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BACKGROUND: To report three cases of autoimmune cerebellar ataxia related to anti-delta/notch-like epidermal growth factor-related receptor (Tr/DNER) antibodies. CASE PRESENTATION: Patients with unknown cerebellar ataxia were screened with autoimmune cerebellar ataxia (ACA)-related antibody panel. The anti-Tr antibody was positive in three female patients in whom the onset ages were 43 years, 35 years and 43 years old. The antibody titres of serum and cerebrospinal fluid were all 1:32. Cerebral ataxia was the most prominent presentation. Mild cerebellar atrophy was found in one of the patients. Immunotherapy was effective in all three patients. CONCLUSION: The Tr antibody is associated with autoimmune ataxia, and it has been suggested that the anti-Tr antibody should be tested in patients with cerebellar ataxia who are negative for routine ACA antibodies. Early immunotherapy may improve patient prognoses.
Assuntos
Ataxia Cerebelar , Humanos , Feminino , Adulto , Autoanticorpos , Imunoterapia , Proteínas do Tecido Nervoso , Receptores de Superfície CelularRESUMO
Recently, the application of LiFePO4 (LFP) batteries in electric vehicles has attracted extensive attention from researchers. This work presents a composite of LFP particles trapped in reduced graphene oxide (rGO) nanosheets obtained through the high-temperature reduction strategy. The obtained LiFePO4/rGO composites indicate spherical morphology and uniform particles. As to the structure mode of the composite, LFP distributes in the interlayer structure of rGO, and the rGO evenly covers the surface of the particles. The LFP/rGO cathodes demonstrate a reversible specific capacity of 165 mA h g-1 and high coulombic efficiency at 0.2 C, excellent rate capacity (up to 10 C), outstanding long-term cycling stability (98%) after 1000 cycles at 5 C. The combined high electron conductivity of the layered rGO coating and uniform LFP particles contribute to the remarkable electrochemical performance of the LFP/rGO composite. The unique LFP/rGO cathode provides a potential application in high-power lithium-ion batteries.
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Fontes de Energia Elétrica , Lítio , Condutividade Elétrica , Eletrodos , ÍonsRESUMO
BACKGROUND: Impaired neurodevelopment of children has become a growing public concern; however, the associations between metals exposure and neurocognitive function have remained largely unknown. OBJECTIVES: We systematically evaluated the associations of multiple metals exposure during pregnancy and childhood on the neurodevelopment of children aged 2-3 years. METHODS: We measured 22 metals in the serum and urine among703 mother-child pairs from the Guangxi Birth Cohort Study. The neurocognitive development of children was assessed by the Gesell Development Diagnosis Scale (GDDS; Chinese version). Multiple linear regression models were used to evaluate the relationship between the metals (selected by elastic net regression) and the outcomes. The Bayesian kernel machine regression (BKMR) was used to evaluate the possible joint effect between the multiple metal mixture and the outcomes. RESULTS: Prenatal aluminum (Al) exposure was negatively associated with the fine motor developmental quotient (DQ) (ß = -1.545, 95%CI: 2.231, -0.859), adaption DQ (ß = -1.182, 95%CI: 1.632, -0.732), language DQ (ß = -1.284, 95% CI: 1.758, -0.809), and social DQ (ß = -1.729, 95% CI: 2.406, -1.052) in the multi-metal model. Prenatal cadmium (Cd) exposure was negatively associated with gross motor DQ (ß = -2.524, 95% CI: 4.060, -0.988), while postpartum Cd exposure was negatively associated with language DQ (ß = -1.678, 95% CI: 3.227, -0.129). In stratified analyses, infants of different sexes had different sensitivities to metal exposure, and neurobehavioral development was more significantly affected by metal exposure in the first and second trimester. BKMR analysis revealed a negative joint effect of the Al, Cd, and selenium (Se) on the language DQ score; postpartum Cd exposure played a major role in this relationship. CONCLUSION: Prenatal exposure to Al, Ba, Cd, molybdenum (Mo), lead (Pb), antimony (Sb), and strontium (Sr), and postpartum exposure to cobalt (Co), Cd, stannum (Sn), iron (Fe), nickel (Ni), and Se are associated with neurological development of infants. The first and second trimester might be the most sensitive period when metal exposure affects neurodevelopment.
