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1.
Cereb Cortex ; 34(2)2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38220574

RESUMO

Parent-child interaction is crucial for children's cognitive and affective development. While bio-synchrony models propose that parenting influences interbrain synchrony during interpersonal interaction, the brain-to-brain mechanisms underlying real-time parent-child interactions remain largely understudied. Using functional near-infrared spectroscopy, we investigated interbrain synchrony in 88 parent-child dyads (Mage children = 8.07, 42.0% girls) during a collaborative task (the Etch-a-Sketch, a joint drawing task). Our findings revealed increased interbrain synchrony in the dorsolateral prefrontal cortex and temporo-parietal areas during interactive, collaborative sessions compared to non-interactive, resting sessions. Linear regression analysis demonstrated that interbrain synchrony in the left temporoparietal junction was associated with enhanced dyadic collaboration, shared positive affect, parental autonomy support, and parental emotional warmth. These associations remained significant after controlling for demographic variables including child age, child gender, and parent gender. Additionally, differences between fathers and mothers were observed. These results highlight the significant association between brain-to-brain synchrony in parent-child dyads, the quality of the parent-child relationship, and supportive parenting behaviors. Interbrain synchrony may serve as a neurobiological marker of real-time parent-child interaction, potentially underscoring the pivotal role of supportive parenting in shaping these interbrain synchrony mechanisms.


Assuntos
Poder Familiar , Espectroscopia de Luz Próxima ao Infravermelho , Feminino , Humanos , Masculino , Poder Familiar/psicologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Relações Pais-Filho , Encéfalo/diagnóstico por imagem , Diencéfalo
2.
Artigo em Inglês | MEDLINE | ID: mdl-38837359

RESUMO

BACKGROUND: Emotion regulation (ER) is considered central in adolescent psychopathology, and ER strategies may change during challenging times, such as a global pandemic. Despite this, there remains a limited understanding of individual differences in ER mechanisms and their associations with psychopathology. This study examined whether and how cognitive reappraisal, expressive suppression, and self-compassion changed over COVID-19 and how these changes uniquely predicted adolescents' depressive symptoms. METHODS: A total of 2,411 adolescents (58.6% females; Mage = 18.51, SD = 0.80) completed the Emotional Regulation Questionnaire, the Self-compassion Scale, and the Symptom Checklist-90 before COVID-19 (in 2019) and during COVID-19 (in 2020). The predictive associations between each ER strategy and depressive symptoms were tested with latent change score models. RESULTS: Adolescents' use of expressive suppression and self-compassion strategies both increased during COVID-19. More increases in expressive suppression predicted more depressive symptoms, whereas more increases in self-compassion predicted fewer depressive symptoms. Although, on average, cognitive reappraisal did not change, it did show significant variations within the sample - increases (vs. decreases) in cognitive appraisal predicted fewer depressive symptoms. CONCLUSIONS: The study indicates how adolescents' ER strategies changed during the unprecedented global pandemic. It underscores protective roles of increased cognitive reappraisal and self-compassion, as well as the adverse consequence of heightened expressive suppression on adolescents' depressive symptoms. Findings offer insights for targeted interventions aimed at addressing specific ER strategies.

3.
Anal Bioanal Chem ; 416(6): 1457-1468, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38231254

RESUMO

Gastrointestinal mesenchymal tumors, as the most common mesenchymal tumors in the gastrointestinal tract, are adjuvantly treated with multi-targeted tyrosine kinase inhibitors, such as imatinib and sunitinib, but there are problems of drug resistance and complex methods of monitoring therapeutic agents. The pathogenesis of this disease is related to mutations in tyrosine kinase (KIT) or platelet-derived growth factor receptor α, an important target for drug therapy. In recent years, the screening of relevant tyrosine kinase inhibitors from traditional Chinese medicine has become a hotspot in antitumor drug research. In the current study, the KIT-SNAP-tag cell membrane chromatography (KIT-SNAP-tag/CMC) column was prepared with satisfying specificity, selectivity, and reproducibility by chemically bonding high KIT expression cell membranes to the silica gel surface using the SNAP-tag technology. The KIT-SNAP-tag/CMC-HPLC-MS two-dimensional coupling system was investigated using the positive drug imatinib, and the results showed that the system was a reliable model for screening potential antitumor compounds from complex systems. This system screened and identified three potential active compounds of evodiamine (EVO), rutaecarpin (RUT), and dehydroevodiamine (DEVO), which possibly target the KIT receptor, from the alcoholic extract of the traditional Chinese medicine Evodia rutaecarpa. Then, the KD values of the interaction of EVO, RUT, and DEVO with KIT receptors measured using nonlinear chromatography were 7.75 (±4.93) × 10-6, 1.42 (±0.71) × 10-6, and 2.34 (±1.86) × 10-6 mol/L, respectively. In addition, the methyl thiazolyl tetrazolium assay validated the active effects of EVO and RUT in inhibiting the proliferation of high KIT-expressing cells in the ranges of 0.1-10 µmol/L and 0.1-50 µmol/L, respectively. In conclusion, the KIT-SNAP-tag/CMC could be a reliable model for screening antitumor components from complex systems.


