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1.
Eur J Med Genet ; 64(10): 104295, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34371190

RESUMO

Defects in the PIEZO1 gene cause lymphatic dysplasia in an autosomal recessive manner, mostly by loss-of-function variants. Moreover, since 2019, the role of PIEZO1 in bone formation has been established, but there have been no PIEZO1-related cases presenting definite skeletal involvement to date. A 21-year-old male with primary lymphatic dysplasia had some other distinctive clinical features, including multiple fracture history during infancy, thoracolumbar scoliosis, short stature, and left-sided facial bone hypoplasia. We analyzed the whole exome of the patient and found two novel pathogenic variants of PIEZO1 in trans: a 93.7 kb heterozygous deletion (chr16:88,782,477-88,876,207; exon 1-50) and c.2858G>A (p.Arg953His). Sanger sequencing validated the deletion with breakpoints, and each variant was inherited from a different parent. This study presented an extremely rare case of a patient with lymphatic dysplasia caused by compound heterozygous variants of PIEZO1, along with additional clinical manifestations including several skeletal phenotypes.


Assuntos
Anormalidades Craniofaciais/genética , Fraturas Ósseas/genética , Canais Iônicos/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Mutação , Fenótipo , Escoliose/genética , Anormalidades Craniofaciais/patologia , Fraturas Ósseas/patologia , Heterozigoto , Humanos , Linfangiectasia Intestinal/patologia , Linfedema/patologia , Masculino , Escoliose/patologia , Adulto Jovem
2.
Medicine (Baltimore) ; 100(31): e26861, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397862

RESUMO

ABSTRACT: Cardiac rehabilitation (CR) can improve clinical indicators in patients with cardiovascular diseases. The literature reports a 20% reduction in all-cause mortality and a 27% reduction in heart-disease mortality following CR. Although its clinical efficacy has been established, there is uncertainty whether center-based (CBCR) is more effective than home-based (HBCR) programs in acute and subacute phases. We aimed to verify significant differences in their effectiveness for the improvement of cardiopulmonary function by analyzing cardiopulmonary exercise (CPX) with laboratory tests following both CR programs.A single-center cohort study of 37 patients, recently diagnosed with underlying cardiovascular diseases, underwent CBCR(18) and HBCR(19). CBCR group performed a supervised exercise regimen at the CR center, for 1 hour, 2 to 3 days a week, for a total of 12 to18 weeks. HBCR group completed a self-monitored exercise program at home under the same guidelines as CBCR. Participants were evaluated by CPX with laboratory tests at 1- and 6-month, following the respective programs.There was no statistical significance in clinical characteristics and laboratory findings. Pre-post treatment comparison showed significant improvement in VO2/kg, minute ventilation/carbon dioxide production slope, breathing reserve, tidal volume (VT), heart rate recovery, oxygen consumption per heart rate, low-density lipoprotein (LDL), LDL/HDL ratio, total cholesterol, ejection fraction (EF) (P < .05). CBCR approach showed greater improvement with significance in VO2/kg, metabolic equivalents, and EF on between groups analysis (P < .05).The time effect of CPX test and laboratory data showed improvement in cardiopulmonary function and serum indicators for both groups. VO2/kg, metabolic equivalents, and EF were among the variables that showed significant differences between groups. In the acute and subacute phases of 1 to 6 months, the CBCR group showed a greater cardiac output improvement than the HBCR group.


Assuntos
Biomarcadores/sangue , Reabilitação Cardíaca , Doenças Cardiovasculares , Terapia por Exercício , Serviços de Assistência Domiciliar/estatística & dados numéricos , Centros de Reabilitação/estatística & dados numéricos , Reabilitação Cardíaca/métodos , Reabilitação Cardíaca/normas , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Pesquisa Comparativa da Efetividade , Teste de Esforço/métodos , Terapia por Exercício/métodos , Terapia por Exercício/organização & administração , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , República da Coreia/epidemiologia , Testes de Função Respiratória/métodos , Testes de Função Respiratória/estatística & dados numéricos , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-34300160

