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1.
Front Public Health ; 11: 1142161, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37719739

RESUMO

Background: Pneumoconiosis is the most dangerous occupational disease in China. According to unofficial records, nearly million migrant workers were affected by pneumoconiosis in 2011, with the number increasing annually. Among them, a large number of migrant workers suffering from pneumoconiosis were not medically diagnosed. Therefore, fundamental questions remain unanswered: what is the background of workers who receive a diagnosis of pneumoconiosis, and how does pneumoconiosis affect their future and well-being? Methods: In this study, we identified and surveyed 1,134 workers with pneumoconiosis in seven selected regions in China with substantially high incidences of pneumoconiosis by using a combination of cluster sampling, convenience sampling, and snowball sampling. We used demographic, medical, and rehabilitation conditions and welfare questionnaires to collect the data. Results: The findings highlighted the socioeconomic status of patients with pneumoconiosis. The majority of workers with pneumoconiosis were adult men who had received no higher education, who lived in rural households, and who were employed in mining or manufacturing industries. Among these workers, 52.8% had been exposed to dust at work for more than 10 years, and 53.1% received a diagnosis of stage II or III pneumoconiosis. More than half of the workers (569 workers, 50.2%) did not receive comprehensive, routine treatment; 33.4% (379 workers) visited a doctor when they experienced physical discomfort, and 6.6% (75 workers) never received treatment. Only 156 workers (13.8%) received rehabilitation services, whereas 978 workers (86.2%) never did. The study results also revealed the severe financial difficulties faced by patients with pneumoconiosis. Only 208 workers (18.3%) had access to work-related injury insurance, with the cost of pneumoconiosis treatment being a substantial burden for 668 workers (60.6%). Conclusion: In this study, we explored the existing health and welfare problems faced by workers with pneumoconiosis in China and identified the social injustice and health disparities that these workers experience. We also clarified the primary challenges in implementing safety, health, and welfare policies for these workers and those who are exposed to high-risk environments, such as those working in mining.


Assuntos
Seguro , Doenças Profissionais , Pneumoconiose , Adulto , Masculino , Humanos , Pneumoconiose/epidemiologia , China/epidemiologia , Nível de Saúde
2.
Viruses ; 14(5)2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35632656

RESUMO

Coronavirus Disease 2019 (COVID-19), caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has highlighted the need for the rapid generation of efficient vaccines for emerging disease. Virus-like particles, VLPs, are an established vaccine technology that produces virus-like mimics, based on expression of the structural proteins of a target virus. SARS-CoV-2 is a coronavirus where the basis of VLP formation has been shown to be the co-expression of the spike, membrane and envelope structural proteins. Here we describe the generation of SARS-CoV-2 VLPs by the co-expression of the salient structural proteins in insect cells using the established baculovirus expression system. VLPs were heterologous ~100 nm diameter enveloped particles with a distinct fringe that reacted strongly with SARS-CoV-2 convalescent sera. In a Syrian hamster challenge model, non-adjuvanted VLPs induced neutralizing antibodies to the VLP-associated Wuhan S protein and reduced virus shedding and protected against disease associated weight loss following a virulent challenge with SARS-CoV-2 (B.1.1.7 variant). Immunized animals showed reduced lung pathology and lower challenge virus replication than the non-immunized controls. Our data suggest SARS-CoV-2 VLPs offer an efficient vaccine that mitigates against virus load and prevents severe disease.


