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1.
Int J Occup Saf Ergon ; 29(4): 1345-1357, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36128788

RESUMO

Miners' unsafe behavior has always been a key issue in coal mine safety management. Numerous studies have shown that leadership is an important factor influencing miners' unsafe behavior. A cross-level structural model was constructed based on social cognitive theory, using psychological safety and safety climate as intermediary variables, to analyze the effect of empowering leadership on miners' unsafe behavior. Data were gathered from 272 coal miners on 59 working teams. Multilevel regression analysis and the Monte Carlo method were employed to analyze the influence of the empowering leadership on miners' unsafe behavior. The results showed that empowering leadership was negatively related to miners' unsafe behavior. Psychological safety and safety climate mediated the relationship between empowering leadership and miners' unsafe behavior, and also jointly mediated in the chain. These findings enrich existing research results on miners' unsafe behavior and provide a beneficial enlightenment to coal mine safety management.


Assuntos
Minas de Carvão , Mineradores , Humanos , Liderança , Mineradores/psicologia , Carvão Mineral , Poder Psicológico
2.
Hum Mol Genet ; 23(23): 6223-34, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24990152

RESUMO

Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3. Despite several studies, the mechanism of CCM lesion onset remains unclear. Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion formation in the retina in order to provide insight into potential mechanisms. We demonstrate that lesions develop in a stereotypic location and pattern, preceded by endothelial hypersprouting as confirmed in a zebrafish model of disease. The vascular defects seen with loss of Ccm1 suggest a defect in endothelial flow response. Taken together, these results suggest new mechanisms of early CCM disease pathogenesis and provide a framework for further study.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Retina/patologia , Animais , Animais Geneticamente Modificados , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Humanos , Proteína KRIT1 , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Peixe-Zebra
3.
EBioMedicine ; 1(2-3): 156-66, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26137522

RESUMO

Lung cancer is a commonly diagnosed cancer. In this era of personalized medicine, genetic predictive models are becoming increasingly important. However, many current predictive models fail verification tests due to small sample sizes and institutional biases. We collected 17 gene expression datasets from public databases to generate our largest training and testing cohorts. After successfully eliminating institutional variations and merging multiple datasets, we generated a training cohort of 1073 and a testing cohort of 659. Using Siggenes, univariate and multivariate analyses, we identified seven gene signatures, and combined them with the clinical parameter age and stage to design the lung cancer prognostic index (LCPI). Using LCPI, we could differentiate lung cancer patients into three risk groups and predict patient survival probabilities at 10 and 15 year post-surgical resection. We extensively verified the predictive ability of LCPI for overall and recurrence free survival using 6 other datasets from five different countries.

4.
Am J Physiol Heart Circ Physiol ; 305(8): H1213-21, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23893162

RESUMO

To determine the roles of the individual S4 segments in domains I and II to activation and inactivation kinetics of sodium current (INa) in NaV1.5, we used a tethered biotin and avidin approach after a site-directed cysteine substitution was made in the second outermost Arg in each S4 (DI-R2C and DII-R2C). We first determined the fraction of gating charge contributed by the individual S4's to maximal gating current (Qmax), and found that the outermost Arg residue in each S4 contributed ∼19% to Qmax with minimal contributions by other arginines. Stabilization of the S4's in DI-R2C and DII-R2C was confirmed by measuring the expected reduction in Qmax. In DI-R2C, stabilization resulted in a decrease in peak INa of ∼45%, while its peak current-voltage (I-V) and voltage-dependent Na channel availability (SSI) curves were nearly unchanged from wild type (WT). In contrast, stabilization of the DII-R2C enhanced activation with a negative shift in the peak I-V relationship by -7 mV and a larger -17 mV shift in the voltage-dependent SSI curve. Furthermore, its INa decay time constants and time-to-peak INa became more rapid than WT. An explanation for these results is that the depolarized conformation of DII-S4, but not DI-S4, affects the receptor for the inactivation particle formed by the interdomain linker between DIII and IV. In addition, the leftward shifts of both activation and inactivation and the decrease in Gmax after stabilization of the DII-S4 support previous studies that showed ß-scorpion toxins trap the voltage sensor of DII in an activated conformation.


Assuntos
Potenciais da Membrana/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/fisiologia , Estrutura Terciária de Proteína/fisiologia , Arginina , Humanos , Técnicas de Patch-Clamp
5.
Cancer Cell ; 23(1): 48-62, 2013 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-23328480

RESUMO

Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Overexpressing NEK2 in cancer cells resulted in enhanced CIN, cell proliferation and drug resistance, while targeting NEK2 by NEK2 shRNA overcame cancer cell drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. Thus, NEK2 represents a strong predictor for drug resistance and poor prognosis in cancer and could be an important target for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Antineoplásicos/metabolismo , Proliferação de Células , Instabilidade Cromossômica/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Quinases Relacionadas a NIMA , Prognóstico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Interferência de RNA
6.
Eur J Haematol ; 89(1): 28-36, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22620863

RESUMO

Identifying the best gene expression pattern associated with low-risk disease in patients with newly diagnosed multiple myeloma (MM) is important to direct clinical treatments. The MM Survival Index14 (MMSI14) was developed from GEP data sets of 22 normal plasma cells (NPC), 5 MM cell lines (MMCL), 44 monoclonal gammopathy of undetermined significance (MGUS), and 351 newly diagnosed MM patients. R/bioconductor and siggenes package were used to obtain heatmap, boxplot and histogram whose results were then analyzed by Kaplan-Meier analysis. Fourteen genes associated with low-risk disease in MM were identified. We validated the disease prognostic power of MMSI14 with an independent data set of other 214 newly diagnosed MM patients and also compared our model with the 70-gene, the 8-subgroup, IFM15, and HMCLs7 models. Survival analysis showed that a low MMSI14 signature was associated with longer survival. Applying MMSI14 to independent data sets, we were able to classify 39% of patients as low-risk, with a survival probability of more than 90% at 60 months. Multiple clinical parameters confirmed significant correlation between low- and high-risk subgroups defined by MMSI14. Comparing previously published models to the same data sets the MMSI14 model retained the best prognostic value. We have developed a new gene model (MMSI14) for defining low-risk, newly diagnosed MM. The multivariate comparative analysis confirmed that MMSI14 is the best available model to predict clinical outcome in MM patients.


