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STUDY QUESTION: Can novel genetic factors contributing to early embryonic arrest in infertile patients be identified, along with the underlying mechanisms of the pathogenic variant? SUMMARY ANSWER: We identified a heterozygous variant in the SPRY4 (sprouty RTK signaling antagonist 4) in infertile patients and conducted in vitro and in vivo studies to investigate the effects of the variant/deletion, highlighting its critical role in female reproductive health. WHAT IS KNOWN ALREADY: SPRY4 acts as a negative regulator of receptor tyrosine kinases (RTKs) and functions as a tumor suppressor. Its abnormal expression can lead to recurrent miscarriage by affecting trophoblast function. In mice, Spry4 knockout (KO) leads to craniofacial anomalies and growth defects. A human study links the SPRY4 variant to a male patient with isolated hypogonadotropic hypogonadism (IHH), hypothetically impacting gonadotropin-releasing hormone (GnRH) neurons, and causing reproductive dysfunctions. SPRY4 is thus potentially integral in regulating endocrine homeostasis and reproductive function. To date, no study has reported SPRY4 variants associated with female fertility, and a causal relationship has not been established with functional evidence. STUDY DESIGN, SIZE, DURATION: Whole-exome sequencing (WES) was performed in 392 infertile women who suffered from primary infertility of unknown reason, and the heterozygous SPRY4 variant were identified in one independent family. The infertile patients presenting were recruited from July 2017 to November 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women diagnosed with primary infertility were recruited from the Reproduction Center of Zhongshan Hospital, Fudan University. Genomic DNA was extracted from peripheral blood for WES analysis. The SPRY4 variant were identified through WES, in silico analysis, and variant screening. All variants were confirmed by Sanger sequencing. The effects of the variants were investigated in human embryonic kidney (HEK) 293T (HEK293T) cells via western blotting, and in mouse oocytes and embryos through complementary RNA (cRNA) injection, RNA sequencing, fluorescence, absorbance, and RT-qPCR assays. Gene function was further examined in Spry4 KO mice via histology, western blotting, ELISA, and RT-qPCR assays. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a missense heterozygous pathogenic variant in SPRY4 (GRCh38, GenBank: NM_030964.5, c.157C>T p.(Arg53Trp), rs200531302) that reduces SPRY4 protein levels in HEK293T cells and disrupts the redox system and mitochondrial function in mouse oocyte, and perturbs developmental potential in mouse embryos. These phenotypes could be partially reversed by the exogenous addition of Nrf1 cRNA. Additionally, Spry4-/- mice exhibit ovarian oxidative stress and decreased ovarian function. LIMITATIONS, REASONS FOR CAUTION: Due to the limited WES data and population, we identified only one family with a SPRY4 mutation. The deeper mechanism and therapeutic strategy should be further investigated through mutant mice and recovery experiment. WIDER IMPLICATIONS OF THE FINDINGS: Our study has identified a pathogenic variant in SPRY4 associated with early embryonic arrest in humans. These findings enhance our understanding of the role of SPRY4 in early embryonic development and present a new genetic marker for female infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (82071643 and 82171655) and Natural Science Foundation of Shanghai (22ZR1456200). None of the authors have any competing interests. TRIAL REGISTRATION NUMBER: N/A.
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AIMS: 5 mC methylation and hydroxymethylation (5hmC) are associated with Alzheimer's disease (AD). However, previous studies were limited by the absence of a 5hmC calculation. This study aims to find AD associated predictors and potential therapeutic chemicals using bioinformatics approach integrating 5 mC, 5hmC, and expression changes, and an AD mouse model. METHODS: Gene expression microarray and 5 mC and 5hmC sequencing datasets were downloaded from GEO repository. 142 AD and 52 normal entorhinal cortex specimens were enrolled. Data from oxidative bisulfite sequencing (oxBS)-treated samples, which represent only 5 mC, were used to calculate 5hmC level. Functional analyses, random forest supervised classification and methylation validation were applied. Potential chemicals were predicted by CMap. Morris water maze, Y maze and novel object recognition behavior tests were performed using FAD4T AD mice model. Cortex and hippocampus tissues were isolated for immunohistochemical staining. RESULTS: C1QTNF5, UBD, ZFP106, NEDD1, AKT3, and MBP genes involving 13 promoter CpG sites with 5mc, 5hmC methylation and expression difference were identified. AKT3 and MBP were down-regulated in both patients and mouse model. Three CpG sites in AKT3 and MBP showed significant methylation difference on validation. FAD4T AD mice showed recession in brain functions and lower AKT3 expression in both cortex and hippocampus. Ten chemicals were predicted as potential treatments for AD. CONCLUSIONS: AKT3 and MBP may be associated with AD pathology and could serve as biomarkers. The ten predicted chemicals might offer new therapeutic approaches. Our findings could contribute to identifying novel markers and advancing the understanding of AD mechanisms.