Assuntos
Baculoviridae , COVID-19 , Animais , Baculoviridae/genética , COVID-19/prevenção & controle , COVID-19/terapia , Cricetinae , Humanos , Imunização Passiva , SARS-CoV-2/genética , Soroterapia para COVID-19
3.
Eur J Protistol ; 82: 125859, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35066346

RESUMO

The morphology and infraciliature of two soil hypotrichous ciliates, Heterourosomoida lanceolata (Shibuya, 1930) Singh and Kamra, 2015 and Gastrostylides dorsicirratus (Foissner, 1982) Foissner, 2016, were investigated using live observation and protargol staining. The Chinese population of H. lanceolata differs slightly from other populations in the body size in vivo, the relative length of the adoral zone, the number of right and left marginal cirri, the total number of dorsal bristles, and the number of micronuclei. The Chinese population of G. dorsicirratus corresponds well with Austrian and Indian populations. We also document the morphogenetic processes during binary fission of G. dorsicirratus, including the formation of the frontoventral-transverse cirral anlagen in a primary pattern. In addition, phylogenetic analyses based on SSU rDNA sequence data reveal that the two populations of G. dorsicirratus for which data are available cluster together with full support and form a clade with Heterourosomoida sinica and two populations of H. lanceolata.


Assuntos
Cilióforos , China , Cilióforos/genética , DNA Ribossômico , Morfogênese , Filogenia , Solo
4.
J Virol ; 96(1): e0167721, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-34669428

RESUMO

Bluetongue virus (BTV), a member of the Orbivirus genus, is transmitted by biting midges (gnats, Culicoides sp.) and is one of the most widespread animal pathogens, causing serious outbreaks in domestic animals, particularly in sheep, with high economic impact. The non-enveloped BTV particle is a double-capsid structure of seven proteins and a genome of 10 double-stranded RNA segments. Although the outermost spike-like VP2 acts as the attachment protein during BTV entry, no specific host receptor has been identified for BTV. Recent high-resolution cryo-electron (cryoEM) structures and biological data have suggested that VP2 may interact with sialic acids (SAs). To confirm this, we have generated protein-based nanoparticles displaying multivalent VP2 and used them to probe glycan arrays. The data show that VP2 binds α2,3-linked SA with high affinity but also binds α2,6-linked SA. Further, Maackia amurensis lectin II (MAL II) and Sambucus nigra lectin (SNA), which specifically bind α2,3-linked and α2,6-linked SAs, respectively, inhibited BTV infection and virus growth in susceptible sheep cells while SNA alone inhibited virus growth in Culicoides-derived cells. A combination of hydrogen deuterium exchange mass spectrometry and site-directed mutagenesis allowed the identification of the specific SA binding residues of VP2. This study provides direct evidence that sialic acids act as key receptor for BTV and that the outer capsid protein VP2 specifically binds SA during BTV entry in both mammalian and insect cells. IMPORTANCE To date no receptor has been assigned for non-enveloped bluetongue virus. To determine if the outermost spike-like VP2 protein is responsible for host cell attachment via interaction with sialic acids, we first generated a protein-based VP2-nanoparticle, for the multivalent presentation of recombinant VP2 protein. Using nanoparticles displaying VP2 to probe a glycan array, we identified that VP2 binds both α2,3-linked and α2,6-linked sialic acids. Lectin inhibitors targeting both linkages of sialic acids showed strong inhibition to BTV infection and progeny virus production in mammalian cells; however the inhibition was only seen with the lectin targeting α2,6-linked sialic acid in insect vector cells. In addition, we identified the VP2 sialic acid binding sites in the exposed tip domain. Our data provides direct evidence that sialic acids act as key receptors for BTV attachment and entry in to both mammalian and insect cells.


Assuntos
Sítios de Ligação , Vírus Bluetongue/fisiologia , Bluetongue/virologia , Proteínas do Capsídeo/metabolismo , Internalização do Vírus , Sequência de Aminoácidos , Animais , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Interações Hospedeiro-Patógeno , Lectinas/metabolismo , Espectrometria de Massas , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptores Virais/química , Receptores Virais/metabolismo , Ácidos Siálicos/metabolismo
5.
Nat Microbiol ; 6(11): 1424-1432, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34702979

