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OBJECTIVE: The objective of the meta-analysis was to determine the influence of uterine fibroids on adverse outcomes, with specific emphasis on multiple or large (≥ 5 cm in diameter) fibroids. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), and SinoMed databases for eligible studies that investigated the influence of uterine fibroids on adverse outcomes in pregnancy. The pooled risk ratio (RR) of the variables was estimated with fixed effect or random effect models. RESULTS: Twenty-four studies with 237 509 participants were included. The pooled results showed that fibroids elevated the risk of adverse outcomes, including preterm birth, cesarean delivery, placenta previa, miscarriage, preterm premature rupture of membranes (PPROM), placental abruption, postpartum hemorrhage (PPH), fetal distress, malposition, intrauterine fetal death, low birth weight, breech presentation, and preeclampsia. However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia. Subgroup analysis showed an association between larger fibroids and significantly elevated risks of breech presentation, PPH, and placenta previa in comparison with small fibroids. Multiple fibroids did not increase the risk of breech presentation, placental abruption, cesarean delivery, PPH, placenta previa, PPROM, preterm birth, and intrauterine growth restriction. Meta-regression analyses indicated that maternal age only affected the relationship between uterine fibroids and preterm birth, and BMI influenced the relationship between uterine fibroids and intrauterine fetal death. Other potential confounding factors had no impact on malposition, fetal distress, PPROM, miscarriage, placenta previa, placental abruption, and PPH. CONCLUSION: The presence of uterine fibroids poses increased risks of adverse pregnancy and obstetric outcomes. Fibroid size influenced the risk of breech presentation, PPH, and placenta previa, while fibroid numbers had no impact on the risk of these outcomes.
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Leiomioma , Resultado da Gravidez , Neoplasias Uterinas , Feminino , Humanos , Gravidez , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Descolamento Prematuro da Placenta/epidemiologia , Descolamento Prematuro da Placenta/etiologia , Apresentação Pélvica/epidemiologia , Cesárea/estatística & dados numéricos , Ruptura Prematura de Membranas Fetais/epidemiologia , Ruptura Prematura de Membranas Fetais/etiologia , Leiomioma/epidemiologia , Leiomioma/complicações , Placenta Prévia/epidemiologia , Hemorragia Pós-Parto/epidemiologia , Hemorragia Pós-Parto/etiologia , Complicações Neoplásicas na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Fatores de Risco , Neoplasias Uterinas/epidemiologia , Neoplasias Uterinas/complicaçõesRESUMO
Social ostracism, a negative affective experience in interpersonal interactions, is thought to modulate the gaze-cueing effect (GCE). However, it is unclear whether the impact of social exclusion on the GCE is related to the identity of the cueing face. Therefore, the present study employed a two-phase paradigm to address this issue. In the first phase, two groups of participants were instructed to complete a Cyberball game with two virtual avatars to establish a binding relationship between a specific face's identity and the emotions of social exclusion or inclusion. In the second phase, these two virtual avatars (exclusion faces/inclusion faces) and two new faces (control faces) were used as cueing faces in the gaze-cueing task. The results found that, for the exclusion group, the magnitudes of the GCEs for the exclusion and exclusion-control faces were similar in the 200 ms stimulus onset asynchrony (SOA) condition, while the exclusion face's GCE was significantly smaller than that of the exclusion-control face in the 700 ms SOA condition. In contrast, for the inclusion group, the GCEs for inclusion and inclusion-control faces in both the 200 ms SOA and 700 ms SOA conditions did not significantly differ. This study reveals that the effect of social exclusion on the GCE is related to the identity of the cueing face, with individuals more reluctant to follow the gaze direction of excluder and shift their attention and provides experimental evidence that the perception of higher social relations can exert a top-down impact on the processing of social spatial cues.