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Doença de Alzheimer , Metilação de DNA , Proteínas Proto-Oncogênicas c-akt , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Animais , Camundongos , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Masculino , Modelos Animais de Doenças , Biomarcadores/metabolismo , Córtex Entorrinal/metabolismo , Córtex Entorrinal/patologia , Feminino , Idoso , Hipocampo/metabolismo , Expressão Gênica , Camundongos TransgênicosRESUMO
Focal cortical dysplasia (FCD) is a structural lesion that is the most common anatomical lesion identified in children, and the second most common in adults with drug-resistant focal-onset epilepsy. These lesions vary in size, location, and histopathological manifestations. FCDs are classified into three subtypes associated with loss-of-function mutations in PI3K/AKT, TSC1/TSC2, RHEB, and DEPDC/NPRL2/NPRL3. During the decades of research into FCD, experimental models have played an irreplaceable role in the research design of studies investigating disease pathogenesis, pathophysiology, and treatment. Further, the establishment of FCD experimental models has moved the field forward by (1) revealing the cellular processes and signaling pathways underlying FCD pathogenesis and (2) varying the methods and materials to study the function of FCD proteins. Currently, FCD experimental models are predominantly murine, with each model providing unique insights into FCD lesions. This review briefly summarizes the pathology and molecular functions of FCD, further comparing the available modeling methods and indexes, as well as the utilization of models, followed by an analysis of the similarities, advantages, and disadvantages between these models and human FCD.
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Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5-78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.
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Cordoma , Humanos , Cordoma/genética , Cordoma/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Adolescente , Adulto Jovem , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Mutação , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Nucleares/genética , Neoplasias da Base do Crânio/genética , Neoplasias da Base do Crânio/patologia , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/patologia , Canadá , Polimorfismo de Nucleotídeo Único , Proteínas Fetais , Histona-Lisina N-MetiltransferaseRESUMO
OBJECTIVES: To explore the relationship between adverse childhood experiences and falls in older adults, and the mediating effects of depression on such associations. METHODS: This is a prospective study used survey data from the China Health and Retirement Longitudinal Study. Twelve expanded ACEs obtained from the 2014 Life History Survey. Depression levels were assessed using the Centre for Epidemiologic Studies Depression Scale-10. Self-reported outcomes of falling evaluated based on "Have you fallen down since the last survey?" and "How many times have you fallen down seriously enough to need medical treatment?" Logistic regression models were used to explore the relationship between ACEs with falls and recurrent falls. Poisson regression models were used to explore the relationship between ACEs and number of severe falls. Besides, mediation analysis was used to explore whether depression mediates the relationship between ACEs and falls in older adults. RESULTS: The more adverse childhood experiences experienced, the higher the risk of fall and recurrent falls, and the more severe the falls. Additionally, depression partially mediated the relationship between adverse childhood experiences and falls. Besides, middle-aged individuals were more susceptible to the impact of adverse childhood experiences on falls than older individuals, especially males. CONCLUSIONS: Exposure to adverse childhood experiences is associated with falls in older adults, and depression partially mediates this association. Middle-aged adults were more susceptible to the impact of adverse childhood experiences on falls. These offer important information for clinical practice and public health interventions to prevent falls and reduce fall-related injuries among older adults.