RESUMO

Bluetongue virus (BTV) is a non-enveloped virus and causes substantial morbidity and mortality in ruminants such as sheep. Fashioning a receptor-binding protein (VP2) and a membrane penetration protein (VP5) on the surface, BTV releases its genome-containing core (VP3 and VP7) into the host cell cytosol after perforation of the endosomal membrane. Unlike enveloped ones, the entry mechanisms of non-enveloped viruses into host cells remain poorly understood. Here we applied single-particle cryo-electron microscopy, cryo-electron tomography and structure-guided functional assays to characterize intermediate states of BTV cell entry in endosomes. Four structures of BTV at the resolution range of 3.4-3.9 Å show the different stages of structural rearrangement of capsid proteins on exposure to low pH, including conformational changes of VP5, stepwise detachment of VP2 and a small shift of VP7. In detail, sensing of the low-pH condition by the VP5 anchor domain triggers three major VP5 actions: projecting the hidden dagger domain, converting a surface loop to a protonated ß-hairpin that anchors VP5 to the core and stepwise refolding of the unfurling domains into a six-helix stalk. Cryo-electron tomography structures of BTV interacting with liposomes show a length decrease of the VP5 stalk from 19.5 to 15.5 nm after its insertion into the membrane. Our structures, functional assays and structure-guided mutagenesis experiments combined indicate that this stalk, along with dagger domain and the WHXL motif, creates a single pore through the endosomal membrane that enables the viral core to enter the cytosol. Our study unveils the detailed mechanisms of BTV membrane penetration and showcases general methods to study cell entry of other non-enveloped viruses.


Assuntos
Vírus Bluetongue/metabolismo , Bluetongue/virologia , Proteínas do Capsídeo/metabolismo , Endossomos/virologia , Animais , Vírus Bluetongue/química , Vírus Bluetongue/genética , Vírus Bluetongue/ultraestrutura , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Microscopia Crioeletrônica , Endossomos/química , Concentração de Íons de Hidrogênio , Modelos Moleculares , Ovinos , Doenças dos Ovinos/virologia , Internalização do Vírus
6.
Int J Disaster Risk Reduct ; 64: 102516, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34426781

RESUMO

A review of the disaster literature indicates that emergency responses to pandemics are often understudied; the current COVID-19 crisis provides an important opportunity to improve awareness and understanding about this and other contagious and disruptive diseases. With this in mind, this study examines Taiwan's response to COVID-19 because it was successful in spite of a high probability of contagion. The paper first explores the assertion that cognition, communication, collaboration, and control are vital for effective disaster response; it then indicates the need to consider two additional Cs: confidence (trust of government's competency) and coproduction (public participation in disaster transmission prevention). The paper also conducts a qualitative descriptive study of the Taiwan government's response timeline with examples of each of these concepts in action. To further illustrate the need for the two additional Cs, survey data illustrate how public confidence serves as a pivot between government's COVID-19 response and citizen coproduction in COVID-19 transmission prevention.

7.
Materials (Basel) ; 14(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34300919

RESUMO

In this experiment, a series of MnCoGe1-xLax (x = 0, 0.01, 0.03) alloy samples were prepared using a vacuum arc melting method. The crystal structure and magnetic properties of alloys were investigated using X-ray diffraction (XRD), Rietveld method, physical property measurement system (PPMS), and vibrating sample magnetometer (VSM) analyses. The results show that all samples were of high-temperature Ni2In-type phases, belonging to space group P63/mmc (194) after 1373 K annealing. The results of Rietveld refinement revealed that the lattice constant and the volume of MnCoGe1-xLax increased along with the values of La constants. The magnetic measurement results show that the Curie temperatures (TC) of the MnCoGe1-xLax series alloys were 294, 281, and 278 K, respectively. The maximum magnetic entropy changes at 1.5T were 1.64, 1.53, and 1.56 J·kg-1·K-1, respectively. The respective refrigeration capacities (RC) were 60.68, 59.28, and 57.72J·kg-1, with a slight decrease along the series. The experimental results show that the doping of La results in decreased TC, basically unchanged magnetic entropy, and slightly decreased RC.