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Atenção , Sinais (Psicologia) , Fixação Ocular , Humanos , Masculino , Feminino , Adulto Jovem , Atenção/fisiologia , Fixação Ocular/fisiologia , Adulto , Reconhecimento Facial/fisiologia , Percepção Social , Distância PsicológicaRESUMO
The auditory gaze cueing effect (auditory-GCE) is a faster response to auditory targets at an eye-gaze cue location than at a non-cue location. Previous research has found that auditory-GCE can be influenced by the integration of both gaze direction and emotion conveyed through facial expressions. However, it is unclear whether the emotional information of auditory targets can be cross-modally integrated with gaze direction to affect auditory-GCE. Here, we set neutral faces with different gaze directions as cues and three emotional sounds (fearful, happy, and neutral) as targets to investigate how the emotion of sound target modulates the auditory-GCE. Moreover, we conducted a controlled experiment using arrow cues. The results show that the emotional content of sound targets influences the auditory-GCE but only for those induced by facial cues. Specifically, fearful sounds elicit a significantly larger auditory-GCE compared to happy and neutral sounds, indicating that the emotional content of auditory targets plays a modulating role in the auditory-GCE. Furthermore, this modulation appears to occur only at a higher level of social meaning, involving the integration of emotional information from a sound with social gaze direction, rather than at a lower level, which involves the integration of direction and auditory emotion.
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Genome-wide association studies (GWAS) have reported substantial genomic loci significantly associated with clinical risk of bipolar disorder (BD), and studies combining techniques of genetics, neuroscience, neuroimaging, and pharmacology are believed to help tackle clinical problems (e.g., identifying novel therapeutic targets). However, translating findings of psychiatric genetics into biological mechanisms underlying BD pathogenesis remains less successful. Biological impacts of majority of BD GWAS risk loci are obscure, and the involvement of many GWAS risk genes in this illness is yet to be investigated. It is thus necessary to review the progress of applying BD GWAS risk genes in the research and intervention of the disorder. A comprehensive literature search found that a number of such risk genes had been investigated in cellular or animal models, even before they were highlighted in BD GWAS. Intriguingly, manipulation of many BD risk genes (e.g., ANK3, CACNA1C, CACNA1B, HOMER1, KCNB1, MCHR1, NCAN, SHANK2 etc.) resulted in altered murine behaviors largely restoring BD clinical manifestations, including mania-like symptoms such as hyperactivity, anxiolytic-like behavior, as well as antidepressant-like behavior, and these abnormalities could be attenuated by mood stabilizers. In addition to recapitulating phenotypic characteristics of BD, some GWAS risk genes further provided clues for the neurobiology of this illness, such as aberrant activation and functional connectivity of brain areas in the limbic system, and modulated dendritic spine morphogenesis as well as synaptic plasticity and transmission. Therefore, BD GWAS risk genes are undoubtedly pivotal resources for modeling this illness, and might be translational therapeutic targets in the future clinical management of BD. We discuss both promising prospects and cautions in utilizing the bulk of useful resources generated by GWAS studies. Systematic integrations of findings from genetic and neuroscience studies are called for to promote our understanding and intervention of BD.
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Transtorno Bipolar , Estudo de Associação Genômica Ampla , Animais , Transtorno Bipolar/diagnóstico , Encéfalo , Predisposição Genética para Doença , Camundongos , FenótipoRESUMO
Genome-wide association studies (GWASs) have revealed substantial genetic components comprised of single nucleotide polymorphisms (SNPs) in the heritable risk of psychiatric disorders. However, genetic risk factors not covered by GWAS also play pivotal roles in these illnesses. Tandem repeats, which are likely functional but frequently overlooked by GWAS, may account for an important proportion in the "missing heritability" of psychiatric disorders. Despite difficulties in characterizing and quantifying tandem repeats in the genome, studies have been carried out in an attempt to describe impact of tandem repeats on gene regulation and human phenotypes. In this review, we have introduced recent research progress regarding the genomic distribution and regulatory mechanisms of tandem repeats. We have also summarized the current knowledge of the genetic architecture and biological underpinnings of psychiatric disorders brought by studies of tandem repeats. These findings suggest that tandem repeats, in candidate psychiatric risk genes or in different levels of linkage disequilibrium (LD) with psychiatric GWAS SNPs and haplotypes, may modulate biological phenotypes related to psychiatric disorders (e.g., cognitive function and brain physiology) through regulating alternative splicing, promoter activity, enhancer activity and so on. In addition, many tandem repeats undergo tight natural selection in the human lineage, and likely exert crucial roles in human brain evolution. Taken together, the putative roles of tandem repeats in the pathogenesis of psychiatric disorders is strongly implicated, and using examples from previous literatures, we wish to call for further attention to tandem repeats in the post-GWAS era of psychiatric disorders.
