO combination therapy resulted in improvements in more functional outcomes than did conventional training alone. The adjustable parameters of the RAGO training were partly associated with training outcomes.
Assuntos
Robótica , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Terapia por Exercício/métodos , Marcha/fisiologia , Humanos , Estudos Retrospectivos , Robótica/métodos , Acidente Vascular Cerebral/complicações , Reabilitação do Acidente Vascular Cerebral/métodos , Resultado do Tratamento , CaminhadaRESUMO
PURPOSE: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS: Canonical immunoglobulin heavy chain translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for 1 patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2 = 0.969. Variant allele frequency (VAF) for 74 mutations were compared between sequencing and ddPCR with concordance of R2 = 0.9849. CONCLUSIONS: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost-effective, comprehensive, clinically actionable, and can be routinely deployed to assist risk stratification at diagnosis or posttreatment to guide sequencing of therapies.
Assuntos
Mieloma Múltiplo , Variações do Número de Cópias de DNA , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Mutação , Translocação Genética , Sequenciamento Completo do GenomaAssuntos
Psicoses Induzidas por Substâncias/complicações , Transtornos Psicóticos/complicações , Risperidona/efeitos adversos , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Humanos , Hidrocefalia/complicações , Hidrocefalia/tratamento farmacológico , Masculino , Risperidona/uso terapêutico , Adulto JovemRESUMO
Whether periodontitis is a risk factor for developing bipolar disorders (BD) has not been investigated. We aimed to determine whether periodontitis is associated with the subsequent development of BD and examine the risk factors for BD among patients with periodontitis.Using ambulatory and inpatient claims data from the National Health Insurance Research Database (NHIRD), we identified 12,337 patients who were aged at least 20 years and newly diagnosed with periodontitis between 2000 and 2004. The date of the first claim with a periodontitis diagnosis was set as the index date. For each patient with periodontitis, 4 subjects without a history of periodontitis were randomly selected from the NHIRD and frequency-matched with the patients with periodontitis according to sex, age (in 5-year bands), and index year.The periodontitis group had a mean age of 44.0â±â13.7 years and slight predominance of men (51.3%). Compared with the subjects without periodontitis, the patients with periodontitis had higher prevalence of diabetes mellitus, hyperlipidemia, hypertension, ischemic heart disease, stroke, head injury, major depressive disorder, chronic obstructive pulmonary disease (COPD), and asthma (Pâ<â.001). The incidence rate of BD was higher in the periodontitis group than in the non-periodontitis group (2.74 vs 1.46 per 1000 person-year), with an adjusted hazard ratio of 1.82 (95% confidence intervalâ=â1.59-2.08) after adjustment for sex, age, and comorbidities.The patients with periodontitis exhibited a significantly higher risk of developing BD. Keep the better oral hygiene to reduce periodontitis might be a preventive strategy for BD.
Assuntos
Transtorno Bipolar/psicologia , Periodontite/epidemiologia , Adulto , Idoso , Transtorno Bipolar/complicações , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Revisão da Utilização de Seguros , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Taiwan/epidemiologia , Adulto JovemRESUMO
Aberrant expression of the steroidogenic acute regulatory (StAR) protein in human endometriotic stromal cells plays an important role in the development of endometriosis. Prostaglandin E(2) (PGE(2)) is a potent inducer of StAR expression in these cells; however, the mechanisms responsible for the transcriptional regulation of StAR remain to be elucidated. Herein we report that PGE(2)-induced StAR expression is independent of the transcriptional suppressor DAX-1 but is regulated by the transcriptional activator cyclic adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB). A promoter activity assay revealed that the cis-element needed for the binding of the CCAAT/enhancer-binding protein (C/EBP) was critical for PGE(2)-induced StAR expression. Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. Results from a chromatin immunoprecipitation assay demonstrated that the binding of C/EBPbeta to the StAR promoter was increased whereas CREB binding was unchanged after PGE(2) treatment. Taken together, PGE(2)-induced StAR promoter activity appears to be regulated by CREB and C/EBPbeta in a cooperative manner in ectopic human endometriotic stromal cells, providing a molecular framework for the etiology of endometriosis.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Dinoprostona/fisiologia , Endometriose/metabolismo , Fosfoproteínas/biossíntese , Sítios de Ligação , Células Cultivadas , Receptor Nuclear Órfão DAX-1 , Proteínas de Ligação a DNA/metabolismo , Endometriose/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Fosfoproteínas/genética , Regiões Promotoras Genéticas , Receptores do Ácido Retinoico/metabolismo , Proteínas Repressoras/metabolismo , Elementos de Resposta , Células Estromais/metabolismoRESUMO