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Metais , Teorema de Bayes , Pré-Escolar , China , Estudos de Coortes , Feminino , Humanos , Lactente , Metais/toxicidade , Gravidez , Estudos ProspectivosRESUMO
FGFR3-TACC3 (F3-T3) gene fusions are regarded as a "low-hanging fruit" paradigm for precision therapy in human glioblastoma (GBM). Small molecules designed to target the kinase in FGFR currently serve as one form of potential treatment but cause off-target effects and toxicity. Here, CRISPR-Cas13a, which is known to directly suppress gene expression at the transcriptional level and induce a collateral effect in eukaryotes, was leveraged as a possible precision therapy in cancer cells harboring F3-T3 fusion genes. A library consisting of crRNAs targeting the junction site of F3-T3 was designed, and an in silico simulation scheme was created to select the optimal crRNA candidates. An optimal crRNA, crRNA1, showed efficiency and specificity in inducing the collateral effect in only U87 cells expressing F3-T3 (U87-F3-T3). Expression profiles obtained with microarray analysis were consistent with induction of the collateral effect by the CRISPR-Cas13a system. Tumor cell proliferation and colony formation were decreased in U87-F3-T3 cells expressing the Cas13a-based tool, and tumor growth was suppressed in an orthotopic tumor model in mice. These findings demonstrate that the CRISPR-Cas13a system induces the collateral damage effect in cancer cells and provides a viable strategy for precision tumor therapy based on the customized design of a CRISPR-Cas13a-based tool against F3-T3 fusion genes.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Glioblastoma/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Fusão Oncogênica/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Perfilação da Expressão Gênica , Glioblastoma/patologia , Xenoenxertos , Humanos , Ligação de Hidrogênio , Camundongos , Proteínas Associadas aos Microtúbulos/química , Modelos Moleculares , Conformação de Ácido Nucleico , Proteínas de Fusão Oncogênica/química , Ligação Proteica , Conformação Proteica , RNA Mensageiro/química , RNA Mensageiro/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/químicaRESUMO
Glioblastoma (GBM) is the most common primary central nervous system tumor and has a poor prognosis, with a median survival time of only 14 months from diagnosis. Abnormally expressed long noncoding RNAs (lncRNAs) are important epigenetic regulators of chromatin modification and gene expression regulation in tumors, including GBM. We previously showed that the lncRNA HOTAIR is related to the cell cycle progression and can be used as an independent predictor in GBM. Lysine-specific demethylase 1 (LSD1), binding to 3' domain of HOTAIR, speciï¬cally removes mono- and di-methyl marks from H3 lysine 4 (H3K4) and plays key roles during carcinogenesis. In this study, we combined a HOTAIR-EZH2 disrupting agent and an LSD1 inhibitor, AC1Q3QWB (AQB) and GSK-LSD1, respectively, to block the two functional domains of HOTAIR and potentially provide therapeutic benefit in the treatment of GBM. Using an Agilent Human ceRNA Microarray, we identified tumor suppressor genes upregulated by AQB and GSK-LSD1, followed by Chromatin immunoprecipitation (ChIP) assays to explore the epigenetic mechanisms of genes activation. Microarray analysis showed that AQB and GSK-LSD1 regulate cell cycle processes and induces apoptosis in GBM cell lines. Furthermore, we found that the combination of AQB and GSK-LSD1 showed a powerful effect of inhibiting cell cycle processes by targeting CDKN1A, whereas apoptosis promoting effects of combination therapy were mediated by BBC3 in vitro. ChIP assays revealed that GSK-LSD1 and AQB regulate P21 and PUMA, respectively via upregulating H3K4me2 and downregulating H3K27me3. Combination therapy with AQB and GSK-LSD1 on tumor malignancy in vitro and GBM patient-derived xenograft (PDX) models shows enhanced anti-tumor efficacy and appears to be a promising new strategy for GBM treatment through its effects on epigenetic regulation.