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Estudo de Associação Genômica Ampla , Transtornos Mentais , Encéfalo , Humanos , Desequilíbrio de Ligação/genética , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências de Repetição em TandemRESUMO
Alternative splicing of schizophrenia risk genes, such as DRD2, GRM3, and DISC1, has been extensively described. Nevertheless, the alternative splicing characteristics of the growing number of schizophrenia risk genes identified through genetic analyses remain relatively opaque. Recently, transcriptomic analyses in human brains based on short-read RNA-sequencing have discovered many "local splicing" events (e.g., exon skipping junctions) associated with genetic risk of schizophrenia, and further molecular characterizations have identified novel spliced isoforms, such as AS3MTd2d3 and ZNF804AE3E4. In addition, long-read sequencing analyses of schizophrenia risk genes (e.g., CACNA1C and NRXN1) have revealed multiple previously unannotated brain-abundant isoforms with therapeutic potentials, and functional analyses of KCNH2-3.1 and Ube3a1 have provided examples for investigating such spliced isoforms in vitro and in vivo. These findings suggest that alternative splicing may be an essential molecular mechanism underlying genetic risk of schizophrenia, however, the incomplete annotations of human brain transcriptomes might have limited our understanding of schizophrenia pathogenesis, and further efforts to elucidate these transcriptional characteristics are urgently needed to gain insights into the illness-correlated brain physiology and pathology as well as to translate genetic discoveries into novel therapeutic targets.
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Processamento Alternativo , Esquizofrenia , Processamento Alternativo/genética , Humanos , Fatores de Transcrição Kruppel-Like/genética , Metiltransferases/genética , Isoformas de Proteínas/genética , Splicing de RNA , Esquizofrenia/genética , Análise de Sequência de RNARESUMO
We investigate the propagation and interaction dynamics of the optical dark bound solitons for the defocusing Lakshmanan-Porsezian-Daniel equation, which is a physically relevant generalization of the nonlinear Schrödinger equation involving the higher-order effects. Explicit N-dark soliton solutions in the compact determinant form are constructed via the binary Darboux transformation method. Bound states of the dark solitons are discussed when the incoherent solitons have the same velocity. We find an interesting phenomenon that dark soliton molecules and double-valley dark solitons (DVDSs) can be obtained by controlling the interval of the bound state dark solitons, and abundant interaction modalities between them can be formed. Moreover, dark soliton molecules always undergo elastic interactions with other solitons, while interactions for the DVDSs are usually inelastic, and special parameter conditions for elastic interaction of DVDSs through asymptotic analysis are obtained. Numerical simulations are employed to verify the stability of the bound state dark solitons. Analytical results obtained in this paper are expected to be useful for the experimental realization of bound-state dark solitons in optical fibers with higher-order effects and a further understanding of their optical transmission properties..