Assuntos
Evodia , Neoplasias Gastrointestinais , Humanos , Mesilato de Imatinib/farmacologia , Evodia/química , Espectrometria de Massa com Cromatografia Líquida , Reprodutibilidade dos Testes , Receptores Proteína Tirosina Quinases , Neoplasias Gastrointestinais/tratamento farmacológico , Membrana Celular
4.
J Youth Adolesc ; 53(6): 1415-1427, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38466530

RESUMO

Conflict in peer and family relationships becomes more common in the adolescent period when compared to previous developmental periods. These typical developmental challenges can be exacerbated in the context of poor emotion regulation skills. Using daily diary data, the current study examined the stress spillover effects of peer and family stress on one another, as well as the moderating role of emotion regulation challenges (i.e., emotional inhibition, dysregulation). A sample of 310 Chinese adolescents (Mage = 13.02 years, SD = 0.76 years, 50.7% boys) completed an initial measure of emotion regulation difficulties, then reported on peer and family stress for 10 consecutive weekdays. Results indicated that there was an overall same-day peer stress spillover effect in which adolescents' peer stress on a given day was negatively associated with later conflictual interactions with their parents. Further, the relation between peer stress and same- and next-day family stress was exacerbated in the context of high levels of emotional inhibition. Family stress did not significantly relate to next-day peer stress, nor was this association moderated by difficulties with emotion regulation. These results highlight the temporal sequence of daily peer-to-family stress spillover. Though emotional inhibition may be culturally adaptive for maintaining interpersonal harmony, it can be maladaptive in managing stress for Chinese adolescents.


Assuntos
Regulação Emocional , Grupo Associado , Estresse Psicológico , Humanos , Masculino , Feminino , Adolescente , Estresse Psicológico/psicologia , China , Comportamento do Adolescente/psicologia , Relações Familiares/psicologia , Relações Pais-Filho , População do Leste Asiático
5.
BMC Genomics ; 24(1): 301, 2023 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-37270481

RESUMO

BACKGROUND: The behaviors and ontogeny of Aedes aegypti are closely related to the spread of diseases caused by dengue (DENV), chikungunya (CHIKV), Zika (ZIKV), and yellow fever (YFV) viruses. During the life cycle, Ae. aegypti undergoes drastic morphological, metabolic, and functional changes triggered by gene regulation and other molecular mechanisms. Some essential regulatory factors that regulate insect ontogeny have been revealed in other species, but their roles are still poorly investigated in the mosquito. RESULTS: Our study identified 6 gene modules and their intramodular hub genes that were highly associated with the ontogeny of Ae. aegypti in the constructed network. Those modules were found to be enriched in functional roles related to cuticle development, ATP generation, digestion, immunity, pupation control, lectins, and spermatogenesis. Additionally, digestion-related pathways were activated in the larvae and adult females but suppressed in the pupae. The integrated protein‒protein network also identified cilium-related genes. In addition, we verified that the 6 intramodular hub genes encoding proteins such as EcKinase regulating larval molt were only expressed in the larval stage. Quantitative RT‒PCR of the intramodular hub genes gave similar results as the RNA-Seq expression profile, and most hub genes were ontogeny-specifically expressed. CONCLUSIONS: The constructed gene coexpression network provides a useful resource for network-based data mining to identify candidate genes for functional studies. Ultimately, these findings will be key in identifying potential molecular targets for disease control.