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Benzofuranos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Histona Desmetilases/antagonistas & inibidores , RNA Longo não Codificante/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Neoplasias Encefálicas/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Humanos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Polymerase I and transcript release factor (PTRF)/Cavin1 regulates RNA polymerase I during transcription and plays a critical role in endocytosis. Abnormal expressions of PTRF were detected in multiple cancers according to increasing research. PTRF has been showed to involve in the formation and secretion of exosomes and can be detected in the exosomes, which suggests that PTRF would be a potential biomarker for diagnosis of clear cell renal cell carcinoma (ccRCC) using urine samples. Approximately 50-90% of ccRCC cases suffered abnormal epidermal growth factor receptor (EGFR), which activates a variety of signaling pathways, including the mitogen-activated protein kinase/extracellular signal-regulated kinase and Phosphoinositide 3-Kinase/Akt pathway. According to bioinformatic analysis of gene expression arrays of kidney clear cell carcinoma from The Cancer Genome Atlas, we found SHC1 was significantly overexpressed in high-grade ccRCC and correlated to poor prognosis, and also SHC1 was annotated in extracellular matrix process, which was regulated by EGFR. Further studies showed that the expression of PTRF was regulated by SHC1 through EGFR-Phosphoinositide 3-Kinase/Akt pathway. PTRF was detected in the exosomes isolated from ccRCC patients' urine and ccRCC cancer cells culture medium. It suggested that the abnormal SHC1-increased PTRF, which is detected in exosomes from urine, would be a potential marker for ccRCC diagnose and treatment.
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Carcinoma de Células Renais/genética , Proteínas de Ligação a RNA/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/urina , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Receptores ErbB/genética , Exossomos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Proteínas de Ligação a RNA/urina , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/urinaRESUMO
RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. METHODS AND RESULTS: HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated ≤2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement-a surrogate for fibrosis-were small. CONCLUSIONS: Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537926.
Assuntos
Acetilcisteína/uso terapêutico , Antioxidantes/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Acetilcisteína/farmacologia , Adulto , Idoso , Antioxidantes/farmacologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Conectina/genética , Método Duplo-Cego , Ecocardiografia Doppler , Exoma , Feminino , Fibrose , Coração/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Projetos Piloto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Elevated exposure to manganese (Mn) could induce cardiovascular dysfunction. However, limited research is available on the effects of occupational Mn exposure on myocardial enzymes. We aimed to evaluate the relationships between Mn exposure and myocardial enzyme elevation among Mn-exposed workers. METHODS: Data were from a follow-up investigation of a Mn-exposed workers healthy cohort in 2017. A total of 744 workers were divided into low-exposure and high-exposure groups according to Mn time-weighted average (Mn-TWA) of less than or equal to 0.15 mg/m3 or greater than 0.15 mg/m3 , respectively. Serum levels of myocardial enzymes, including creatine kinase (CK) and creatine kinase-MB (CK-MB), lactic dehydrogenase, α-hydroxybutyrate dehydrogenase, and aspartate transaminase, were assessed, as well as airborne Mn exposure levels. RESULTS: After adjustment for sex, body mass index, seniority, education, current smoking status, current drinking status, and hypertension, Mn-TWA levels were positively associated with the risk of CK elevation (odds ratio [OR] = 1.47 (95% confidence interval [CI]: 1.18-1.83) per interquartile range [IQR] increase), and risk of CK-MB elevation [OR = 1.57 (95% CI: 1.03-2.38) per IQR increase]. In a stratified analysis, Mn-TWA levels were positively correlated with CK elevation in workers of seniority greater than 19 years, male workers, current smokers, and drinkers. CONCLUSION: Our results suggest that occupational exposure to Mn is associated with increased risk of CK and CK-MB elevation. The potential mechanisms of the associations between airborne exposure to Mn and increased risk of these myocardial enzyme elevations warrant further investigation.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Creatina Quinase Forma MB/sangue , Creatina Quinase/sangue , Manganês/efeitos adversos , Metalurgia , Exposição Ocupacional/efeitos adversos , Adulto , Poluentes Ocupacionais do Ar/análise , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Ferro , Masculino , Manganês/análise , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Razão de Chances , Fatores de RiscoRESUMO