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Increased expression of the 3.1 isoform of the KCNH2 potassium channel has been associated with cognitive dysfunction and with schizophrenia, yet little is known about the underlying pathophysiological mechanisms. Here, by using in vivo wireless local field potential recordings during working memory processing, in vitro brain slice whole-cell patching recordings and in vivo stereotaxic hippocampal injection of AAV-encoded expression, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and functional connectivity associated with reductions of SERPING1, CFH, and CD74 in the KCNH2-3.1 overexpression transgenic mice. The differentially expressed genes in mice are enriched in neurons and microglia, and reduced expression of these genes dysregulates the complement cascade, which has been previously linked to synaptic plasticity. We find that knockdown of these genes in primary neuronal-microglial cocultures from KCNH2-3.1 mice impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Translating to humans, we find analogous dysfunctional interactions between hippocampus and prefrontal cortex in coupling of the fMRI blood oxygen level-dependent (BOLD) signal during working memory in healthy subjects carrying alleles associated with increased KCNH2-3.1 expression in brain. Our data uncover a previously unrecognized role of the truncated KCNH2-3.1 potassium channel in mediating complement activation, which may explain its association with altered hippocampal-prefrontal connectivity and synaptic function. These results provide a potential molecular link between increased KCNH2-3.1 expression, synapse alterations, and hippocampal-prefrontal circuit abnormalities implicated in schizophrenia.
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Ativação do Complemento/fisiologia , Canal de Potássio ERG1/metabolismo , Memória de Curto Prazo/fisiologia , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Ativação do Complemento/imunologia , Canal de Potássio ERG1/genética , Feminino , Hipocampo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transmissão Sináptica/fisiologia , Lobo Temporal/metabolismoRESUMO
BACKGROUND: Acute postoperative pain plays an important role in the perioperative neurocognitive disorders (PND). The pathogenesis of PND is still unknown, but it is generally believed that peripheral and central nervous system inflammation play an important role, and acute postoperative pain is also thought to aggravate postoperative inflammatory response. The aim of the present study is to explore the effect of acute postoperative pain on peripheral and central nervous system inflammation and related cognitive impairment behaviour in elderly rats after surgery. METHODS: Rats were assigned into four groups: control, surgery for internal fixation for tibial fracture, surgery with analgesia using intraperitoneal morphine, and morphine without surgery. Pain was assessed by the Subjective Pain Scale. The spatial memory of rats was assessed by the Morris water maze (delayed matching task) from the second day to the seventh day after surgery (POD2-POD7). In part of the rats, the pro-inflammatory cytokines TNF-α in plasma, the medial prefrontal cortex (mPFC), and the hippocampus were determined by ELISA on the POD2. The activation of microglia and the expression of c-Fos in the hippocampal CA1 regions and mPFC were detected by the immunohistochemical method on the POD2. RESULTS: Acute postoperative pain and spatial memory impairment occurred after operation, and postoperative analgesia could significantly improve the both parameters. Additionally, on the POD2, the levels of TNF-α in plasma, hippocampus and mPFC were significantly increased, while the activation of microglia cells and the expression c-Fos in the hippocampal CA1 regions and mPFC were significantly increased. And postoperative analgesia with morphine significantly inhibited the above reactions. CONCLUSION: Our data suggest that acute postoperative pain increases the incidence of perioperative neurocognitive disorders. Peripheral and central nervous system inflammation may be involved in this cognitive impairment. And reducing the intensity of acute postoperative pain may be one of the main preventive strategies for PND.
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Inflamação/complicações , Transtornos Neurocognitivos/complicações , Dor Pós-Operatória/complicações , Complicações Pós-Operatórias/fisiopatologia , Fraturas da Tíbia/cirurgia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Inflamação/fisiopatologia , Fixadores Internos , Masculino , Dor Pós-Operatória/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
Visual attention and visual working memory (VWM) are two major cognitive functions in humans, and they have much in common. A growing body of research has investigated the effect of emotional information on visual attention and VWM. Interestingly, contradictory findings have supported both a negative bias and a positive bias toward emotional faces (e.g., angry faces or happy faces) in the attention and VWM fields. We found that the classical paradigms-that is, the visual search paradigm in attention and the change detection paradigm in VWM-are considerably similar. The settings of these paradigms could therefore be responsible for the contradictory results. In this paper, we compare previous controversial results from behavioral and neuroscience studies using these two paradigms. We suggest three possible contributing factors that have significant impacts on the contradictory conclusions regarding different emotional bias effects; these factors are stimulus choice, experimental setting, and cognitive process. We also propose new research directions and guidelines for future studies.