8.
J Emerg Manag ; 20(7): 57-69, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35412644

RESUMO

During the COVID-19 pandemic, some nonprofit organizations (NPOs) have been struggling to maintain their operations, while others are able to coordinate with partners to provide programs and services locally and globally. This study explores how NPOs are able to survive and actively engage in local and global COVID-19 responses by investigating the organizational capacities of the Tzu Chi Foundation, a Taiwan-based international NPO. This study employs interview data and secondary data from a variety of sources to answer the research questions. Through this case study, we find that Tzu Chi Foundation's capacity to coordinate local and global COVID-19 issues quickly, broadly, and effectively can be attributed to three main factors: (1) clear mission and charismatic leadership, (2) rich experience of disaster relief and recovery strategies, and (3) committed and active volunteers. Moreover, we find that financial management capacity and adaptive capacity are two crucial kinds of capacity for enabling the Tzu Chi Foundation to survive and continuously engage in emergency responses during the pandemic. We conclude with implications for future nonprofit capacity and emergency management research.


Assuntos
COVID-19 , Desastres , COVID-19/epidemiologia , Humanos , Organizações sem Fins Lucrativos , Pandemias , Taiwan
9.
Brain Imaging Behav ; 14(4): 981-997, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31041662

RESUMO

Studies using diffusion tensor imaging (DTI) have documented alterations in the attention and executive system in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). While abnormalities in the frontal lobe have also been reported, the associated white matter fiber bundles have not been investigated comprehensively due to the complexity in tracing them through fiber crossings. Furthermore, most studies have used a non-specific DTI model to understand white matter abnormalities. We present results from a first study that uses a multi-shell diffusion MRI (dMRI) data set coupled with an advanced multi-fiber tractography algorithm to probe microstructural measures related to axonal/cellular density and volume of fronto-striato-thalamic pathways in children with ADHD (N = 30) and healthy controls (N = 28). Head motion was firstly examined as a priority in order to assure that no group difference existed. We investigated 45 different white matter fiber bundles in the brain. After correcting for multiple comparisons, we found lower axonal/cellular packing density and volume in ADHD children in 8 of the 45 fiber bundles, primarily in the right hemisphere as follows: 1) Superior longitudinal fasciculus-II (SLF-II) (right), 2) Thalamus to precentral gyrus (right), 3) Thalamus to superior-frontal gyrus (right), 4) Caudate to medial orbitofrontal gyrus (right), 5) Caudate to precentral gyrus (right), 6) Thalamus to paracentral gyrus (left), 7) Caudate to caudal middlefrontal gyrus (left), and 8) Cingulum (bilateral). Our results demonstrate reduced axonal/cellular density and volume in certain frontal lobe white matter fiber tracts, which sub-serve the attention function and executive control systems. Further, our work shows specific microstructural abnormalities in the striato-thalamo-cortical connections, which have not been previously reported in children with ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Substância Branca , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Criança , Imagem de Tensor de Difusão , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
10.
ISA Trans ; 99: 479-487, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31515089

RESUMO

Free lime (f-CaO) content is a crucial quality parameter for cement clinkers in rotary cement kiln. Due to lack of hardware sensors, f-CaO content in cement clinker is mostly obtained by offline laboratory measurement, making timely control rather difficult and even impossible. In this work, a soft sensor approach named as support vector machine ensemble (ESVM) model is proposed to estimate f-CaO content. The process data employed to train and test the model were collected from a cement plant in China, covering a time span of about 30 days. The raw data were preprocessed by filters and time-series matching. The processed data were then clustered by fuzzy c-means clustering algorithm to capture process features at different operating conditions. For each individual cluster, a base SVM regressor was trained to estimate f-CaO content. Finally, an ensemble model consisting of four base SVM regressors was established to estimate f-CaO content at multifarious process conditions. The effectiveness of the proposed ESVM model was investigated by comparing it with manual measurements and other models available in literature. The results demonstrate that the proposed ESVM model achieves improvements in model accuracy as well as generalization capability. The proposed ESVM model has a broad application space in cement production process for automatic monitoring of f-CaO content.