Assuntos
Perfilação da Expressão Gênica , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prognóstico , Risco
7.
Pflugers Arch ; 461(1): 91-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20981437

RESUMO

Previous studies have shown that lidocaine and other local anesthetic drugs (LAs) cause use-dependent block of sodium current (I (Na)), i.e., block that increases with membrane depolarization by allosteric coupling between drug binding in the inner pore and the S4s in domains III and IV. MTSET protection experiments have established that LAs stabilize DIIIS4 in an outward, depolarized position. Similar tests have not been reported for the DIVS4, although LAs have been shown to reduce DIV's contribution to total gating charge by about one third and to alter its movement such that it contributes more gating charge at negative potentials around -100 mV compared to non-drug-bound sodium (Na) channels. To investigate whether lidocaine reduces the gating charge of DIVS4 by causing it to adopt either a depolarized position at rest or by restricting its outward movement upon depolarization, we performed MTSET protection experiments on I (Na) of the mutant Na channel, R1628C (R3C-DIV), in the presence and absence of 10 mM lidocaine. The results indicate that lidocaine causes the DIVS4 to assume a more depolarized position, which facilitates its movement upon depolarization leading to the excess gating charge at potentials near -100 mV.


Assuntos
Ativação do Canal Iônico/efeitos dos fármacos , Lidocaína/farmacologia , Canais de Sódio/efeitos dos fármacos , Anestésicos Locais/farmacologia , Arritmias Cardíacas/fisiopatologia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Mesilatos/farmacologia , Estrutura Terciária de Proteína/efeitos dos fármacos , Canais de Sódio/fisiologia
8.
Am J Physiol Heart Circ Physiol ; 288(6): H2666-76, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15665061

RESUMO

Deletion of a phenylalanine at position 1617 (delF1617) in the extracellular linker between segments S3 and S4 in domain IV of the human heart Na(+) channel (hH1a) has been tentatively associated with long QT syndrome type 3 (LQT3). In a mammalian cell expression system, we compared whole cell, gating, and single-channel currents of delF1617 with those of wild-type hH1a. The half points of the peak activation-voltage curve for the two channels were similar, as were the deactivation time constants at hyperpolarized test potentials. However, delF1617 demonstrated a significant negative shift of -7 mV in the half point of the voltage-dependent Na(+) channel availability curve compared with wild type. In addition, both the time course of decay of Na(+) current (I(Na)) and two-pulse development of inactivation of delF1617 were faster at negative test potentials, whereas they tended to be slower at positive potentials compared with wild type. Mean channel open times for delF1617 were shorter at potentials <0 mV, whereas they were longer at potentials >0 mV compared with wild type. Using anthopleurin-A, a site-3 toxin that inhibits movement of segment S4 in domain IV (S4-DIV), we found that gating charge contributed by the S4-DIV in delF1617 was reduced 37% compared with wild type. We conclude that deletion of a single amino acid in the S3-S4 linker of domain IV alters the voltage dependence of fast inactivation via a reduction in the gating charge contributed by S4-DIV and can cause either a gain or loss of I(Na), depending on membrane potential.


Assuntos
Deleção de Sequência , Canais de Sódio/fisiologia , Sequência de Aminoácidos , Humanos , Ativação do Canal Iônico , Cinética , Potenciais da Membrana/fisiologia , Dados de Sequência Molecular , Canal de Sódio Disparado por Voltagem NAV1.5 , Valores de Referência , Canais de Sódio/genética
9.
Am J Physiol Heart Circ Physiol ; 283(3): H966-75, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12181125

RESUMO

DeltaKPQ, a three amino acid [lysine (K), proline (P), glutamine (Q)] deletion mutation of the human cardiac Na channel (hH1), which is one cause of long QT syndrome (LQT3), has impaired inactivation resulting in a late sodium current. To better understand inactivation in DeltaKPQ, we applied a site-3 toxin anthopleurin A, which has been shown to inhibit inactivation from the open state with little or no effect on inactivation from the closed state(s) in wild-type hH1. In contrast to the effect of site-3 toxins on wild-type hH1, inactivation from closed state(s) in toxin-modified DeltaKPQ demonstrated a large negative shift in the Na channel availability curve of nearly -14 mV. Recovery from inactivation showed that toxin-modified DeltaKPQ channels recovered slightly faster than those in control, whereas development of inactivation at potentials negative to -80 mV showed that inactivation developed much more rapidly in toxin-modified DeltaKPQ channels compared with control. An explanation for our results is that closed-state inactivation in toxin-modified DeltaKPQ is enhanced by the mutated inactivation lid being positioned "closer" to its receptor resulting in an increased rate of association between the inactivation lid and its receptor.


Assuntos
Ativação do Canal Iônico/fisiologia , Síndrome do QT Longo/fisiopatologia , Canais de Sódio/genética , Canais de Sódio/metabolismo , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Linhagem Celular Transformada , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Ativação do Canal Iônico/efeitos dos fármacos , Rim/citologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Mutação/fisiologia , Técnicas de Patch-Clamp , Peptídeos/metabolismo , Peptídeos/farmacologia
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