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Atenção/fisiologia , Emoções , Expressão Facial , Memória de Curto Prazo/fisiologia , Modelos Neurológicos , Ira , Eletroencefalografia , Felicidade , Humanos , Imageamento por Ressonância Magnética , FotografaçãoRESUMO
Many neuropsychiatric and neurodevelopmental disorders commonly share genetic risk factors. To date, the mechanisms driving the pathogenesis of these disorders, particularly how genetic variations affect the function of risk genes and contribute to disease symptoms, remain largely unknown. Neurexins are a family of synaptic adhesion molecules, which play important roles in the formation and establishment of synaptic structure, as well as maintenance of synaptic function. Accumulating genomic findings reveal that genetic variations within genes encoding neurexins are associated with a variety of psychiatric conditions such as schizophrenia, autism spectrum disorder, and some developmental abnormalities. In this review, we focus on NRXN1, one of the most compelling psychiatric risk genes of the neurexin family. We performed a comprehensive survey and analysis of current genetic and molecular data including both common and rare alleles within NRXN1 associated with psychiatric illnesses, thus providing insights into the genetic risk conferred by NRXN1. We also summarized the neurobiological evidences, supporting the function of NRXN1 and its protein products in synaptic formation, organization, transmission and plasticity, as well as disease-relevant behaviors, and assessed the mechanistic link between the mutations of NRXN1 and synaptic and behavioral pathology in neuropsychiatric disorders.
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Proteínas de Ligação ao Cálcio/genética , Transtornos Mentais/genética , Moléculas de Adesão de Célula Nervosa/genética , Alelos , Transtorno do Espectro Autista/genética , Proteínas de Ligação ao Cálcio/metabolismo , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/metabolismo , Esquizofrenia/genéticaRESUMO
BACKGROUND: Chronic postsurgical pain (CPSP) is common and would reduce the quality of life of patients. Transversus abdominal plane (TAP) block has been widely used in lower abdominal surgery and many researches demonstrated that it could improve acute postsurgical pain. We aim to determine whether TAP block could improve chronic postoperative pain at 3 months and 6 months after colorectal surgery. METHODS: A total of 307 patients received selective colorectal surgery under general anesthesia between January, 2015 and January, 2019 in a single university hospital were included: 128 patients received TAP block combined with patient-controlled intravenous analgesia (PCIA) for postsurgical analgesia (group TP) and 179 only administrated with PCIA (group P). Main outcome was the NRS score of pain at 3 months after colorectal surgery. The data was analyzed by two-way repeated measures anova and the chi-square test. RESULTS: The NRS score at rest and during movement was decreased significantly at 24 h after surgery (rest NRS 1.07 ± 1.34 vs 1.65 ± 1.67, movement NRS 3.00 ± 1.45 vs 3.65 ± 1.89; all P = 0.003) in group TP than those of group P. There was no significant difference of NRS score at 48 h after surgery (P > 0.05). At 3 months after surgery, the NRS score during movement was also lower in group TP than that in group P (0.59 ± 1.23 vs 0.92 ± 1.65, P = 0.045). There was no significant difference of NRS score at 6 months after surgery (P > 0.05). The prevalence of CPSP was 19.5% (25/128) in group TP and 20.7% (37/179) in group P at 3 months after surgery. 13.2% (17/128) of patients suffered from CPSP in group TP and 13.9% (25/179) in group P at 6 months after surgery. Both at 3 months and 6 months after surgery, there was no statistical difference of the prevalence of CPSP between the two groups (all P > 0.05) . CONCLUSIONS: TAP block reduced NRS during movement at 3 months after surgery but did not reduce the incidence of CPSP at 3 months and 6 months after selective colorectal surgery.