The histone variant H2A.Z is essential for maintaining embryonic stem cell (ESC) identity in part by keeping developmental genes in a poised bivalent state. However, how H2A.Z is deposited into the bivalent domains remains unknown. In mammals, two chromatin remodeling complexes, Tip60/p400 and SRCAP, exchange the canonical histone H2A for H2A.Z in the chromatin. Here we show that Glioma Amplified Sequence 41 (Gas41), a shared subunit of the two H2A.Z-depositing complexes, functions as a reader of histone lysine acetylation and recruits Tip60/p400 and SRCAP to deposit H2A.Z into specific chromatin regions including bivalent domains. The YEATS domain of Gas41 bound to acetylated histone H3K27 and H3K14 both in vitro and in cells. The crystal structure of the Gas41 YEATS domain in complex with the H3K27ac peptide revealed that, similar to the AF9 and ENL YEATS domains, Gas41 YEATS forms a serine-lined aromatic cage for acetyllysine recognition. Consistently, mutations in the aromatic residues of the Gas41 YEATS domain abrogated the interaction. In mouse ESCs, knockdown of Gas41 led to flattened morphology of ESC colonies, as the result of derepression of differentiation genes. Importantly, the abnormal morphology was rescued by expressing wild-type Gas41, but not the YEATS domain mutated counterpart that does not recognize histone acetylation. Mechanically, we found that Gas41 depletion led to reduction of H2A.Z levels and a concomitant reduction of H3K27me3 levels on bivalent domains. Together, our study reveals an essential role of the Gas41 YEATS domain in linking histone acetylation to H2A.Z deposition and maintenance of ESC identity.
RESUMO
OBJECTIVE: Rheumatoid arthritis (RA) has been associated with inhaled pollutants in several studies, and it is a disease of chronic inflammation. The association between air pollution and the risk of RA remains unclear. Therefore, we conducted this nationwide, retrospective, sex-stratification study to evaluate this association. METHODS: We collected data from the Longitudinal Health Insurance Database (LHID), maintained by the Taiwan Bureau of National Health Insurance, and the Taiwan Air Quality-Monitoring Database (TAQMD), released by the Taiwan Environmental Protection Agency. The TAQMD provides the daily concentrations of particulate matter with the aerodynamic diameter <2.5µm (PM2.5) and nitrogen dioxide (NO2) from 74 ambient air quality-monitoring stations distributed all over Taiwan during 1998-2010. The LHID and TAQMD were linked according to the residential areas of insurants and the areas where the air quality-monitoring stations were located. A residential area was defined according to the location of the clinic and hospital that treated acute upper respiratory tract infections. The yearly average air pollutant concentrations were categorized into 4 levels based on quartiles. We evaluated the risk of RA in residents exposed to 4 levels of PM2.5 and NO2 concentrations. RESULTS: We detected an increased risk of RA in participants exposed to PM2.5 and NO2. Among four quartiles of NO2 concentration, namely Q1, Q2, Q3, and Q4, the adjusted hazard ratios (aHRs) in Q2, Q3, and Q4 compared with that in Q1 were 1.07 (95% confidence interval [CI]=0.76-1.50), 1.63 (95% CI=1.16-2.31),and 1.49 (95% CI=1.05-2.12), respectively. Regarding the PM2.5 concentrations, the aHRs after exposure to the Q2, Q3, and Q4 levels were 1.22 (95% CI=0.85-1.74), 1.15 (95% CI=0.82-1.62), and 0.79 (95% CI=0.53-1.16), respectively. CONCLUSION: The results of this nationwide study suggest an increased risk of RA in residents exposed to NO2.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Artrite Reumatoide/epidemiologia , Dióxido de Nitrogênio/efeitos adversos , Material Particulado/efeitos adversos , Adolescente , Adulto , Artrite Reumatoide/induzido quimicamente , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Taiwan/epidemiologia , Adulto JovemRESUMO
