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1.
Yonsei Med J ; 61(11): 909-922, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107234

RESUMO

Through this meta-analysis, we sought to examine the prevalence of, risks for, and factors associated with bullying involvement (victimization, perpetration, perpetration-victimization) among students with autism spectrum disorder (ASD). Additionally, we attempted to examine sources of variance in the prevalence and effect sizes of bullying in students with ASD across studies. Systematic database and literature review identified 34 relevant studies (31 for Western countries, three for Eastern countries). Pooled prevalence estimates for victimization, perpetration, and perpetration-victimization in general were 67%, 29%, and 14%, respectively. The risk of victimization in students with ASD was significantly higher than that in typically developing students and students with other disabilities. Further, deficits in social interaction and communication, externalizing symptoms, internalizing symptoms, and integrated inclusive school settings were related to higher victimization, and externalizing symptoms were related to higher perpetration. Finally, moderation analyses revealed significant variations in the pooled prevalences thereof depending on culture, age, school settings, and methodological quality and in the pooled effect sizes according to publication year and methodological quality. Our results highlight needs for bullying intervention for students with ASD, especially those who are younger, are in an inclusive school setting, and have higher social difficulties and externalizing/internalizing symptoms; for intensive research of bullying experiences among students with ASD in Eastern countries; and for efforts to improve the methodological quality of such research.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Bullying/estatística & dados numéricos , Vítimas de Crime/estatística & dados numéricos , Comparação Transcultural , Estudantes/psicologia , Adolescente , Transtorno do Espectro Autista/etnologia , Transtorno do Espectro Autista/psicologia , Bullying/psicologia , Criança , Pré-Escolar , Vítimas de Crime/psicologia , Feminino , Humanos , Relações Interpessoais , Masculino , Prevalência , Estudantes/estatística & dados numéricos , Adulto Jovem
2.
Eur J Clin Microbiol Infect Dis ; 39(10): 1951-1957, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32537677

RESUMO

Staphylococcus aureus is a virulent gram-positive organism, which rarely involves the biliary tract. This study aimed to analyze the clinical characteristics and outcomes of S. aureus bacteremia (SAB) originating from the biliary tract by comparing them with those of catheter-related SAB and biliary Klebsiella pneumoniae bacteremia. A matched case-control study within a prospective observational cohort of patients with SAB was conducted. Biliary SAB was defined as the isolation of S. aureus from blood cultures with symptoms and signs of biliary infection. Biliary SAB patients were matched (1:3) with the control groups: patients with catheter-related SAB and biliary Klebsiella pneumoniae bacteremia. Out of 1818 patients with SAB enrolled in the cohort, 42 (2%) had biliary SAB. Majority of these patients had solid tumors involving the pancreaticobiliary tract or liver, biliary drainage stent, and/or recent broad-spectrum antibiotic exposure. Patients with biliary SAB were more likely to have community-onset SAB, solid tumors, and lower APACHE II score than those with catheter-related SAB. They were less likely to have community-acquired infection and solid tumors and more likely to have lower Charlson comorbidity index and higher APACHE II score as compared with biliary K. pneumoniae bacteremia. The 12-week mortality in the biliary SAB group was higher than those in other control groups (60% vs. 20% and 14%). After adjusting for confounding factors, biliary SAB was independently associated with higher mortality. Biliary SAB is relatively rare. When it is clinically suspected, early aggressive treatment should be considered due to high mortality.

3.
Ann Hematol ; 99(6): 1231-1239, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32382770

RESUMO

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0-2), moderate (3-5), and high risk (6-8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p < 0.005, Harrell's C-index = 0.84). PIV infection can result in substantial mortality in patients with hematologic malignancy if it progresses to LRTI. The immunodeficiency risk score presented here may be useful for distinguishing moderate and high risk groups that might benefit from antiviral therapy.