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Colo/cirurgia , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Reto/cirurgia , Músculos Abdominais/inervação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling. As such, bispecific antibodies may be particularly useful in activating multicomponent receptor complexes. Here, we describe a biparatopic (i.e. targeting two different epitopes on the same target) format that can activate the endocrine fibroblast growth factor (FGF) 21 receptor (FGFR) complex containing ß-Klotho and FGFR1c. This format was constructed by grafting two different antigen-specific VH domains onto the VH and VL positions of an IgG, yielding a tetravalent binder with two potential geometries, a close and a distant, between the two paratopes. Our results revealed that the biparatopic molecule provides activities that are not observed with each paratope alone. Our approach could help address the challenges with heterogeneity inherent in other bispecific formats and could provide the means to adjust intramolecular distances of the antibody domains to drive optimal activity in a bispecific format. In conclusion, this format is versatile, is easy to construct and produce, and opens a new avenue for agonistic antibody discovery and development.
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Anticorpos Biespecíficos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Sítios de Ligação de Anticorpos , Linhagem Celular , Epitopos/metabolismo , Humanos , Proteínas Klotho , Ligantes , Ratos , Anticorpos de Cadeia Única/metabolismoRESUMO
Senile plaque accumulation and neurofibrillary tangles are primary characteristics of Alzheimer's disease. We aimed to assess the protective functions of naringenin against ß-amyloid protein fragment 25-35 (Aß25-35)-caused nerve damage in differentiated PC12 cells, and study the potential mechanisms. We evaluated cell viability and apoptosis using the 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test and flow cytometry, respectively. Moreover, we measured protein kinase B (Akt), glycogen synthase kinase-3ß (GSK-3ß), and caspase-3 activity via western blotting and RT-PCR. We found that naringenin protected cell against Aß25-35-caused nerve damage by increasing cell viability, promoting Akt and GSK3ß activation, and inhibiting cell apoptosis and caspase-3 activity. However, treatment with the estrogen receptor (ER) antagonist ICI182, 780 or phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 suppressed the effects of naringenin. Our results suggested that naringenin could effectively suppress Aß25-35-caused nerve damage in PC12 cells by regulating the ER and PI3K/Akt pathways.
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Peptídeos beta-Amiloides/toxicidade , Citoproteção/fisiologia , Retículo Endoplasmático/metabolismo , Flavanonas/farmacologia , Fragmentos de Peptídeos/toxicidade , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Retículo Endoplasmático/efeitos dos fármacos , Células PC12 , Inibidores de Fosfoinositídeo-3 Quinase , RatosRESUMO
Producing pure and well behaved bispecific antibodies (bsAbs) on a large scale for preclinical and clinical testing is a challenging task. Here, we describe a new strategy for making monovalent bispecific heterodimeric IgG antibodies in mammalian cells. We applied an electrostatic steering mechanism to engineer antibody light chain-heavy chain (LC-HC) interface residues in such a way that each LC strongly favors its cognate HC when two different HCs and two different LCs are co-expressed in the same cell to assemble a functional bispecific antibody. We produced heterodimeric IgGs from transiently and stably transfected mammalian cells. The engineered heterodimeric IgG molecules maintain the overall IgG structure with correct LC-HC pairings, bind to two different antigens with comparable affinity when compared with their parental antibodies, and retain the functionality of parental antibodies in biological assays. In addition, the bispecific heterodimeric IgG derived from anti-HER2 and anti-EGF receptor (EGFR) antibody was shown to induce a higher level of receptor internalization than the combination of two parental antibodies. Mouse xenograft BxPC-3, Panc-1, and Calu-3 human tumor models showed that the heterodimeric IgGs strongly inhibited tumor growth. The described approach can be used to generate tools from two pre-existent antibodies and explore the potential of bispecific antibodies. The asymmetrically engineered Fc variants for antibody-dependent cellular cytotoxicity enhancement could be embedded in monovalent bispecific heterodimeric IgG to make best-in-class therapeutic antibodies.