11.
Eur J Protistol ; 72: 125646, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785489

RESUMO

A new urostylid ciliate, Anteholosticha songi nov. spec., isolated from forest soil in Tibet, and an American population of Holosticha pullaster (Müller, 1773) Foissner et al., 1991, isolated from a freshwater pond in the USA, are investigated in terms of their morphology, ontogenesis, and molecular biology. Anteholosticha songi nov. spec. is characterized by a slender to ellipsoidal body measuring 160-205 × 40-55 µm in vivo; rod-shaped yellowish cortical granules arranged in irregular short rows; four dorsal kineties; adoral zone consisting of 35-40 membranelles; three frontal, one buccal, one parabuccal, two frontoterminal, two pretransverse, and four to six transverse cirri and 14-25 midventral pairs; 12-22 ellipsoidal macronuclear nodules longitudinally arranged in pairs left of cell mid-line. Supplemental information on morphogenesis in Holosticha pullaster is also presented. The phylogenetic relationship of Anteholosticha and Holosticha inferred from SSU rDNA sequence data are concordant with previous studies and showing that Holosticha is monophyletic whereas Anteholosticha is polyphyletic and should be split into two or more genera.


Assuntos
Hypotrichida/classificação , Filogenia , Hypotrichida/citologia , Hypotrichida/genética , Lagoas/parasitologia , RNA Ribossômico 18S/genética , Especificidade da Espécie , Estados Unidos
12.
Waste Manag ; 91: 99-107, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31203948

RESUMO

Citizen engagement in waste management and recycling programs is crucial in achieving environmental sustainability. Existing studies have explored the determinants of waste management and recycling behavior as well as the adoption of selected waste management and recycling programs at both the individual and organizational levels. However, existing research has not explored, from a civic engagement perspective, why individuals who possess selected waste management and recycling tools fail to use them. Through individual level analysis, this study examines the reasons why residents fail to use their green curbside composting carts. Results indicate that subjective time pressure explains why individuals do not use their composting carts. Additionally, age and household size have different effects on the failure to use green curbside composting carts.


Assuntos
Compostagem , Eliminação de Resíduos , Gerenciamento de Resíduos , Humanos , Reciclagem , Rotação , Solo
13.
J Exp Clin Cancer Res ; 38(1): 133, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898167

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive form of astrocytoma among adult brain tumors. Multiple studies have shown that long non-coding RNAs (lncRNAs) play important roles in acting as molecular sponge for competing with microRNAs (miRNAs) to regulate downstream molecules in tumor progression. We previously reported that miR155 host gene (miR155HG), an lncRNA, and its derivative miR-155 promote epithelial-to-mesenchymal transition in glioma. However, the other biological functions and mechanisms of miR155HG sponging miRNAs have been unknown. Considering ANXA2 has been generally accepted as oncogene overexpressed in a vast of cancers correlated with tumorigenesis, which might be the target molecule of miR155HG sponging miRNA via bioinformatics analysis. We designed this study to explore the interaction of miR155HG and ANXA2 to reveal the malignancy of them in GBM development. METHODS: The expression of miR155HG was analyzed in three independent databases and clinical GBM specimens. Bioinformatics analysis was performed to assess the potential tumor-related functions of miR155HG. The interaction of miR155HG and miR-185 and the inhibition of ANXA2 by miR-185 were analyzed by luciferase reporter experiments, and biological effects in GBM were explored by colony formation assays, EDU cell proliferation assays, flow cytometric analysis and intracranial GBM mouse model. Changes in protein expression were analyzed using western blot. We examined the regulatory mechanism of ANXA2 on miR155HG in GBM by gene expression profiling analysis, double immunofluorescence staining, chromatin immunoprecipitation and luciferase reporter assays. RESULTS: We found that miR155HG was upregulated in GBM tissues and cell lines. Bioinformatic analyses of three GBM databases showed that miR155HG expression levels were closely associated with genes involved in cell proliferation and apoptosis. Knocking down miR155HG suppressed GBM cell proliferation in vitro, induced a G1/S-phase cell cycle arrest, and increased apoptosis. We also found that miR155HG functions as a competing endogenous RNA for miR-185. Moreover, miR-185 directly targets and inhibits ANXA2, which exhibits oncogenic functions in GBM. We also found that ANXA2 promoted miR155HG expression via STAT3 phosphorylation. CONCLUSION: Our results demonstrated that overexpressed miR155HG in GBM can sponge miR-185 to promote ANXA2 expression, and ANXA2 stimulates miR155HG level through phosphorylated STAT3 binding to the miR155HG promoter. We establish the miR155HG/miR185/ANXA2 loop as a mechanism that underlies the biological functions of miR155HG and ANXA2 in GBM and further suggest this loop may serve as a therapeutic target and/or prognostic biomarker for GBM.