Assuntos
Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidade , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/mortalidade , Infecções por Paramyxoviridae/diagnóstico , Infecções por Paramyxoviridae/mortalidade , Adulto , Estudos de Coortes , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Infecções por Paramyxoviridae/imunologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
4.
Mol Cells ; 43(3): 304-311, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-31940717

RESUMO

Methionyl-tRNA synthetase (MRS) is essential for translation. MRS mutants reduce global translation, which usually increases lifespan in various genetic models. However, we found that MRS inhibited Drosophila reduced lifespan despite of the reduced protein synthesis. Microarray analysis with MRS inhibited Drosophila revealed significant changes in inflammatory and immune response genes. Especially, the expression of anti-microbial peptides (AMPs) genes was reduced. When we measured the expression levels of AMP genes during aging, those were getting increased in the control flies but reduced in MRS inhibition flies agedependently. Interestingly, in the germ-free condition, the maximum lifespan was increased in MRS inhibition flies compared with that of the conventional condition. These findings suggest that the lifespan of MRS inhibition flies is reduced due to the down-regulated AMPs expression in Drosophila.


Assuntos
Drosophila/genética , Longevidade/genética , Metionina tRNA Ligase/metabolismo , Animais
5.
Artigo em Inglês | MEDLINE | ID: mdl-31395550

RESUMO

In this study, finger force control abilities are quantified by the concept of multi-finger synergy in conjunction with uncontrolled manifold (UCM) analysis. Two indices, named repeatability and flexibility, representing features of multi-finger synergy were proposed to overcome the limitation of previously introduced indices, such as floor effects and distortion problems. The proposed indices were applied to stroke patients and healthy adults through specifically designed experiments. The experimental results showed a clear difference between stroke patients and healthy adults. Also, interestingly, there was a difference in outcome between two stroke patient subgroups: stroke patients in whom the dominant hand was affected and non-dominant hand was affected groups.

6.
IEEE Trans Neural Syst Rehabil Eng ; 27(6): 1253-1262, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31071050

RESUMO

In this study, finger force control abilities are quantified by the concept of multi-finger synergy in conjunction with uncontrolled manifold (UCM) analysis. Two indices, namely, repeatability and flexibility, representing features of multi-finger synergy were proposed to overcome the limitation of previously introduced indices, such as floor effects and distortion problems. The proposed indices were applied to stroke patients and healthy adults through specifically designed experiments. The experimental results showed a clear difference between stroke patients and healthy adults. Also, interestingly, there was a difference in an outcome between two-stroke patient subgroups: stroke patients in whom the dominant hand was affected and non-dominant hand was affected groups.


Assuntos
Dedos/fisiologia , Destreza Motora/fisiologia , Adulto , Algoritmos , Fenômenos Biomecânicos/fisiologia , Feminino , Lateralidade Funcional , Força da Mão , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor , Valores de Referência , Robótica , Acidente Vascular Cerebral/fisiopatologia , Reabilitação do Acidente Vascular Cerebral/métodos , Adulto Jovem
7.
Dis Model Mech ; 12(5)2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31043432

RESUMO

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors such as neuroblastoma in DS patients and increased vascular anomalies in DS fetuses suggest a potential role of DYRK1A in angiogenic processes, but in vivo evidence is still scarce. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that DYRK1A plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases.


Assuntos
Vasos Sanguíneos/patologia , Sinalização do Cálcio , Técnicas de Inativação de Genes , Proteínas Quinases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Vasos Sanguíneos/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/embriologia , Encéfalo/patologia , Encéfalo/ultraestrutura , Hemorragia Cerebral/patologia , Ácido Egtázico/farmacologia , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Desenvolvimento Embrionário/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Harmina/farmacologia , Espaço Intracelular/metabolismo , Mutação/genética , Fenótipo , Transcriptoma/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/antagonistas & inibidores
8.
Nat Commun ; 10(1): 1357, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902983

RESUMO

A fundamental question in biology is how vertebrates evolved and differ from invertebrates, and little is known about differences in the regulation of translation in the two systems. Herein, we identify a threonyl-tRNA synthetase (TRS)-mediated translation initiation machinery that specifically interacts with eIF4E homologous protein, and forms machinery that is structurally analogous to the eIF4F-mediated translation initiation machinery via the recruitment of other translation initiation components. Biochemical and RNA immunoprecipitation analyses coupled to sequencing suggest that this machinery emerged as a gain-of-function event in the vertebrate lineage, and it positively regulates the translation of mRNAs required for vertebrate development. Collectively, our findings demonstrate that TRS evolved to regulate vertebrate translation initiation via its dual role as a scaffold for the assembly of initiation components and as a selector of target mRNAs. This work highlights the functional significance of aminoacyl-tRNA synthetases in the emergence and control of higher order organisms.