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Imunoglobulina G/química , Eletricidade Estática , Aminoácidos/química , Animais , Citotoxicidade Celular Dependente de Anticorpos , Células CHO , Linhagem Celular , Cricetulus , Dimerização , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/imunologia , Camundongos , Engenharia de Proteínas , Ressonância de Plasmônio de SuperfícieRESUMO
Signal transducers and activators of transcription 1 (STAT1) is activated by tyrosine phosphorylation upon interferon-gamma (IFN-gamma) stimulation. Phosphorylated STAT1 translocates into nucleus to initiate the transcription of IFN-gamma target genes that are important in mediating antiviral, antiproliferative, and immune response. The inactivation of STAT1 is mainly accomplished via tyrosine dephosphorylation by the nuclear isoform of T cell protein tyrosine phosphatase (TC45) in nucleus. Here we show that beta-arrestin1 directly interacts with STAT1 in nucleus after IFN-gamma treatment and accelerates STAT1 tyrosine dephosphorylation by recruiting TC45. Consequently, beta-arrestin1 negatively regulates STAT1 transcription activity as well as the IFN-gamma-induced gene transcription. Application of beta-arrestin1 siRNA significantly enhances IFN-gamma-induced antiviral response in vesicular stomatitis virus (VSV)-infected cells. Our results reveal that nuclear beta-arrestin1, acting as a scaffold for the dephosphorylation of STAT1, is an essential negative regulator of IFN-gamma signaling and participates in the IFN-gamma-induced cellular antiviral response.
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Antivirais/metabolismo , Arrestinas/metabolismo , Núcleo Celular/metabolismo , Interferon gama/metabolismo , Fator de Transcrição STAT1/metabolismo , Animais , Arrestinas/genética , Linhagem Celular , Regulação da Expressão Gênica , Genes Reporter , Humanos , Interferon gama/genética , Camundongos , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fator de Transcrição STAT1/genética , Técnicas do Sistema de Duplo-Híbrido , beta-ArrestinasRESUMO
Dysbindin is a schizophrenia susceptibility gene required for the development of dendritic spines. The expression of dysbindin proteins is decreased in the brains of schizophrenia patients, and neurons in mice carrying a deletion in the dysbindin gene have fewer dendritic spines. Hence, dysbindin might contribute to the spine pathology of schizophrenia, which manifests as a decrease in the number of dendritic spines. The development of dendritic spines is a dynamic process involving formation, retraction, and transformation of dendritic protrusions. It has yet to be determined whether dysbindin regulates the dynamics of dendritic protrusions. Here we address this question using time-lapse imaging in hippocampal neurons. Our results show that dysbindin is required to stabilize dendritic protrusions. In dysbindin-null neurons, dendritic protrusions are hyperactive in formation, retraction, and conversion between different types of protrusions. We further show that CaMKIIα is required for the stabilization of mushroom/thin spines, and that the hyperactivity of dendritic protrusions in dysbindin-null neurons is attributed in part to decreased CaMKIIα activity resulting from increased inhibition of CaMKIIα by Abi1. These findings elucidate the function of dysbindin in the dynamic morphogenesis of dendritic protrusions, and reveal the essential roles of dysbindin and CaMKIIα in the stabilization of dendritic protrusions during neuronal development.
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Espinhas Dendríticas/fisiologia , Proteínas Associadas à Distrofina/fisiologia , Esquizofrenia/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Espinhas Dendríticas/ultraestrutura , Disbindina , Proteínas Associadas à Distrofina/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , TransfecçãoRESUMO
Many previous event-related potential (ERP) studies have linked the feedback related negativity (FRN) component with medial frontal cortex processing and associated this component with depression. Few if any studies have investigated the processing of neutral feedback in mildly depressive subjects in the normal population. Two experiments compared brain responses to neutral feedback with behavioral performance in mildly depressed subjects who scored highly on the Beck Depression Inventory (high BDI) and a control group with lower BDI scores (low BDI). In the first study, the FRN component was recorded when neutral, negative or positive feedback was pseudo-randomly delivered to the two groups in a time estimation task. In the second study, real feedback was provided to the two groups in the same task in order to measure their actual accuracy of performance. The results of experiment one (Exp. 1) revealed that a larger FRN effect was elicited by neutral feedback than by negative feedback in the low BDI group, but no significant difference was found between neutral condition and negative condition in the High BDI group. The present findings demonstrated that depressive tendencies influence the processing of neutral feedback in medial frontal cortex. The FRN effect may work as a helpful index for investigating cognitive bias in depression in future studies.