RESUMO

PURPOSE: COVID-19 guidelines for persons with disabilities published globally during the early phase of the pandemic by non-governmental organizations and federal agencies were reviewed and analyzed by trends of information provided under various settings. METHOD: The Google search engine was used by applying the following search terms: COVID-19, Coronavirus 2019, Disability, and Guidelines. Search efforts yielded 514 records from 1 December 2019 to 16 May 2020. The selected 26 guidelines were classified for analysis by organizations (NGOs, non-profit, and governmental institutions), information provided (risks, prevention, and countermeasures), target group (people with disability, service and support providers, and family members), and environmental setting (hospital, community, and home). RESULTS: Government agencies from eight countries published results. Eight of the 26 guidelines were presented by non-governmental organizations, and 18 were not. There were 15 guidelines for individuals with disabilities; seven for service providers, staff, and families providing care; and four addressing both the individuals with a disability and care providers. In terms of appropriate environment and scope, there were 19 guidelines produced for community, government, home, and hospital. The information predominantly presented regarded the prevention of COVID-19 with 22 sources, followed by general information containing risks and response strategies. CONCLUSION: The majority of the published guidelines focused primarily on the risks and prevention of COVID-19 for people with disabilities. Future procedures should include specific methods in guiding COVID-19 response strategies for the disabled and caregivers who provide essential health services with access to online resources in multiple languages and dialects.


Assuntos
COVID-19 , Pessoas com Deficiência , Governo , Humanos , Pandemias/prevenção & controle , SARS-CoV-2
4.
Mol Brain ; 14(1): 73, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892766

RESUMO

Loss-of-function mutations in the human oligophrenin-1 (OPHN1) gene cause intellectual disability, a prevailing neurodevelopmental condition. However, the role OPHN1 plays during neuronal development is not well understood. We investigated the role of the Drosophila OPHN1 ortholog Graf in the development of the mushroom body (MB), a key brain structure for learning and memory in insects. We show that loss of Graf causes abnormal crossing of the MB ß lobe over the brain midline during metamorphosis. This defect in Graf mutants is rescued by MB-specific expression of Graf and OPHN1. Furthermore, MB α/ß neuron-specific RNA interference experiments and mosaic analyses indicate that Graf acts via a cell-autonomous mechanism. Consistent with the negative regulation of epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) signaling by Graf, activation of this pathway is required for the ß-lobe midline-crossing phenotype of Graf mutants. Finally, Graf mutants have impaired olfactory long-term memory. Our findings reveal a role for Graf in MB axon development and suggest potential neurodevelopmental functions of human OPHN1.

5.
J Cell Biol ; 220(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33683284

RESUMO

Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Endossomos/metabolismo , Endossomos/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/fisiologia , Esclerose Amiotrófica Lateral/genética , Animais , Transporte Biológico/fisiologia , Morte Celular/genética , Sobrevivência Celular/genética , Células Cultivadas , Drosophila/genética , Drosophila/metabolismo , Drosophila/fisiologia , Endossomos/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Mutação/genética , Fenótipo , Densidade Pós-Sináptica/genética , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rab5 de Ligação ao GTP/metabolismo
6.
Indoor Air ; 31(4): 1134-1143, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33682971

RESUMO

After the WHO designated COVID-19 a global pandemic, face masks have become a precious commodity worldwide. However, uncertainty remains around several details regarding face masks, including the potential for transmission of bioaerosols depending on the type of mask and secondary spread by face masks. Thus, understanding the interplay between face mask structure and harmful bioaerosols is essential for protecting public health. Here, we evaluated the microbial survival rate at each layer of commercial of filtering facepiece respirators (FFRs) and surgical masks (SMs) using bacterial bioaerosols. The penetration efficiency of bacterial particles for FFRs was lower than that for SMs; however, the microbial survival rate for all tested masks was >13%, regardless of filtration performance. Most bacterial particles survived in the filter layer (44%-77%) (e.g., the core filtering layer); the outer layer also exhibited significant survival rates (18%-29%). Most notably, survival rates were determined for the inner layers (<1% for FFRs, 3%-16% for SMs), which are in contact with the respiratory tract. Our comparisons of the permeability and survival rate of bioaerosols in each layer will contribute to bioaerosol-face mask research, while also providing information to facilitate the establishment of a mask-reuse protocol.