Assuntos
Iniciação Traducional da Cadeia Peptídica , Treonina-tRNA Ligase/metabolismo , Sequência de Aminoácidos , Animais , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/metabolismo , Fator de Iniciação 4E em Eucariotos , Fator de Iniciação 4F em Eucariotos/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteínas de Ligação ao Cap de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Especificidade da Espécie , Treonina-tRNA Ligase/química , Vertebrados/crescimento & desenvolvimento , Vertebrados/metabolismo , Peixe-Zebra
9.
Nat Commun ; 10(1): 708, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755616

RESUMO

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.


Assuntos
Encefalopatias/genética , Microcefalia/genética , Valina-tRNA Ligase/genética , Alelos , Animais , Encefalopatias/enzimologia , Encefalopatias/patologia , Linhagem Celular , Modelos Animais de Doenças , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/patologia , Feminino , Fibroblastos , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/patologia , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Prosencéfalo/patologia , Peixe-Zebra
10.
Nanoscale ; 11(7): 3396, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30608099

RESUMO

Correction for 'Bioaccumulation of polystyrene nanoplastics and their effect on the toxicity of Au ions in zebrafish embryos' by Wang Sik Lee et al., Nanoscale, 2019, DOI: 10.1039/c8nr09321k.

11.
Nanoscale ; 11(7): 3173-3185, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30534785

RESUMO

As nano- and micro-sized plastics accumulate in the environment and the food chain of animals, including humans, it is imperative to assess the effects of nanoplastics in living organisms in a systematic manner, especially because of their ability to adsorb potential toxicants such as pollutants, heavy metals, and organic macromolecules that coexist in the environment. Using the zebrafish embryo as an animal model, we investigated the bioaccumulation and in vivo toxicity of polystyrene (PS) nanoplastics individually or in combination with the Au ion. We showed that smaller PS nanoplastics readily penetrated the chorion and developing embryos and accumulated throughout the whole body, mostly in lipid-rich regions such as in yolk lipids. We also showed that PS nanoplastics induced only marginal effects on the survival, hatching rate, developmental abnormalities, and cell death of zebrafish embryos but that these effects were synergistically exacerbated by the Au ion in a dose- and size-dependent manner. Such exacerbation of toxicity was well correlated with the production of reactive oxygen species and the pro-inflammatory responses synergized by the presence of PS, supporting the combined toxicity of PS and Au ions. The synergistic effect of PS on toxicity appeared to relate to mitochondrial damage as determined by ultrastructural analysis. Taken together, the effects of PS nanoplastics were marginal but could be a trigger for exacerbating the toxicity induced by other toxicants such as metal ions.


Assuntos
Embrião não Mamífero/metabolismo , Ouro/toxicidade , Nanopartículas/toxicidade , Poliestirenos/toxicidade , Peixe-Zebra/metabolismo , Animais , Embrião não Mamífero/patologia , Íons/toxicidade
12.
Microb Pathog ; 127: 56-59, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30508625

RESUMO

Streptococcus parauberis is the major infectious agent of streptococcosis in the olive flounder (Paralichthys olivaceus), causing serious economic damage. In this study, we identified potential vaccine candidates against S. parauberis by reverse vaccinology. In total, the 2 out of 21 proteins were identified as vaccine candidates from two available S. parauberis genomes. The membrane-anchored protein SEC10/PgrA and the metal ABC transporter substrate-binding lipoprotein mtsA were potent antigenic proteins based on western blotting with mouse-derived antiserum against whole bacteria of S. parauberis serotypes I and II. In particular, metal ABC transporter substrate-binding lipoprotein (mtsA) showed similar protective immunity to that of whole-cell bacterins against S. parauberis in a zebrafish model. These results suggest that mtsA may be considered as a novel candidate in the development of vaccines against S. parauberis.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Infecções Estreptocócicas/prevenção & controle , Streptococcus/imunologia , Vacinologia/métodos , Animais , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/isolamento & purificação , Modelos Animais de Doenças , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Análise de Sobrevida , Peixe-Zebra
13.
Sensors (Basel) ; 18(11)2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30424510