Assuntos
Aedes , Dengue , Febre Amarela , Infecção por Zika virus , Zika virus , Masculino , Animais , Feminino , Febre Amarela/genética , Zika virus/genética , Redes Reguladoras de Genes , Mosquitos Vetores , Proteínas/genética , Larva
6.
J Hum Genet ; 68(12): 867-874, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37737486

RESUMO

The human SET nuclear proto-oncogene (SET) gene is a protein-coding gene that encodes proteins that affects chromatin remodeling and gene transcription. Mutations in the SET gene have been reported to cause intellectual disability (ID) and epilepsy. In this study, we collected and analyzed clinical, genetic, and transcript features of two unrelated Chinese patients with ID. Both patients were characterized by moderate intellectual disability. Whole-exome sequencing identified two novel heterozygous mutations in the SET gene: NM_001122821.1:c.532-3 T > A and NM_001122821.1:c.3 G > C (p.0?). Additionally, RNA sequencing revealed widespread dysregulation of genes involved in NF-kB signaling and neuronal system in these two patients. To our knowledge, this is the first report of SET mutations causing ID in the Chinese population, broadening the genetic and ethnic spectrum of SET-related disorders and highlighting the importance of screening for SET gene variants.


Assuntos
Epilepsia , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Sequenciamento do Exoma , Mutação , Epilepsia/genética , Perfilação da Expressão Gênica , Linhagem
7.
Dev Psychopathol ; : 1-11, 2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37345291

RESUMO

Childhood maltreatment exerts long-term consequences on sleep health, and different subtypes could constitute maltreatment patterns. However, how naturally occurring patterns of childhood maltreatment affect subsequent sleep quality and the underlying mechanisms remain relatively unclear, particularly in youths undergoing a transitional period and in the Chinese cultural context. In this study, we identified childhood maltreatment patterns and explored how these patterns predicted sleep problems through differential emotion regulation strategies. We tracked 1929 Chinese youths (M age = 18.49; 63.1% females) for one year. Three latent profiles were identified: low maltreatment exposure, high physical and emotional maltreatment, and high sexual abuse. Compared with "low maltreatment exposure," youths in "high physical and emotional maltreatment" used fewer cognitive reappraisal strategies, and those in "high sexual abuse" used more expressive suppression, and then leading to more sleep problems. This study reveals new insights into the patterns of childhood maltreatment in Chinese youths and implies that individuals exposed to sexual abuse or a combination of physical and emotional maltreatment experience sleep problems through the impairment of differential emotion regulation processes. It also highlights the necessity of setting differential targets on emotion regulation strategies for distinct groups of maltreatment and considering the co-occurrence of physical and emotional maltreatment.

8.
Ann Noninvasive Electrocardiol ; 28(2): e13022, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36537052

RESUMO

OBJECTIVE: The aim of this study was to investigate whether there was a difference in survival after initial percutaneous coronary intervention (PCI) among ST-segment elevation myocardial infarction (STEMI) patients with different body mass index (BMI). METHODS: Literature retrieval was conducted on PubMed, Web of Science, Embase, CNKI, and Wanfang databases to obtain the published studies on the survival of STEMI patients with different BMI after initial PCI from the establishment of the database to 2022. All statistical analyses were performed using STATA16.0. RESULTS: Two hundred thirty-nine studies were retrieved, and 12 studies were eventually included. Meta-analysis showed that overweight patients [OR = 0.66, 95% CI (0.58, 0.76), p < .001] and obese patients [OR = 0.60, 95% CI (0.51, 0.72), p < .001] had lower in-hospital mortality than healthy-weight patients. Overweight patients [OR = 0.66, 95% CI (0.58, 0.74), p < .001] and obese patients [OR = 0.62, 95% CI (0.53, 0.72), p < .001] had lower short-term mortality than healthy-weight patients. In addition, overweight patients [OR = 0.63, 95% CI (0.58, 0.69), p < .001] and obese patients [OR = 0.59, 95% CI (0.52, 0.66), p < .001] also had lower long-term mortality than healthy-weight patients. There was no significant difference in in-hospital mortality [OR = 1.06, 95% CI (0.89, 1.27), p > .05], short-term mortality [OR = 1.04, 95% CI (0.89, 1.22), p > .05], and long-term mortality [OR = 1.07, 95% CI (0.95, 1.20), p > .05] between overweight and obese patients. CONCLUSION: This meta-analysis confirmed an obesity paradox in STEMI patients following PCI. The obesity paradox exists in in-hospital, short-term, and long-term conditions.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Fatores de Risco , Sobrepeso , Paradoxo da Obesidade , Resultado do Tratamento , Eletrocardiografia , Obesidade/complicações
9.
BMC Med Educ ; 23(1): 657, 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37691113