Assuntos
Máscaras/estatística & dados numéricos , Aerossóis , Microbiologia do Ar , COVID-19 , Filtração , Humanos , Staphylococcus epidermidis
7.
Soa Chongsonyon Chongsin Uihak ; 31(3): 121-130, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32665756

RESUMO

Objectives: We investigated the differences in cognitive and emotional empathic ability between adolescents and adults, and the differences of the brain activation during cognitive and emotional empathy tasks. Methods: Adolescents (aged 13-15 years, n=14) and adults (aged 19-29 years, n=17) completed a range of empathic ability questionnaires and were scanned functional magnetic resonance imaging (fMRI) during both cognitive and emotional empathy task. Differences in empathic ability and brain activation between the groups were analyzed. Results: Both cognitive and emotional empathic ability were significantly lower in the adolescent compared to the adult group. Comparing the adolescent to the adult group showed that brain activation was significantly greater in the right transverse temporal gyrus (BA 41), right insula (BA 13), right superior parietal lobule (BA 7), right precentral gyrus (BA 4), and right thalamus whilst performing emotional empathy tasks. No brain regions showed significantly greater activation in the adolescent compared to the adult group while performing cognitive empathy task. In the adolescent group, scores of the Fantasy Subscale in the Interpersonal Reactivity Index, which reflects cognitive empathic ability, negatively correlated with activity of right superior parietal lobule during emotional empathic situations (r=-0.739, p=0.006). Conclusion: These results strongly suggest that adolescents possess lower cognitive and emotional empathic abilities than adults do and require compensatory hyperactivation of the brain regions associated with emotional empathy or embodiment in emotional empathic situation. Compensatory hyperactivation in the emotional empathy-related brain areas among adolescents are likely associated with their lower cognitive empathic ability.

8.
Sensors (Basel) ; 20(9)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32354052

RESUMO

In the Republic of Korea, 90.5% of those living with spinal cord injury (SCI) are faced with medical complications that require chronic care. Some of the more common ones include urinary tract infections, pressure sores, and pain symptomatology. These and other morbidities have been recognized to deteriorate the individual's health, eventually restricting their community participation. Telerehabilitation, using information and communication technology, has propelled a modern-day movement in providing comprehensive medical services to patients who have difficulty in mobilizing themselves to medical care facilities. This study aims to verify the effectiveness of health care and management in the SCI population by providing ICT-based health care services. We visited eight individuals living with chronic SCI in the community, and provided ICT-based health management services. After using respiratory and urinary care devices with the provision of home visit occupational therapy, data acquisition was achieved and subsequently entered into a smart device. The entered information was readily accessible to the necessary clinicians and researchers. The clients were notified if there were any concerning results from the acquired data. Subsequently, they were advised to follow up with their providers for any immediate medical care requirements. Digital hand-bike ergometers and specialized seating system cushions are currently in development. The ICT-based health care management service for individuals with SCI resulted in a favorable expected level of outcome. Based on the results of this study, we have proposed and are now in preparation for a randomized clinical trial.


Assuntos
Terapia Ocupacional/métodos , Traumatismos da Medula Espinal/urina , Estudos de Viabilidade , Feminino , Pesquisas sobre Serviços de Saúde , Serviços de Assistência Domiciliar , Humanos , Masculino , Pessoa de Meia-Idade
9.
Cancers (Basel) ; 12(5)2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32466217

RESUMO

It is controversial as to whether papillary thyroid microcarcinoma (PTMC) has some genomic and transcriptomic characteristics that differentiate between an early-stage lesion that would eventually evolve into the larger papillary thyroid cancer (PTC), and an occult indolent cancer in itself. To investigate this, we comprehensively elucidated the genomic and transcriptomic landscapes of PTMCs of different sizes, using a large-scaled database. This study included 3435 PTCs, 1985 of which were PTMCs. We performed targeted next-generation sequencing for 221 PTCs and integrated these data with the data including The Cancer Genome Atlas (TCGA) project. The frequency of v-raf murine sarcoma viral oncogene homolog B (BRAF)V600E mutation was higher in PTMCs >0.5 cm than that in very small PTMCs (≤0.5 cm) and decreased again in PTCs >2 cm. Among PTMCs, the prevalence of mutations in rat sarcoma (RAS) and telomerase reverse transcriptase (TERT) promoter was not significantly different according to their size, but lower than in large PTCs. There was no change in the tumor mutational burden, the number of driver mutations, and transcriptomic profiles with tumor size, among PTMCs and all PTCs. Although a few genes with differential expression and TERT promoter mutations were found in a few PTMCs, our findings showed that there were no useful genomic or transcriptomic characteristics for the prediction of the future progression of PTMC.