Assuntos
Anexina A2/genética , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Humanos , Camundongos , Transplante de Neoplasias
14.
J Virol ; 93(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30518645

RESUMO

Bluetongue virus (BTV), in the family Reoviridae, is an insect-borne, double-capsid virus causing hemorrhagic disease in livestock around the world. Here, we elucidate how outer capsid proteins VP2 and VP5 coordinate cell entry of BTV. To identify key functional residues, we used atomic-level structural data to guide mutagenesis of VP2 and VP5 and a series of biological and biochemical approaches, including site-directed mutagenesis, reverse genetics-based virus recovery, expression and characterization of individual recombinant mutant proteins, and various in vitro and in vivo assays. We demonstrate the dynamic nature of the conformational change process, revealing that a unique zinc finger (CCCH) in VP2 acts as the major low pH sensor, coordinating VP2 detachment, subsequently allowing VP5 to sense low pH via specific histidine residues at key positions. We show that single substitution of only certain histidine residues has a lethal effect, indicating that the location of histidine in VP5 is critical to inducing changes in VP5 conformation that facilitates membrane penetration. Further, we show that the VP5 anchoring domain alone recapitulates sensing of low pH. Our data reveal a novel, multiconformational process that overcomes entry barriers faced by this multicapsid nonenveloped virus.IMPORTANCE Virus entry into a susceptible cell is the first step of infection and a significant point at which infection can be prevented. To enter effectively, viruses must sense the cellular environment and, when appropriate, initiate a series of changes that eventually jettison the protective shell and deposit virus genes into the cytoplasm. Many viruses sense pH, but how this happens and the events that follow are often poorly understood. Here, we address this question for a large multilayered bluetongue virus. We show key residues in outer capsid proteins, a pH-sensing histidine of a zinc finger within the receptor-binding VP2 protein, and certain histidine residues in the membrane-penetrating VP5 protein that detect cellular pH, leading to irreversible changes and propel the virus through the cell membrane. Our data reveal a novel mechanism of cell entry for a nonenveloped virus and highlight mechanisms which may also be used by other viruses.


Assuntos
Vírus Bluetongue/genética , Vírus Bluetongue/metabolismo , Interações entre Hospedeiro e Microrganismos/fisiologia , Vírus Bluetongue/patogenicidade , Proteínas do Capsídeo/genética , Linhagem Celular , Membrana Celular/metabolismo , Vírus de DNA/genética , Concentração de Íons de Hidrogênio , Ligação Proteica/fisiologia , Reoviridae/genética , Vírion/genética , Internalização do Vírus
15.
Oncogene ; 38(15): 2706-2721, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30542120