RESUMO

BACKGROUND: Class attendance is important for academic performance. Personal interactions between teachers and students are difficult in large classes; the number of medical undergraduate students in China ranges from dozens to over 100. It is important for teachers to control the teaching process to improve student attendance and participation. METHODS: Two classes of fourth-year undergraduate medical students, with each class comprising 115 students, participated in the study. One class, the trial group, was taught by the block-based teaching method based on cybernetics. This study was conducted with three of the courses in the Introduction to Oncology subject, and the trial group's courses included several blocks. Each block had a test paper that the students responded to immediately in class using the Internet. The teacher obtained feedback from the students when the rate of correct responses to block-test questions was less than 90%. The teacher adjusted the teaching in the following blocks according to the feedback information. The other class, the control group, was taught using the traditional lecture-based teaching method. RESULTS: The average attendance in the trial group was 104/115 (90.43%), and that in the control group was 83/115 (72.17%) (p = 0.0003). The teacher adjusted the teaching three times in the radiotherapy course owing to the complex ideas. After feedback, information on chemotherapy for the upper body was adjusted once, as was that on chemotherapy for the lower body, owing to students' attitudes. The average total score of the trial group was 86.06 ± 17.46 and that of the control group was 80.38 ± 6.97 (p = 0.041). Questionnaire I showed that the trial group students' attendance and participation were better than in the control group. Questionnaire II showed that the block-based teaching method based on cybernetics was approved by the students. CONCLUSIONS: The block-based teaching method based on cybernetics used in medical classes with large numbers of Chinese undergraduate students had positive effects.


Assuntos
Educação de Graduação em Medicina , Estudantes de Medicina , Humanos , Povo Asiático , Cibernética , População do Leste Asiático , Pessoal de Educação , Ensino , Educação de Graduação em Medicina/métodos , Avaliação Educacional
10.
Int J Mol Sci ; 24(15)2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37569378

RESUMO

Alzheimer's disease (AD) is a prevalent neurodegenerative disease and the world's primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aß) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one of the major features of AD, which involves a network of interactions between immune cells. The mast cell (MC) is an innate immune cell type known to serve as a first responder to pathological changes and crosstalk with microglia and neurons. Although an increased number of mast cells were found near the sites of Aß deposition, how mast cells are activated in AD is not clear. We developed a 3D culture system to culture MCs and investigated the activation of MCs by Aß peptides. Because collagen I is the major component of extracellular matrix (ECM) in the brain, we encapsulated human LADR MCs in gels formed by collagen I. We found that 3D-cultured MCs survived and proliferated at the same level as MCs in suspension. Additionally, they can be induced to secrete inflammatory cytokines as well as MC proteases tryptase and chymase by typical MC activators interleukin 33 (IL-33) and IgE/anti-IgE. Culturing with peptides Aß1-42, Aß1-40, and Aß25-35 caused MCs to secrete inflammatory mediators, with Aß1-42 inducing the maximum level of activation. These data indicate that MCs respond to amyloid deposition to elicit inflammatory responses and demonstrate the validity of collagen gel as a model system to investigate MCs in a 3D environment to understand neuroinflammation in AD.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Idoso , Humanos , Mastócitos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hidrogéis/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neuroinflamatórias , Doença de Alzheimer/metabolismo
11.
Mol Psychiatry ; 26(8): 4511-4528, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32015466

RESUMO

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.