RESUMO

We report the electrical characteristics and pH responses of a Si-nanonet ion-sensitive field-effect transistor with ultra-thin parylene-H as a gate sensing membrane. The fabricated device shows excellent DC characteristics: a low subthreshold swing of 85 mV/dec, a high current on/off ratio of ~107 and a low gate leakage current of ~10-10 A. The low interface trap density of 1.04 × 1012 cm-2 and high field-effect mobility of 510 cm²V-1s-1 were obtained. The pH responses of the devices were evaluated in various pH buffer solutions. A high pH sensitivity of 48.1 ± 0.5 mV/pH with a device-to-device variation of ~6.1% was achieved. From the low-frequency noise characterization, the signal-to-noise ratio was extracted as high as ~3400 A/A with the lowest noise equivalent pH value of ~0.002 pH. These excellent intrinsic electrical and pH sensing performances suggest that parylene-H can be promising as a sensing membrane in an ISFET-based biosensor platform.

14.
Nanomaterials (Basel) ; 8(9)2018 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-30142912

RESUMO

A silver nanoparticle is one of the representative engineered nanomaterials with excellent optical, electrical, antibacterial properties. Silver nanoparticles are being increasingly used for medical products, water filters, and cosmetics, etc. However, silver nanoparticles are known to cause adverse effects on the ecosystem and human health. To utilize silver nanoparticles with minimized negative effects, it is important to understand the behavior of silver nanoparticles released to the environment. In this study, we compared toxicity behaviors of citrate-stabilized silver nanoparticles with polyethylene glycol coated silver nanoparticles in two different ionic environments, which are aquatic environments for developing zebrafish embryo. Depending on the composition of the ionic environment, citrate-stabilized silver nanoparticles and polyethylene glycol coated silver nanoparticles exhibited different behaviors in dissolution, aggregation, or precipitation, which governed the toxicity of silver nanoparticles on zebrafish embryos.

15.
Tuberc Respir Dis (Seoul) ; 81(3): 216-221, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29926541

RESUMO

BACKGROUND: The number of immigrants with tuberculosis (TB) increases each year in South Korea. Determining the transmission dynamics based on whole genome sequencing (WGS) to cluster the strains has been challenging. METHODS: WGS, annotation refinement, and orthology assignment for the GenBank accession number acquisition were performed on two clinical isolates from Chinese immigrants. In addition, the genomes of the two isolates were compared with the genomes of Mycobacterium tuberculosis isolates, from two native Korean and five native Chinese individuals using a phylogenetic topology tree based on the Multiple Alignment of Conserved Genomic Sequence with Rearrangements (Mauve) package. RESULTS: The newly assigned accession numbers for two clinical isolates were CP020381.2 (a Korean-Chinese from Yanbian Province) and CP022014.1 (a Chinese from Shandong Province), respectively. Mauve alignment classified all nine TB isolates into a discriminative collinear set with matched regions. The phylogenetic analysis revealed a rooted phylogenetic tree grouping the nine strains into two lineages: strains from Chinese individuals and strains from Korean individuals. CONCLUSION: Phylogenetic trees based on the Mauve alignments were supposed to be useful in revealing the dynamics of TB transmission from immigrants in South Korea, which can provide valuable information for scaling up the TB screening policy for immigrants.

16.
J Nanosci Nanotechnol ; 18(9): 6598-6601, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29677841

RESUMO

The analog figure-of-merits (FOMs) of conventional inversion-mode (IM) and junctionless (JL) NanoWire Field Effect Transistor (NWFET) have been investigated, considering the gate Work-Function Variability (WFV) and Random Discrete Dopant (RDD) using 3-dimensional (3D) TCAD simulation. While the JL-NWFET shows higher immune to WFV on analog FOMs, it can be easily affected by RDD due to higher channel doping level. On the other hand, the IM-NWFET shows stronger correlation between transconductance (gm) and gate capacitance (Cgg), leading to similar variation in cut-off frequency (ft) even though it shows larger gm and Cgg variation compared to JL-NWFET.