RESUMO

Temozolomide was recognized as the first-line therapy for glioblastoma to prolong the survival of patients noticeably, while recent clinical studies found that some patients were not sensitive to temozolomide treatment. The possible mechanisms seemed to be methylguanine-DNA-methyltransferase (MGMT), mismatch repair, PARP, etc. And the abnormal expression of MGMT might be the most direct factor. In this study, we provide evidence that Fstl1 plays a vital role in temozolomide resistance by sequentially regulating DIP2A protein distribution, H3K9 acetylation (H3K9Ac), and MGMT transcription. As a multifunctional protein widely distributed in cells, DIP2A cooperates with the HDAC2-DMAP1 complex to enhance H3K9Ac deacetylation, prevent MGMT transcription, and increase temozolomide sensitivity. Fstl1, a glycoprotein highly expressed in glioblastoma, competitively binds DIP2A to block DIP2A nuclear translocation, so as to hinder DIP2A from binding the HDAC2-DMAP1 complex. The overexpression of Fstl1 promoted the expression of MGMT in association with increased promoter H3K9Ac. Upregulation of Fstl1 enhanced temozolomide resistance, whereas Fstl1 silencing obviously sensitized GBM cells to temozolomide both in vivo and in vitro. Moreover, DIP2A depletion abolished the effects of Fstl1 on MGMT expression and temozolomide resistance. These findings highlight an important role of Fstl1 in the regulation of temozolomide resistance by modulation of DIP2A/MGMT signaling.


Assuntos
Proteínas de Transporte/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Relacionadas à Folistatina/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Proteínas Nucleares/genética , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Acetilação , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Histona Desacetilase 2 , Humanos , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/genética , Transdução de Sinais/genética , Transcrição Gênica/genética , Regulação para Cima/genética
16.
Biochem Biophys Res Commun ; 508(1): 295-301, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502089

RESUMO

Gliomas are the most common primary malignant brain tumor in adults. Although these tumors are aggressive and frequently lethal, there are currently few therapeutic approaches available to prolong patient survival. MicroRNAs play important roles in regulating the expression of genes that control diverse cellular processes. Here, we investigated the expression and function of miR-139-3p in gliomas using clinical specimens, cultured cells, and a mouse xenograft tumor model. We found that miR-139-3p expression is markedly lower in human glioma tissues than in normal brain tissues. We identified melanoma differentiation-associated gene-9 (MDA-9)/syntenin, an adaptor protein implicated in tumor metastasis, as a novel direct target of miR-139-3p and showed that syntenin mRNA and miR-139-3p levels were inversely correlated in clinical specimens (r = -0.6817, P = 0.0002). Overexpression of miR-139-3p in human glioma cell lines inhibited cell proliferation, migration, and invasion, and these effects were rescued by co-transfection with syntenin. Our results indicate that miR-139-3p plays a significant role in controlling behaviors associated with the malignant progression of gliomas, and we identify the miR-139-3p-syntenin axis as a potential therapeutic target for glioma.


Assuntos
Movimento Celular/genética , Glioma/genética , Glioma/terapia , MicroRNAs/genética , Sinteninas/biossíntese , Sinteninas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Glioma/metabolismo , Glioma/patologia , Humanos , Sinteninas/metabolismo
17.
Cancer Lett ; 436: 10-21, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30102952

RESUMO

Chemoresistance blunts the effect of Temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). Whether exosomal transfer of miRNAs derived from TMZ-resistant GBM cells could confer TMZ resistance remains to be determined. qPCR was used to determine miR-151a expression in two TMZ-resistant GBM cell lines. The direct targets of miR-151a were identified by microarray assays, bioinformatics and further RNA chromatin immunoprecipitation (RNA-ChIP) assay. We characterized exosomes from TMZ-resistant cell lines, serum and cerebrospinal fluid (CSF) and determined the effect of exosomes from TMZ-resistant cells on recipient GBM cells. miR-151a loss drove the acquisition of TMZ resistance. Restored miR-151a expression sensitized TMZ-resistant GBM cells via inhibiting XRCC4-mediated DNA repair. TMZ-resistant GBM cells conferred TMZ chemoresistance to recipient TMZ-sensitive cells in an exosomal miR-151a loss-dependent manner. Restoration of exosomal miR-151a from donor TMZ-resistant cells abolished the chemoresistance dissemination that was directed by donor TMZ-resistant cells. CSF-derived exosomes contained miRNA signatures reflective of the underlying chemoresistant status of GBMs in terms of miR-151a expression levels. Exosomal miR-151a is not only essentially a less-invasive 'liquid biopsy' that might predict chemotherapy response, but also represents a promising therapeutic target for therapy-refractory GBMs.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Exossomos/genética , Glioblastoma/tratamento farmacológico , MicroRNAs/genética , Temozolomida/uso terapêutico , Adulto , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/líquido cefalorraquidiano , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise de Sobrevida , Temozolomida/farmacologia
18.
Eur J Protistol ; 65: 1-15, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29787911