Tumor heterogeneity has been one of the most important factors leading to the failure of conventional cancer therapies due to the accumulation of genetically distinct tumor-cell subpopulations during the tumor development process. Due to the diversity of genetic mutations during tumor growth, combining the use of multiple drugs has only achieved limited success in combating heterogeneous tumors. Herein, we report a novel antitumor strategy that effectively addresses tumor heterogeneity by using a CRISPR/Cas9-based nanoRNP carrying a combination of sgRNAs. Such nanoRNP is synthesized from Cas9 ribonucleoprotein, any combinations of required sgRNAs, and a rationally designed responsive polymer that endows nanoRNP with high circulating stability, enhanced tumor accumulation, and the efficient gene editing in targeted tumor cells eventually. By carrying a combination of sgRNAs that targets STAT3 and RUNX1, the nanoRNP exhibited efficient gene expression disruptions on a heterogeneous tumor model with two subsets of cells whose proliferations were sensitive to the reduced expression of STAT3 and RUNX1, respectively, leading to the effective growth inhibition of the heterogeneous tumor. Considering the close relationship between tumor heterogeneity and cancer progression, resistance to therapy, and recurrences, nanoRNP provides a feasible strategy to overcome tumor heterogeneity in the development of more advanced cancer therapy against malignant tumors.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Terapia Genética/métodos , Humanos , Camundongos , Camundongos Nus , Nanomedicina/métodos , Neoplasias/genética , Neoplasias/patologia , Fator de Transcrição STAT3/genéticaRESUMO
Long non-coding RNAs (lncRNAs) have been reported to play important roles in glioma; however, most of them promote glioma progression. We constructed a competing endogenous (ceRNA) network based on the Chinese Glioma Genome Atlas dataset, and lncRNA hect domain and RLD 2 pseudogene 2 (HERC2P2) is the core of this network. Highly connected genes in the ceRNA network classified the glioma patients into three clusters with significantly different survival rates. The expression of HERC2P2 is positively correlated with survival and negatively correlated with clinical grade. Cell colony formation, Transwell and cell scratch tests were performed to evaluate the role of HERC2P2 in glioblastoma growth. Furthermore, we overexpressed HERC2P2 in U87 cells and established a mouse intracranial glioma model to examine the function of HERC2P2 in vivo. In conclusion, we identified a lncRNA with tumor suppressor functions in glioma that could be a potential biomarker for glioma patients.
Assuntos
Biomarcadores Tumorais/genética , Glioma/genética , Prognóstico , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Biologia Computacional , Bases de Dados Factuais , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Genes Supressores de Tumor , Glioma/patologia , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , MicroRNAs/genética , Taxa de SobrevidaRESUMO
RATIONALE: Hypertrophic cardiomyopathy (HCM) is a prototypic single-gene disease caused mainly by mutations in genes encoding sarcomere proteins. Despite the remarkable advances, the causal genes in ≈40% of the HCM cases remain unknown, typically in small families and sporadic cases, wherein cosegregation could not be established. OBJECTIVE: To test the hypothesis that the missing causal genes in HCM is, in part, because of an oligogenic cause, wherein the pathogenic variants do not cosegregate with the phenotype. METHODS AND RESULTS: A clinically affected trio with HCM underwent clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, and whole exome sequencing. Pathogenic variants in the whole exome sequencing data were identified using established algorithms. Family members were genotyped by Sanger sequencing and cosegregation was analyzed. The siblings had a severe course, whereas the mother had a mild course. Variant analysis showed that the trio shared 145 heterozygous pathogenic variants in 139 genes, including 2 in cardiomyopathy genes TTN and ALPK3. The siblings also had the pathogenic variant p.Ala13Thr variant in MYL2, a known gene for HCM. The sibling's father also carried the p.Ala13Thr variant, in whom an unambiguous diagnosis of HCM could not be made because of concomitant severe aortic stenosis. The TTN variant segregated with HCM, except in a 7-year-old boy, who had a normal phenotype. The ALPK3 variant, shared by the affected trio, did not segregate with the phenotype. CONCLUSIONS: We posit that a subset of HCM might be oligogenic caused by multiple pathogenic variants that do not perfectly cosegregate with the phenotype.