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Acidentes por Quedas , Experiências Adversas da Infância , Depressão , Humanos , Acidentes por Quedas/estatística & dados numéricos , Masculino , Feminino , Idoso , Experiências Adversas da Infância/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Depressão/epidemiologia , Depressão/psicologia , Estudos Longitudinais , China/epidemiologia , Fatores de Risco , Idoso de 80 Anos ou mais , Modelos LogísticosRESUMO
ABSTRACT: Interpreting genes of interest is essential for identifying molecular mechanisms, but acquiring such information typically involves tedious manual retrieval. To streamline this process, the fanyi package offers tools to retrieve gene information from sources like National Center for Biotechnology Information (NCBI), significantly enhancing accessibility. Additionally, understanding the latest research advancements and sharing achievements are crucial for junior researchers. However, language barriers often restrict knowledge absorption and career development. To address these challenges, we developed the fanyi package, which leverages artificial intelligence (AI)-driven online translation services to accurately translate among multiple languages. This dual functionality allows researchers to quickly capture and comprehend information, promotes a multilingual environment, and fosters innovation in academic community. Meanwhile, the translation functions are versatile and applicable beyond biomedicine research to other domains as well. The fanyi package is freely available at https://github.com/YuLab-SMU/fanyi .
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Inteligência Artificial , Humanos , Barreiras de Comunicação , IdiomaRESUMO
PURPOSE: The transverse relaxation time T 2 $$ {}_2 $$ holds significant relevance in clinical applications and research studies. Conventional T 2 $$ {}_2 $$ mapping approaches rely on spin-echo sequences, which require lengthy acquisition times and involve high radiofrequency (RF) power deposition. An alternative gradient echo (GRE) phase-based T 2 $$ {}_2 $$ mapping method, utilizing steady-state acquisitions at one small RF spoil phase increment, was recently demonstrated. Here, a modified magnitude- and phase-based T 2 $$ {}_2 $$ mapping approach is proposed, which improves T 2 $$ {\mathrm{T}}_2 $$ estimations by simultaneous fitting of T 1 $$ {\mathrm{T}}_1 $$ and signal amplitude ( A â P D $$ A\propto PD $$ ) at three or more RF spoiling phase increments, instead of assuming a fixed T 1 $$ {\mathrm{T}}_1 $$ value. METHODS: The feasibility of the magnitude-phase-based method was assessed by simulations, in phantom and in vivo experiments using skipped-CAIPI three-dimensional-echo-planar imaging (3D-EPI) for rapid GRE imaging. T 2 $$ {\mathrm{T}}_2 $$ , T 1 $$ {\mathrm{T}}_1 $$ and PD estimations obtained by our method were compared to T 2 $$ {\mathrm{T}}_2 $$ of the phase-based method and T 1 $$ {\mathrm{T}}_1 $$ and PD of spoiled GRE-based multi-parameter mapping using a multi-echo version of the same sequence. RESULTS: The agreement of the proposed T 2 $$ {\mathrm{T}}_2 $$ with ground truth and reference T 2 $$ {\mathrm{T}}_2 $$ values was higher than that of phase-based T 2 $$ {\mathrm{T}}_2 $$ in simulations and in phantom data. While phase-based T 2 $$ {\mathrm{T}}_2 $$ overestimation increases with actual T 2 $$ {\mathrm{T}}_2 $$ and T 1 $$ {\mathrm{T}}_1 $$ , the proposed method is accurate over a large range of physiologically meaningful T 2 $$ {\mathrm{T}}_2 $$ and T 1 $$ {\mathrm{T}}_1 $$ values. At the same time, precision is improved. In vivo results were in line with these observations. CONCLUSION: Accurate magnitude-phase-based T 2 $$ {}_2 $$ mapping is feasible in less than 5 min scan time for 1 mm nominal isotropic whole-head coverage at 3T and 7T.