RESUMO

A distinct population of Anteholosticha intermedia was isolated from soil in the Great Smoky Mountains of North Carolina, USA, and its morphology, morphogenesis and molecular phylogeny investigated by microscopic observations of live and protargol-prepared specimens and analyses of the sequence of small subunit (SSU) rDNA. Our population closely resembles the populations from Austria and Korea. Members of the genus Anteholosticha have been regarded as ontogenetically diverse, which is confirmed by the present work. The most noteworthy ontogenetic feature of the American population of A. intermedia is that the oral primordium in the proter appears apokinetally at the posterior end of the undulating membranes anlage at the beginning of division and then dedifferentiates midway through morphogenesis. Molecular phylogenetic analyses demonstrate, with high support, that the American population of A. intermedia is clearly distinct from congeners and branches as part of a sister lineage to the Bakuella-Urostyla clade that belongs to the major clade comprising the order Urostylida.


Assuntos
Cilióforos/classificação , Cilióforos/citologia , Filogenia , Microbiologia do Solo , Cilióforos/genética , DNA Ribossômico/genética , North Carolina , Especificidade da Espécie
19.
Oncol Lett ; 15(4): 4404-4410, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29541209

RESUMO

Nuclear factor κB (NF-κB) exhibits an important role in inflammation and tumorigenesis. The key regulatory protein of the pathway, RELB Proto-Oncogene, NF-KB Subunit (relB), is overexpressed and associated with the pathogenesis of a variety of malignant tumors. However, the molecular features and clinical signature of relB expression in gliomas remains to be elucidated. The present study obtained the raw sequencing data of 325 glioma samples of all grades from the Chinese Glioma Genome Atlas (CGGA) database and human glioma cell line (LN229) from the Chinese Academy of Sciences cell bank. Cell proliferation, invasion and wound healing assays were used for functional annotation of relB. Western blot analysis was used for validating the protein expression of relB, matrix metalloproteinase (MMP)-2 and MMP-9 in a further 77 glioma samples. In Diffuse Glioma data, relB expression was associated with glioma grade, demonstrated a mesenchymal subtype preference and cell development association. The downregulation of relB expression inhibited glioma cell migration and invasion by regulating the MMPs in vitro. relB expression was independently associated with grade and prognosis of grade III and grade IV gliomas, suggesting that relB is a novel biomarker with therapeutic potential for predicting prognosis in glioma.

20.
Neuroimage ; 171: 341-354, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29337279

RESUMO

This work presents a suprathreshold fiber cluster (STFC) method that leverages the whole brain fiber geometry to enhance statistical group difference analyses. The proposed method consists of 1) a well-established study-specific data-driven tractography parcellation to obtain white matter tract parcels and 2) a newly proposed nonparametric, permutation-test-based STFC method to identify significant differences between study populations. The basic idea of our method is that a white matter parcel's neighborhood (nearby parcels with similar white matter anatomy) can support the parcel's statistical significance when correcting for multiple comparisons. We propose an adaptive parcel neighborhood strategy to allow suprathreshold fiber cluster formation that is robust to anatomically varying inter-parcel distances. The method is demonstrated by application to a multi-shell diffusion MRI dataset from 59 individuals, including 30 attention deficit hyperactivity disorder patients and 29 healthy controls. Evaluations are conducted using both synthetic and in-vivo data. The results indicate that the STFC method gives greater sensitivity in finding group differences in white matter tract parcels compared to several traditional multiple comparison correction methods.


Assuntos
Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Processamento de Imagem Assistida por Computador/métodos , Substância Branca/diagnóstico por imagem , Humanos
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