Assuntos
Miosinas Cardíacas/economia , Cardiomiopatia Hipertrófica/genética , Conectina/genética , Proteínas Musculares/genética , Cadeias Leves de Miosina/economia , Proteínas Quinases/genética , Adulto , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/diagnóstico , Criança , Exoma , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Proteínas Musculares/metabolismo , Mutação , Cadeias Leves de Miosina/genética , Linhagem , Fenótipo , Proteínas Quinases/metabolismoRESUMO
BACKGROUND: Advances in the nucleic acid sequencing technologies have ushered in the era of genetic-based "precision medicine". Applications of the genetic discoveries to practice of medicine, however, are hindered by phenotypic variability of the genetic variants. The report illustrates extreme pleiotropic phenotypes associated with an established causal mutation for hereditary cardiomyopathy. CASE PRESENTATION: We report a 61-year old white female who presented with syncope and echocardiographic and cardiac magnetic resonance (CMR) imaging findings consistent with the diagnosis of hypertrophic cardiomyopathy (HCM). The electrocardiogram, however, showed a QRS pattern resembling an Epsilon wave, a feature of arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole exome sequencing (mean depth of coverage of exons 178X) analysis did not identify a pathogenic variant in the known HCM genes but identified an established causal mutation for ARVC. The mutation involves a canonical splice accepter site (c.2146-1G > C) in the PKP2 gene, which encodes plakophillin 2. Sanger sequencing confirmed the mutation. PKP2 is the most common causal gene for ARVC but has not been implicated in HCM. Findings on echocardiography and CMR during the course of 4-year follow up showed septal hypertrophy and a hyperdynamic left ventricle, consistent with the diagnosis of HCM. However, neither baseline nor follow up echocardiography and CMR studies showed evidence of ARVC. The right ventricle was normal in size, thickness, and function and there was no evidence of fibro-fatty infiltration in the myocardium. CONCLUSIONS: The patient carries an established pathogenic mutation for ARVC and a subtle finding of ARVC but exhibits the classic phenotype of HCM, a contrasting phenotype to ARVC. The case illustrates the need for detailed phenotypic characterization for patients with hereditary cardiomyopathies as well as the challenges physicians face in applying the genetic discoveries in practicing genetic-based "precision medicine".
Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/diagnóstico por imagem , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Análise Mutacional de DNA , Ecocardiografia , Feminino , Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Linhagem , Fenótipo , Placofilinas/genéticaRESUMO
Biomass-derived porous carbon BPC-700, incorporating micropores and small mesopores, was prepared through pyrolysis of banana peel followed by activation with KOH. A high specific BET surface area (2741â m2 g-1 ), large specific pore volume (1.23â cm3 g-1 ), and well-controlled pore size distribution (0.6-5.0â nm) were obtained and up to 65â wt % sulfur content could be loaded into the pores of the BPC-700 sample. When the resultant C/S composite, BPC-700-S65, was used as the cathode of a Li-S battery, a large initial discharge capacity (ca.â 1200â mAh g-1 ) was obtained, indicating a good sulfur utilization rate. An excellent discharge capacity (590â mAh g-1 ) was also achieved for BPC-700-S65 at the high current rate of 4â C (12.72â mA cm-2 ), showing its extremely high rate capability. A reversible capacity of about 570â mAh g-1 was achieved for BPC-700-S65 after 500 cycles at 1â C (3.18â mA cm-2 ), indicating an outstanding cycling stability.
RESUMO
RATIONALE: A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the ubiquitin-proteasome system (UPS). OBJECTIVE: To determine the pathogenic role of TRIM63 in human hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Sequencing of TRIM63 gene in 302 HCM probands (250 white individuals) and 339 control subjects (262 white individuals) led to identification of 2 missense (p.A48V and p.I130M) and a deletion (p.Q247*) variants exclusively in the HCM probands. These 3 variants were absent in 751 additional control subjects screened by TaqMan assays. Likewise, rare variants were enriched in the white HCM population (11/250, 4.4% versus 3/262, 1.1%, respectively, P=0.024). Expression of the mutant TRIM63 was associated with mislocalization of TRIM63 to sarcomere Z disks, impaired auto-ubiquitination, reduced ubiquitination and UPS-mediated degradation of myosin heavy chain 6, cardiac myosin binding protein C, calcineurin (PPP3CB), and p-MTOR in adult cardiac myocytes. Induced expression of the mutant TRIM63 in the mouse heart was associated with cardiac hypertrophy, activation of the MTOR-S6K and calcineurin pathways, and expression of the hypertrophic markers, which were normalized on turning off expression of the mutant protein. CONCLUSIONS: TRIM63 mutations, identified in patients with HCM, impart loss-of-function effects on E3 ligase activity and are probably causal mutations in HCM. The findings implicate impaired protein degradation in the pathogenesis of HCM.
Assuntos
Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Deleção de Genes , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação de Sentido Incorreto/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Animais , Calcineurina/metabolismo , Cardiomiopatia Hipertrófica/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Dados de Sequência Molecular , Proteínas Musculares/química , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Sarcômeros/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/químicaRESUMO
Aroma is a crucial indicator of hop quality. This study analyzed the differences in aroma compound composition among six hop varieties from three regions: North America, Europe, and Asia. Descriptive analysis and sensomic approaches including gas chromatography-olfactometry/aroma extract dilution analysis, odour activity value calculation and aroma recombination were used for the detailed characterization and comparative analysis of hop aroma. A total of 55 aroma-active compounds were identified. Among them, linalool, geraniol, ß-myrcene, 2-undecanone, and methyl decanoate contributed significantly to hop aroma. Orthogonal partial least squares discriminant analysis revealed that, except for the SAAZ and XinYuan hops with some similarities in their aroma composition, the remaining hops exhibited unique aroma characteristics. A total of 16 compounds, including methyl 5-methylhexanoate and (E)-ß-farnesene, were identified as differentiating aroma compounds in the six hop samples. This study enriches the knowledge on hop flavour with different origins and provides valuable insights into its application.