Assuntos
Metilação de DNA , RNA Longo não Codificante , Esquizofrenia , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Regulação para Baixo , Humanos , Inflamação , Camundongos , RNA Longo não Codificante/genética , Esquizofrenia/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
12.
Nucleic Acids Res ; 48(D1): D517-D525, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31665441

RESUMO

The Comprehensive Antibiotic Resistance Database (CARD; https://card.mcmaster.ca) is a curated resource providing reference DNA and protein sequences, detection models and bioinformatics tools on the molecular basis of bacterial antimicrobial resistance (AMR). CARD focuses on providing high-quality reference data and molecular sequences within a controlled vocabulary, the Antibiotic Resistance Ontology (ARO), designed by the CARD biocuration team to integrate with software development efforts for resistome analysis and prediction, such as CARD's Resistance Gene Identifier (RGI) software. Since 2017, CARD has expanded through extensive curation of reference sequences, revision of the ontological structure, curation of over 500 new AMR detection models, development of a new classification paradigm and expansion of analytical tools. Most notably, a new Resistomes & Variants module provides analysis and statistical summary of in silico predicted resistance variants from 82 pathogens and over 100 000 genomes. By adding these resistance variants to CARD, we are able to summarize predicted resistance using the information included in CARD, identify trends in AMR mobility and determine previously undescribed and novel resistance variants. Here, we describe updates and recent expansions to CARD and its biocuration process, including new resources for community biocuration of AMR molecular reference data.


Assuntos
Bases de Dados Genéticas , Farmacorresistência Bacteriana , Genes Bacterianos , Software , Bactérias/efeitos dos fármacos , Bactérias/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo
13.
J Hum Nutr Diet ; 35(1): 14-22, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33908101

RESUMO

BACKGROUND: The value of caregivers with respect to ensuring safety during home nasogastric tube (NGT) feeding is increasingly acknowledged. However, little attention has been given to the experience of caregivers. METHODS: A qualitative descriptive design using semi-structured interviews via purposive sampling at a comprehensive hospital in China was employed. Family caregivers of patients with home NGT feeding were recruited. Interviews were recorded, transcribed verbatim and analysed qualitatively using inductive content analysis. RESULTS: Thirteen family caregivers of patients with home NGT feeding were interviewed. Four main themes were generated: negative experience (uncertainty and ambivalence, transition gaps between hospitals and home care services), new role: adapting to the lifestyle (participating in decision-making, being responsible for everything, adjusting own life to NGT feeding), perceived benefit of caregiving (personal growth, development of positive attitudes and achievements) and expectations (expectations from continuity health system services, expectations from social support). CONCLUSIONS: The present study highlights the vulnerability and perceived benefits embedded in the role of a family caregiver. Improving communication and standardising practices between home and hospitals should be considered.


Assuntos
Cuidadores , Serviços de Assistência Domiciliar , Nutrição Enteral , Humanos , Intubação Gastrointestinal , Pesquisa Qualitativa
14.
Fam Process ; 61(4): 1696-1714, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35132622

RESUMO

Problematic Internet use (PIU), a common phenomenon, has negative effects on adolescents, especially during the COVID-19 pandemic. Adolescents with PIU pose great challenges to parenting. However, little is known about the mediating mechanisms underlying this relationship. The study examines the chain mediating roles of parenting stress and parental expectations between PIU and parental involvement across early, middle, and late adolescence. Families (N = 1206) that included fathers, mothers, and adolescents (48.9% females, Mage  = 13.86 ± 2.48) participated in the study. Adolescents provided a rating of PIU, and fathers and mothers reported their own parenting stress, parental expectations, and parental involvement. The results showed that paternal parenting stress and then expectations mediated the association between PIU and paternal involvement, and maternal parenting stress and then expectations mediated the association between PIU and maternal involvement, indicating a spillover effect. By contrast, the crossover effect was established only in that maternal parenting stress was negatively related to paternal expectations in middle adolescents. Moreover, maternal expectations showed the strongest association with maternal involvement in middle adolescents, whereas paternal expectations were most associated with paternal involvement in late adolescents. These findings underline the necessity of understanding parenting by assessing adolescent developmental stages and paternal and maternal parenting separately. Furthermore, the mediators of parenting stress and parental expectations can be the focus on facilitating parental involvement; the effect of maternal parenting stress on paternal expectations may suggest that intervention programs for fathers should consider more contextual factors.