10.
ACS Appl Mater Interfaces ; 12(5): 5730-5738, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31918549

RESUMO

Cr poisoning of cathode materials is one of the main degradation issues hampering the operation of solid oxide fuel cells (SOFCs). To overcome this shortcoming, LaNi0.6Fe0.4O3-δ (LNF) has been developed as an alternative cathode material owing to its superior chemical stability in Cr environments. In this study, we develop a hybrid electrochemical deposition technique to fabricate a nanostructured LNF-gadolinium-doped ceria (GDC) (n-LNF-GDC) cathode with enhanced active reaction sites for the oxygen reduction reaction. For this purpose, Fe and Ni cations are co-deposited onto an electrically conductive carbon nanotube-modified GDC backbone by electroplating, whereas La cations are successively deposited through a chemically assisted electrodeposition method. The proposed method involves a low-temperature (900 °C) calcination step of electrodeposited cations, which avoids the need of fabricating a GDC diffusion barrier layer which is otherwise needed to avoid the formation of insulating phases (e.g., La2Zr2O7) when fabricating by conventional high-temperature (≥1000 °C) sintering. Scanning electron microscopy images reveal a unique nanofibrous structure of n-LNF-GDC, which is believed to play an instrumental role in enhancing the electrochemical characteristics by increasing the active triple-phase boundaries. An anode-supported SOFC with the n-LNF-GDC cathode showed the superior performance of 0.984 W cm-2 at an intermediate temperature of 750 °C as compared to the power densities of 0.495 and 0.874 W cm-2 produced by LNF-GDC and state-of-the-art La0.6Sr0.4Co0.2Fe0.8O3-δ (LSCF)-GDC composite cathodes fabricated by conventional sintering. A short-term accelerated Cr-poisoning durability test indicated good electrochemical stability of n-LNF-GDC, whereas LSCF exhibited severe degradation. The electrochemically engineered nanostructured n-LNF-GDC can serve as an effective cathode for SOFCs to achieve high performance and long-term durability.

11.
PLoS One ; 14(9): e0222533, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31525235

RESUMO

Dutasteride, a dual inhibitor of both type I and II 5α-reductases, is used to treat male pattern hair loss (MPHL). However, patient response to dutasteride varies in each individual, the cause of which is yet to be identified. To identify genetic variants associated with response to dutasteride treatment for MPHL, a total of 42 men with moderate MPHL who had been treated with dutasteride for 6 months were genotyped and analysed by quantitative linear regression, case-control association tests, and Fisher's exact test. The synonymous single nucleotide polymorphism (SNP) rs72623193 in DHRS9 was most significantly associated with response to dutasteride, followed by the non-synonymous SNP rs2241057 in CYP26B1. Additionally, variants in ESR1, SRD5A1, CYP19A1, and RXRG are suggested to be associated with response to dutasteride. Cumulative effect and interaction among these SNPs were presented in both additive and non-additive models.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Alopecia/genética , Dutasterida/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Cabelo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Nat Commun ; 10(1): 684, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737382

RESUMO

Retrograde BMP trans-synaptic signaling is essential for synaptic development. Despite the importance of endocytosis-regulated BMP receptor (BMPR) control of this developmental signaling, the mechanism remains unknown. Here, we provide evidence that Abelson interactor (Abi), a substrate for Abl kinase and component of the SCAR/WAVE complex, links Abl and Rac1 GTPase signaling to BMPR macropinocytosis to restrain BMP-mediated synaptic development. We find that Abi acts downstream of Abl and Rac1, and that BMP ligand Glass bottom boat (Gbb) induces macropinocytosis dependent on Rac1/SCAR signaling, Abl-mediated Abi phosphorylation, and BMPR activation. Macropinocytosis acts as the major internalization route for BMPRs at the synapse in a process driven by Gbb activation and resulting in receptor degradation. Key regulators of macropinocytosis (Rabankyrin and CtBP) control BMPR trafficking to limit BMP trans-synaptic signaling. We conclude that BMP-induced macropinocytosis acts as a BMPR homeostatic mechanism to regulate BMP-mediated synaptic development.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas/genética , Proteínas de Transporte/genética , Drosophila , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Fosforilação/genética , Fosforilação/fisiologia , Proteínas Tirosina Quinases/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sinapses/metabolismo , Proteínas rac de Ligação ao GTP/genética
13.
Diabetes ; 67(9): 1892-1902, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29941447