Assuntos
Encéfalo/fisiopatologia , Depressão/fisiopatologia , Potenciais Evocados/fisiologia , Retroalimentação Psicológica/fisiologia , Adolescente , Adulto , Mapeamento Encefálico , Depressão/psicologia , Eletroencefalografia , Feminino , Humanos , Masculino , Adulto JovemRESUMO
The gene DTNBP1 encodes the protein dysbindin and is among the most promising and highly investigated schizophrenia-risk genes. Accumulating evidence suggests that dysbindin plays an important role in the regulation of neuroplasticity. Dysbindin was reported to be a stable component of BLOC-1 complex in the cytosol. However, little is known about the endogenous dysbindin-containing complex in the brain synaptosome. In this study, we investigated the associated proteome of dysbindin in the P2 synaptosome fraction of mouse brain. Our data suggest that dysbindin has three isoforms associating with different complexes in the P2 fraction of mouse brain. To facilitate immunopurification, BAC transgenic mice expressing a tagged dysbindin were generated, and 47 putative dysbindin-associated proteins, including all components of BLOC-1, were identified by mass spectrometry in the dysbindin-containing complex purified from P2. The interactions of several selected candidates, including WDR11, FAM91A1, snapin, muted, pallidin, and two proteasome subunits, PSMD9 and PSMA4, were verified by coimmunoprecipitation. The specific proteasomal activity is significantly reduced in the P2 fraction of the brains of the dysbindin-null mutant (sandy) mice. Our data suggest that dysbindin is functionally interrelated to the ubiquitin-proteasome system and offer a molecular repertoire for future study of dysbindin functional networks in brain.
Assuntos
Encéfalo/metabolismo , Proteínas Associadas à Distrofina/metabolismo , Complexos Multiproteicos/metabolismo , Plasticidade Neuronal/fisiologia , Proteoma/metabolismo , Esquizofrenia/genética , Sinaptossomos/metabolismo , Animais , Proteínas de Transporte/metabolismo , Disbindina , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular , Lectinas/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos/isolamento & purificação , Isoformas de Proteínas/metabolismoRESUMO
A novel electrode material of the three-dimensional (3D) multicomponent oxide NiCo2O4@NiMoO4 core-shell was synthesized via a facile two-step hydrothermal method using a post-annealing procedure. The uniform NiMoO4 nanosheets were grown on the seaurchin-like NiCo2O4 backbone to form a NiCo2O4@NiMoO4 core-shell material constructed by interconnected ultrathin nanosheets, so as to produce hierarchical mesopores with a large specific surface area of 100.3 m(2) g(-1). The porous feature and core-shell structure can facilitate the penetration of electrolytic ions and increases the number of electroactive sites. Hence, the NiCo2O4@NiMoO4 material exhibited a high specific capacitance of 2474 F g(-1) and 2080 F g(-1) at current densities of 1 A g(-1) and 20 A g(-1) respectively, suggesting that it has not only a very large specific capacitance, but also a good rate performance. In addition, the capacitance loss was only 5.0% after 1000 cycles of charge and discharge tests at the current density of 10 A g(-1), indicating high stability. The excellent electrochemical performance is mainly attributed to its 3D core-shell and hierarchical mesoporous structures which can provide unobstructed pathways for the fast diffusion and transportation of ions and electrons, a large number of active sites and good strain accommodation.