The purpose of this study was to evaluate the effects of exercise training on cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways in ovariectomized rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from three groups of Sprague-Dawley rats, which were divided into a sham-operated group, a bilaterally ovariectomized group (OVX), and a bilaterally ovariectomized group that underwent treadmill running exercise for 60 min/day, 5 sessions/wk, for 10 wk (OVX-EX). The abnormal myocardial architecture, cardiac trichome-stained fibrosis and cardiac TUNEL-positive apoptotic cells in ovariectomized rats improved after exercise training. The protein levels of tumor necrosis factor-α, tumor necrosis factor receptor 1, Fas ligand, Fas receptors, Fas-associated death domain, activated caspase-8 and activated caspase-3 (Fas receptor-dependent apoptotic pathways), as well as t-Bid, Bad, Bak, Bax, cytosolic cytochrome c, activated caspase-9, and activated caspase-3 (mitochondria-dependent apoptotic pathways) were decreased in the OVX-EX group compared with the OVX group. Exercise training suppressed ovariectomy-induced cardiac Fas receptor-dependent and mitochondria-dependent apoptotic pathways in ovariectomized rat models. These findings might indicate a new therapeutic effect for exercise training to prevent cardiac apoptosis in menopausal or bilaterally oophorectomized women.
Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Apoptose/imunologia , Isquemia Miocárdica/imunologia , Miocárdio/imunologia , Ovariectomia/efeitos adversos , Condicionamento Físico Animal/métodos , Animais , Feminino , Mitocôndrias Cardíacas/imunologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
OBJECTIVE: We determine the association between dementia and the subsequent peptic ulcer disease (PUD). METHODS: We identified patients with diagnosed dementia in the Taiwan National Health Insurance Research Database. A comparison cohort without dementia was frequency-matched by age, sex, and comorbidities, and the occurrence of PUD was evaluated in both cohorts. RESULTS: The dementia and control cohort consisted of 6014 patients with dementia and 17 830 frequency-matched patients without dementia, respectively. The incidence of PUD (hazard ratio, 1.27; 95% confidence interval, 1.18-1.37; P < .001) was higher among patients with dementia. Cox models showed that being female, diabetes mellitus, chronic kidney disease, coronary artery disease, and chronic obstructive pulmonary disease were independent risk factors for PUD in patients with dementia. CONCLUSION: Dementia might increase the risk of developing PUD.
Assuntos
Demência/epidemiologia , Úlcera Péptica/epidemiologia , Idoso , Doença Crônica , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Taiwan/epidemiologiaRESUMO
Acquired sensory hearing loss (SHL) is suggested to be associated with depression. However, some studies have reported conflicting results. Our study investigated the relationship between the prevalence of SHL and the incidence of depression over 12 years of follow-up by using data from the Taiwan National Health Insurance Research Database (NHIRD). We sought to determine the association between SHL and subsequent development of depression and discuss the pathophysiological mechanism underlying the association.Patients with SHL were identified from the NHIRD (SHL cohort). A non-SHL cohort, comprising patients without SHL frequency-matched with the SHL patients according to age group, sex, and the year of diagnosis of SHL at the ratio of 1:4, was constructed, and the incidence of depression was evaluated in both cohorts. A multivariable model was adjusted for age, sex, and comorbidity.The SHL cohort and non-SHL cohort comprised 5043 patients with SHL and 20,172 patients without SHL, respectively. The incidences density rates were 9.50 and 4.78 per 1000 person-years in the SHL cohort and non-SHL cohort, respectively. After adjustment for age, sex, and comorbidities, the risk of depression was higher in the SHL cohort than in the non-SHL cohort (hazard ratioâ=â1.73, 95% confidence intervalâ=â1.49-2.00).Acquired SHL may increase the risk of subsequent depression. The results demonstrated that SHL was an independent risk factor regardless of sex, age, and comorbidities. Moreover, a strong association between hearing loss and subsequent depression among Taiwanese adults of all ages, particularly those aged ≤49 and >65 years and without using steroids for the treatment of SHL was observed. Prospective clinical and biomedical studies on the relationship between hearing loss and depression are warranted for determining the etiopathology.