Assuntos
COVID-19 , Uso da Internet , Adolescente , Humanos , Feminino , Criança , Masculino , Pandemias , Pais , Mães
15.
J Clin Psychol ; 78(5): 971-982, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34655439

RESUMO

OBJECTIVES: Both nonsuicidal self-injury (NSSI) and Internet addiction (IA) are important health issues for adolescents, and social support has been extensively examined as a protective factor for both. This study aims to compare the effect of offline and online social support on IA, and that on NSSI as well. METHOD: A total of 1911 Chinese adolescents (53.27% females, Mage = 16.83 ± 0.37) completed self-report questionnaires assessing offline social support, online social support, IA, and NSSI. RESULTS: The structural equation modeling analysis showed that offline social support was negatively associated with IA and NSSI, while online social support was positively associated with IA and NSSI; IA was positively associated with NSSI. Furthermore, implications for preventions and interventions of IA and NSSI were discussed. The indirect model explained a relatively small variance of NSSI, indicating the possibility of additional factors in the development of NSSI that should be further investigated. CONCLUSION: This study indicated the differences between offline and online social support, and their different associations with IA and NSSI.


Assuntos
Transtorno de Adição à Internet , Comportamento Autodestrutivo , Adolescente , Feminino , Humanos , Transtorno de Adição à Internet/epidemiologia , Masculino , Autorrelato , Comportamento Autodestrutivo/epidemiologia , Apoio Social , Inquéritos e Questionários
16.
Mol Psychiatry ; 25(11): 2672-2684, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32826963

RESUMO

Genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms (SNPs) associated with bipolar disorder (BD), but what the causal variants are and how they contribute to BD is largely unknown. In this study, we used FUMA, a GWAS annotation tool, to pinpoint potential causal variants and genes from the latest BD GWAS findings, and performed integrative analyses, including brain expression quantitative trait loci (eQTL), gene coexpression network, differential gene expression, protein-protein interaction, and brain intermediate phenotype association analysis to identify the functions of a prioritized gene and its connection to BD. Convergent lines of evidence prioritized protein-coding gene G Protein Nucleolar 3 (GNL3) as a BD risk gene, with integrative analyses revealing GNL3's roles in cell proliferation, neuronal functions, and brain phenotypes. We experimentally revealed that BD-related eQTL SNPs rs10865973, rs12635140, and rs4687644 regulate GNL3 expression using dual luciferase reporter assay and CRISPR interference experiment in human neural progenitor cells. We further identified that GNL3 knockdown and overexpression led to aberrant neuronal proliferation and differentiation, using two-dimensional human neural cell cultures and three-dimensional forebrain organoid model. This study gathers evidence that BD-related genetic variants regulate GNL3 expression which subsequently affects neuronal proliferation and differentiation.


Assuntos
Transtorno Bipolar/genética , Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
17.
PLoS Comput Biol ; 16(4): e1007522, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282793

RESUMO

Studies of complex disorders benefit from integrative analyses of multiple omics data. Yet, sample mix-ups frequently occur in multi-omics studies, weakening statistical power and risking false findings. Accurately aligning sample information, genotype, and corresponding omics data is critical for integrative analyses. We developed DRAMS (https://github.com/Yi-Jiang/DRAMS) to Detect and Re-Align Mixed-up Samples to address the sample mix-up problem. It uses a logistic regression model followed by a modified topological sorting algorithm to identify the potential true IDs based on data relationships of multi-omics. According to tests using simulated data, the more types of omics data used or the smaller the proportion of mix-ups, the better that DRAMS performs. Applying DRAMS to real data from the PsychENCODE BrainGVEX project, we detected and corrected 201 (12.5% of total data generated) mix-ups. Of the 21 mix-ups involving errors of racial identity, DRAMS re-assigned all data to the correct racial group in the 1000 Genomes project. In doing so, quantitative trait loci (QTL) (FDR<0.01) increased by an average of 1.62-fold. The use of DRAMS in multi-omics studies will strengthen statistical power of the study and improve quality of the results. Even though very limited studies have multi-omics data in place, we expect such data will increase quickly with the needs of DRAMS.