RESUMO

We investigated ethnicity-specific exonic variants of type 2 diabetes (T2D) and its related clinical phenotypes in an East Asian population. We performed whole-exome sequencing in 917 T2D case and control subjects, and the findings were validated by exome array genotyping in 3,026 participants. In silico replication was conducted for seven nonsynonymous variants in an additional 13,122 participants. Single-variant and gene-based association tests for T2D were analyzed. A total of 728,838 variants were identified by whole-exome sequencing. Among nonsynonymous variants, PAX4 Arg192His increased risk of T2D and GLP1R Arg131Gln decreased risk of T2D in genome-wide significance (odds ratio [OR] 1.48, P = 4.47 × 10-16 and OR 0.84, P = 3.55 × 10-8, respectively). Another variant at PAX4 192 codon Arg192Ser was nominally associated with T2D (OR 1.62, P = 5.18 × 10-4). In T2D patients, PAX4 Arg192His was associated with earlier age at diagnosis, and GLP1R Arg131Gln was associated with decreased risk of cardiovascular disease. In control subjects without diabetes, the PAX4 Arg192His was associated with higher fasting glucose and GLP1R Arg131Gln was associated with lower fasting glucose and HbA1c level. Gene-based analysis revealed that SLC30A8 was most significantly associated with decreased risk of T2D (P = 1.0 × 10-4). In summary, we have identified nonsynonymous variants associated with risk of T2D and related phenotypes in Koreans.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Variação Genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição Box Pareados/genética , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Substituição de Aminoácidos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/metabolismo , Sistemas Especialistas , Feminino , Frequência do Gene , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição Box Pareados/química , Fatores de Transcrição Box Pareados/metabolismo , República da Coreia , Sequenciamento Completo do Exoma
14.
ChemSusChem ; 11(15): 2620-2627, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29808966

RESUMO

State-of-the-art cathodes for solid oxide fuel cells (SOFCs), such as (La,Sr)MnO3 -(Y2 O3 )0.08 (ZrO2 )0.92 (LSM-YSZ), suffer from sluggish oxygen reduction reaction (ORR) kinetics at reduced temperatures, leading to a significant decline in their performance. Herein, we report a tailored SOFC cathode with high ORR activity at intermediate temperatures using a simple but effective approach based on "electrochemical" surface modification. The proposed process involves chemically assisted electrodeposition (CAED) of a metal hydroxide (LaCo(OH)x ) on LSM-YSZ surfaces followed by in situ thermal conversion of LaCo(OH)x to perovskite-type LaCoO3 (LCO) nanoparticles during the SOFC startup. This method facilitates easy loading of the LCO nanoparticles with a precisely controlled morphology without the need for repeated deposition/annealing processes. An anode-supported SOFC with the LCO-tailored LSM-YSZ electrode exhibits a remarkably increased power density, approximately 180 % at 700 °C, compared with an SOFC with the pristine electrode as well as excellent long-term stability, which are attributed to the beneficial role of the CAED-derived LCO nanoparticles in enlarging the active areas for ORR and promoting oxygen adsorption/diffusion. This work demonstrates that controlled surface tailoring of the cathode by CAED could be an effective approach for improving the performance of SOFCs at reduced temperatures.

15.
Soa Chongsonyon Chongsin Uihak ; 29(3): 101-113, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32595302

RESUMO

Objectives: The purpose of this study was to investigate whether the neural activity of autism spectrum disorder (ASD) patients is different from that of normal individuals when performing aesthetic judgments. Methods: We recruited typical ASD patients without savant skills (ASD group, n=17) and healthy controls (HC group, n=19) for an functional magnetic resonance imaging study. All subjects were scanned while performing aesthetic judgment tasks on two kinds of artwork (magnificent landscape images and fractal images). Differences in brain activation between the two groups were assessed by contrasting neural activity during the tasks. Results: The aesthetic judgment score for all images was significantly lower in the ASD group than in the HC group. During the aesthetic judgment tasks, the ASD group showed less activation than the HC group in the anterior region of the superior frontal gyrus, and more activation in the temporoparietal area and insula, regardless of the type of images being judged. In addition, during the aesthetic judgment task for the fractal images, the ASD group exhibited greater neural activity in the amygdala and the posterior region of the middle/inferior temporal gyrus (Brodmann area 37) than the HC group. Conclusion: The results of this study suggest that the brain activation patterns associated with aesthetic experiences in ASD patients may differ from those of normal individuals.

16.
Exp Neurobiol ; 27(6): 550-563, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30636905

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation.