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Circadian dysregulation involved in the pathophysiology of spinal cord injury (SCI). Modulation of circadian rhythms hold promise for the SCI treatment. Here, we aim to investigated the mechanism of olfactory ensheathing cells (OEC) in alleviating neuroinflammation via modulating clock gene expression in microglia. In this study, SCI rats were randomly divided into OEC group and vehicle group. At 1 day after the surgery, OECs were intravenously transplanted into OEC group SCI rat, while the rats in vehicle group received culture medium. After 7 days post of OEC transplantation, tissues were collected from the brain (prefrontal cortex, hypothalamus, spinal cord) for PCR, western blotting and immunohistochemistry (IHC) assay at zeitgeber time (ZT) 6, ZT 12, ZT 18, and ZT 24. The roles of OEC in modulating REV-ERBα in microglia were studied by experimental inhibition of gene expression and the co-culture experiment. In the vehicle group, IHC showed a significant increase of Iba-1 expression in the cerebral white matter and spinal cord compared with control group (P < 0.0001 for all comparisons). The expression of Iba-1 was significantly decreased (P < 0.0001 for all comparisons). In the OEC group, the expression of PER 1, PER 2, CLOCK, and REV-ERBα was in a rhythmical manner in both spinal cord and brain regions. SCI disrupted their typical rhythms. And OECs transplantation could modulate those dysregulations by upregulating REV-ERBα. In vitro study showed that OECs couldn't reduce the activation of REV-ERBα inhibited microglia. The intravenous transplantation of OECs can mediate cerebral and spinal microglia activation through upregulation REV-ERBα after SCI.
Assuntos
Microglia , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Regulação para Cima , Animais , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/metabolismo , Microglia/metabolismo , Ratos , Doenças Neuroinflamatórias/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Masculino , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismoRESUMO
Among central nervous system-associated malignancies, glioblastoma (GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Fenótipo , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/classificação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/classificação , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Transição Epitelial-Mesenquimal/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
AIMS: To investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair-related genes and the development of chemoresistance in gliomas. METHODS: We conducted a comprehensive analysis of deep-targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I-TASSER for homology modeling. We elucidated the functional changes induced by high-frequency site mutations in these genes and investigated their impact on glioma progression. RESULTS: The analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis. CONCLUSION: The ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.
Assuntos
Proteínas de Ligação a DNA , Glioblastoma , Fatores de Transcrição , Humanos , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Mutação/genética , Proteínas Nucleares/genética , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: Smoking is an independent risk factor for the formation and rupture of intracranial aneurysms (IA). However, the underlying mechanism remains unclear. METHODS: In this study, we performed miRNA sequencing on plasma from 10 smoking patients with IA, 10 non-smoking patients with IA, and 10 healthy controls. The differentially expressed miRNAs (DE miRNAs) between smoking and non-smoking patients with IA were identified. Functional and pathway enrichment analysis is employed to investigate the potential functions of those DE miRNA target genes. The correlations with the clinical parameters were assessed using receiver operating characteristic curve (ROC) analysis. RESULTS: In total, we identified 428 DE miRNAs. Functional enrichment analysis showed the target genes were significantly enriched in biological aspects related to cell characteristics, such as cell cycle, cell differentiation, and cell migration. Pathway analysis showed DE miRNAs mainly enriched in the PI3K-Akt signaling pathway, Focal adhesion, and JAK-STAT signaling pathway. The expressions of miR-574-5p, miR-151a-3p, and miR-652-3p correlated well with aneurysm parameters. The AUC of miR-574-5p, miR-151a-3p, and miR-652-3p were 97%, 92%, and 99%, respectively. CONCLUSION: Our study indicated that smoking significantly altered the plasma miRNA profile in patients with IA. The expression of miR-574-5p, miR-151a-3p, and miR-652-3p correlated with aneurysm parameters, which may play a significant role in the formation and rupture of IA.