Assuntos
Biologia Computacional/métodos , Lobo Frontal/metabolismo , Genômica/métodos , Polimorfismo de Nucleotídeo Único , Algoritmos , Cromatina/química , Simulação por Computador , Etnicidade , Feminino , Genoma , Genótipo , Humanos , Modelos Logísticos , Masculino , Modelos Genéticos , Análise de Sequência com Séries de Oligonucleotídeos , RNA-Seq , Reprodutibilidade dos Testes , Fatores Sexuais , Software , Interface Usuário-Computador , Sequenciamento Completo do Genoma
18.
Bioorg Chem ; 114: 105110, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34175719

RESUMO

Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure-activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 µg/mL) and displayed good Pks13 affinity and inhibition (IC50 = 14.3 µM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Policetídeo Sintases/antagonistas & inibidores , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Policetídeo Sintases/metabolismo , Relação Estrutura-Atividade
19.
FASEB J ; 33(7): 8375-8385, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31002527

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease associated with synovial hyperplasia and bone and cartilage destruction. T cells, notably T helper (Th)-1 and Th17 cells, play a critical role in the pathologic process of RA. However, it remains unclear how Th1 and Th17 cells are regulated during RA. In this study, we report that the small ubiquitin-like protein X-linked gene in the G6PD cluster at Xq28 (GdX) regulates the balance of Th17 and regulatory T (Treg) cells during collagen-induced arthritis (CIA). We discovered that the splenocytes of GdX-knockout (KO) mice were insensitive to T-cell stimulants. Correspondingly, GdX-KO mice showed alleviative Th1-mediated delayed-type hypersensitivity and were resistant to CIA compared with wild-type mice. GdX-KO mice showed fewer swollen paws, lower serum proinflammatory cytokine and anti-collagen IgG levels, and decreased synovial hyperplasia. Mechanistically, we observed that deletion of GdX decreased the transcription of proinflammatory cytokines and impaired the Th1 and Th17 differentiation but increased the Treg cell proliferation. Consistently, deletion of GdX decreased the transcription level of T-cell-specific T-box transcription factor and RAR-related orphan receptor-γ transcription factor but increased that of forkhead box P3 after being challenged with type-II collagen. These findings suggested that GdX functions as an important regulator of Th1 or Th17 and Treg cell balance during the inflammatory responses. Therefore, GdX may be a potential target for the therapy of RA.-Fu, Y., Liu, S., Wang, Y., Ren, F., Fan, X., Liang, J., Liu, C., Li, J., Ju, Y., Chang, Z. GdX/UBL4A-knockout mice resist collagen-induced arthritis by balancing the population of Th1/Th17 and regulatory T cells.


Assuntos
Artrite Experimental/enzimologia , Linfócitos T Reguladores/enzimologia , Células Th1/enzimologia , Células Th17/enzimologia , Ubiquitinas/deficiência , Animais , Artrite Experimental/genética , Artrite Experimental/patologia , Citocinas/genética , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Células Th1/patologia , Células Th17/patologia , Transcrição Gênica , Ubiquitinas/metabolismo
20.
J Adolesc ; 79: 103-111, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31927450

RESUMO

BACKGROUND: In recent years, many studies have examined risks factors that facilitated the transition from suicide ideation to suicide attempts. Few studies, however, have examined protective factors against this transition. The current study thus assessed two protective factors, self-compassion and family cohesion, in buffering the transition from suicide ideation to suicide attempts. METHOD: A number of 520 Chinese adolescents (43.46% females, mean age = 12.96 years) completed questionnaires assessing self-compassion, family cohesion, suicide ideation, and suicide attempts two times with a 12-month interval. RESULTS: Self-compassion significantly moderated the association between Wave 1 SI and later SA. The positive dimension of self-compassion thwarted the transition from SI and SA, and the negative dimension of self-compassion strengthened the associations. In addition, family cohesion also significantly moderated the transition from SI to SA. CONCLUSION: Increasing the levels of self-compassion and family cohesion may be the targets for treating adolescents with suicide ideation to prevent them from attempting suicide.


Assuntos
Empatia , Relações Familiares/psicologia , Autoimagem , Ideação Suicida , Tentativa de Suicídio/psicologia , Adolescente , China , Feminino , Humanos , Masculino , Fatores de Risco , Tentativa de Suicídio/prevenção & controle , Tentativa de Suicídio/estatística & dados numéricos , Inquéritos e Questionários
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