17.
Mol Brain ; 10(1): 62, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29282074

RESUMO

In Drosophila, precise regulation of BMP signaling is essential for normal synaptic growth at the larval neuromuscular junction (NMJ) and neuronal survival in the adult brain. However, the molecular mechanisms underlying fine-tuning of BMP signaling in neurons remain poorly understood. We show that loss of the Drosophila PDZ guanine nucleotide exchange factor Gef26 significantly increases synaptic growth at the NMJ and enhances BMP signaling in motor neurons. We further show that Gef26 functions upstream of Rap1 in motor neurons to restrain synaptic growth. Synaptic overgrowth in gef26 or rap1 mutants requires BMP signaling, indicating that Gef26 and Rap1 regulate synaptic growth via inhibition of BMP signaling. We also show that Gef26 is involved in the endocytic downregulation of surface expression of the BMP receptors thickveins (Tkv) and wishful thinking (Wit). Finally, we demonstrate that loss of Gef26 also induces progressive brain neurodegeneration through Rap1- and BMP signaling-dependent mechanisms. Taken together, these results suggest that the Gef26-Rap1 signaling pathway regulates both synaptic growth and neuronal survival by controlling BMP signaling.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Animais , Encéfalo/citologia , Linhagem Celular , Sobrevivência Celular , Endocitose , Epistasia Genética , Proteína do X Frágil de Retardo Mental/metabolismo , Microtúbulos/metabolismo , Modelos Biológicos , Degeneração Neural/patologia , Junção Neuromuscular/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo
18.
Development ; 144(22): 4159-4172, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993397

RESUMO

GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation.


Assuntos
Proteínas de Transporte/metabolismo , Compartimento Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Endocitose , Receptores ErbB/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Hematopoese , Receptores de Peptídeos de Invertebrados/metabolismo , Animais , Proliferação de Células , Clatrina/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Hemócitos/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Modelos Biológicos , Mutação/genética , Ligação Proteica , Proteólise , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , Proteínas ras/metabolismo
19.
Exp Mol Med ; 49(5): e333, 2017 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-28524178

RESUMO

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE. The results showed that the genes related to the MAP kinase and calcium-signaling pathways were significantly downregulated in CTE. The altered expression of protein phosphatases (PPs) in these networks further suggested that the tauopathy observed in CTE involves common pathological mechanisms similar to Alzheimer's disease (AD). Using cell lines and animal models, we also showed that reduced PPP3CA/PP2B phosphatase activity is directly associated with increases in phosphorylated (p)-tau proteins. These findings provide important insights into PP-dependent neurodegeneration and may lead to novel therapeutic approaches to reduce the tauopathy associated with CTE.


Assuntos
Calcineurina/genética , Encefalopatia Traumática Crônica/metabolismo , Processamento de Proteína Pós-Traducional , Transcriptoma , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Encefalopatia Traumática Crônica/genética , Encefalopatia Traumática Crônica/patologia , Regulação para Baixo , Feminino , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosforilação
20.
Int J Cancer ; 140(1): 86-94, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27605020

RESUMO

Recently reported genome-wide association studies have identified more than 20 common low-penetrance colorectal cancer (CRC) susceptibility loci. Recent studies have reported that copy number variations (CNVs) are considered important human genomic variants related to cancer, while the contribution of CNVs remains unclear. We performed array comparative genomic hybridization (aCGH) in 36 CRC patients and 47 controls. Using breakpoint PCR, we confirmed the breakpoint of the PKD1L2 deletion region. High frequency of PKD1L2 CNV was observed in CRC cases. We validated the association between PKD1L2 variation and CRC risk in 1,874 cases and 2,088 controls (OR = 1.44, 95% CI = 1.04-1.98, p = 0.028). Additionally, PKD1L2 CNV is associated with increased CRC risk in patients younger than 50 years (OR = 2.14, 95% CI 1.39-3.30, p = 5.8 × 10-4 ). In subgroup analysis according to body mass index (BMI), we found that the CN loss of PKD1L2 with BMI above or equal to 25 exhibited a significant increase in CRC risk (OR = 2.29, 95% CI 1.29-4.05, p = 0.005). PKD1L2 CNV with BMI above or equal to 25 and age below 50 is associated with a remarkably increased risk of colorectal cancer (OR = 5.24, 95% CI 2.36-11.64, p= 4.8 × 10-5 ). Moreover, we found that PKD1L2 variation in obese patients (BMI ≥ 25) was associated with poor survival rate (p = 0.026). Our results suggest that the common PKD1L2 CNV is associated with CRC, and PKD1L2 CNV with high BMI and/or age below 50 exhibited a significant increased risk of CRC. In obese patients, PKD1L2 variation was associated with poor survival.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Colorretais/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Receptores Acoplados a Proteínas G/genética , Idoso , Índice de Massa Corporal , Neoplasias Colorretais/mortalidade , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Fatores de Risco , Deleção de Sequência , Análise de Sobrevida
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