17.
Sci Rep ; 8(1): 4393, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29535354

RESUMO

Fluorescent polydopamine nanoparticles (FPNPs) are prepared via the ethylenediamine (EDA)-induced degradation of as-prepared non-fluorescent polydopamine (PDA) and used for targeted bioimaging. The reductive treatment of PDA in the presence of EDA yields fluorescent precipitates, inspiring us to seek various biological approaches to preparing FPNPs with excellent optical and biocompatible properties. Moreover, we firstly found that FPNPs selectively label neuromast hair cells in the lateral line of zebrafish, their applications as a reliable fluorescent indicator to investigate the neuromast hair cells, to in turn determine the viability of hair cells, was demonstrated. FPNPs also provided a minimal toxicity enable to assay the number of functional hair cells per neuromast in live animals as development proceeds. Upon combined incubation with TO-PRO-3, a well-established hair cell marker, all hair cells that were rapidly labeled with FPNPs were observed to be also completely labeled with the TO-PRO-3, labeling hair cells in neuromasts positioned in the supraorbital, otic and occipital lateral line as well as in posterior lateral line of living zebrafish larvae. Their potential efficacy for biological applications was demonstrated by their excellent optical and biocompatible properties, offering new opportunities in cancer research, real-time monitoring of stem cell transplantation and other cell-based therapies.


Assuntos
Corantes Fluorescentes , Células Ciliadas Auditivas/metabolismo , Indóis , Imagem Molecular , Nanopartículas , Polímeros , Animais , Biomarcadores , Corantes Fluorescentes/química , Células Ciliadas Auditivas/ultraestrutura , Células HeLa , Humanos , Indóis/química , Nanopartículas/química , Polímeros/química , Análise Espectral , Peixe-Zebra
18.
Mol Autism ; 8: 50, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29021890

RESUMO

BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. METHODS: We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. RESULTS: Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. CONCLUSIONS: In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/psicologia , Síndrome de Down/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Comportamento Social , Animais , Comportamento Animal , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Criança , Análise Mutacional de DNA , Síndrome de Down/diagnóstico , Feminino , Técnicas de Inativação de Genes , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Fenótipo , Deleção de Sequência , Peixe-Zebra
19.
Oncotarget ; 8(33): 55280-55297, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903419

RESUMO

Genetically engineered animal tumor models have traditionally been generated by the gain of single or multiple oncogenes or the loss of tumor suppressor genes; however, the development of live animal models has been difficult given that cancer phenotypes are generally induced by somatic mutation rather than by germline genetic inactivation. In this study, we developed somatically mutated tumor models using TALEN-mediated somatic gene inactivation of cdkn2a/b or rb1 tumor suppressor genes in zebrafish. One-cell stage injection of cdkn2a/b-TALEN mRNA resulted in malignant peripheral nerve sheath tumors with high frequency (about 39%) and early onset (about 35 weeks of age) in F0 tp53e7/e7 mutant zebrafish. Injection of rb1-TALEN mRNA also led to the formation of brain tumors at high frequency (58%, 31 weeks of age) in F0 tp53e7/e7 mutant zebrafish. Analysis of each tumor induced by somatic inactivation showed that the targeted genes had bi-allelic mutations. Tumors induced by rb1 somatic inactivation were characterized as medulloblastoma-like primitive neuroectodermal tumors based on incidence location, histopathological features, and immunohistochemical tests. In addition, 3' mRNA Quanti-Seq analysis showed differential activation of genes involved in cell cycle, DNA replication, and protein synthesis; especially, genes involved in neuronal development were up-regulated.

20.
IEEE Int Conf Rehabil Robot ; 2017: 1488-1493, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28814030

RESUMO

To investigate, improve, and observe the effect of rehabilitation therapy, many studies have been conducted on evaluating the motor function quantitatively by developing various types of robotic systems. Even though the robotic systems have been developed, functional evaluation of the hand has been rarely investigated, because it is difficult to install a number of actuators or sensors to the hand due to limited space around the fingers. Therefore, in this study, a hand exoskeleton was developed to satisfy the required specifications for evaluating the hand functions including spasticity of finger flexors, finger independence, and multi-digit synergy and algorithms to evaluate such functions were proposed. The hand exoskeleton was composed with the four 4-bar linkages, two motors, and three loadcells for each finger, and it was able to flex/extend the metacarpal (MCP) and proximal interphalangeal(PIP) joints independently while measuring the pulling force at each phalanx. Using the hand exoskeleton, the hand functions of the three healthy subject were evaluated and the experimental results were analyzed.


Assuntos
Exoesqueleto Energizado , Mãos/fisiopatologia , Reabilitação do Acidente Vascular Cerebral/instrumentação , Adulto , Fenômenos Biomecânicos , Desenho de Equipamento , Dedos/fisiopatologia , Humanos , Espasticidade Muscular/reabilitação , Amplitude de Movimento Articular/fisiologia , Adulto Jovem
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