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Algoritmos , Encéfalo , Imageamento por Ressonância Magnética , Imagens de Fantasmas , Ondas de Rádio , Humanos , Imageamento por Ressonância Magnética/economia , Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: Osteosarcopenia adversely affects the quality of life and physical health of older adults. We sought to explore the association between dietary patterns and osteosarcopenia in community-dwelling older adults. METHODS: This is a cross-sectional study from Northeast China, in which, we included older community adults aged 60 and above. Through face-to-face interviews, we collected dietary information from participants using a food frequency questionnaire. Subsequently, principal component analysis (PCA) was used to obtain the dietary patterns of the participants. Through physical examination, we obtained the participants' information on osteosarcopenia, which was defined by the coexist of osteopenia and sarcopenia. We analysed the association between dietary patterns and dietary compositions with ostesarcopenia. RESULTS: In this study, a total of 9429 participants were included, and the prevalence of osteosarcopenia in community-dwelling older adults was 6.2%. PCA identified three main dietary patterns, and the lacto-ovo-vegetarian dietary pattern was inversely associated with osteosarcopenia. Compared to the lowest lacto-ovo-vegetarian quartile (Q1), the Q4 group (OR = 0.64, 95% CI:0.49-0.83) was inversely associated with osteosarcopenia. Through the weighted quantile sum regression model, we also found that the overall effect of the lacto-ovo-vegetarian dietary components was inversely associated with osteosarcopenia (OR = 0.58, 95% CI: 0.37-0.92); the largest contributors were vegetables, fresh milk, eggs, and dairy products. CONCLUSION: Overall, we found that a lacto-ovo-vegetarian dietary pattern, particularly the consumption of vegetables, fresh milk, eggs, and dairy products, was inversely associated with osteosarcopenia in older adults. And this might provide new insights for the prevention and treatment of osteosarcopenia.
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Dieta Vegetariana , Qualidade de Vida , Humanos , Idoso , Estudos Transversais , Dieta/efeitos adversos , VerdurasRESUMO
OBJECTIVES: To examine the relationships between adverse childhood experiences (ACEs) and developing sarcopenia in older adults and the modifying effects of active social participation. METHODS: This prospective cohort study used survey data from the China Health and Retirement Longitudinal Study, including baseline surveys from 2011, follow-up data from 2013, follow-up data from 2015, and information on ACEs from the 2014 Life History Survey. Information concerning 10 ACEs, including five threat-related ACEs and five deprivation-related ACEs before 17 years of age was obtained by questionnaires through face-to-face interviews. Sarcopenia status was assessed according to the Asian Working Group for Sarcopenia 2019 algorithm, consisted of low muscle mass, and low muscle strength, or poor physical performance. The relationship between ACEs, social participation, and sarcopenia was evaluated using Cox proportional hazard regression models. RESULTS: The study population comprised 6859 older adults in main analyses. Having experienced ≥ 3 ACEs led to an increased 31% risk of developing sarcopenia (hazard ratio [HR]:1.31, 95% confidence interval [CI]:1.10-1.56). Participants having experienced ≥ 2 threat-related ACEs (HR:1.22, 95%CI:1.04-1.43) or deprivation-related ACEs (HR:1.22, 95%CI:1.02-1.46) had a 22% higher risk of developing sarcopenia. Active social participation significantly modified the association between ACEs (p < 0.05), especially threat-related ACEs (p < 0.05), and sarcopenia. CONCLUSIONS: ACEs were associated with the development of sarcopenia; however, social participation had a modifying effect. These findings provide insights for early identification of vulnerable groups, advance intervention timing, and highlight the benefits of promoting active social participation among individuals with sarcopenia who have experienced ACEs.
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Experiências Adversas da Infância , Sarcopenia , Humanos , Idoso , Estudos de Coortes , Sarcopenia/epidemiologia , Estudos Longitudinais , Estudos Prospectivos , Participação SocialRESUMO
Primary cilia are distributed extensively within the corneal epithelium and endothelium. However, the presence of cilia in the corneal stroma and the dynamic changes and roles of endothelial and stromal cilia in corneal homeostasis remain largely unknown. Here, we present compelling evidence for the presence of primary cilia in the corneal stroma, both in vivo and in vitro. We also demonstrate dynamic changes of both endothelial and stromal cilia during corneal development. In addition, our data show that cryoinjury triggers dramatic cilium formation in the corneal endothelium and stroma. Furthermore, depletion of cilia in mutant mice lacking intraflagellar transport protein 88 compromises the corneal endothelial capacity to establish the effective tissue barrier, leading to an upregulation of α-smooth muscle actin within the corneal stroma in response to cryoinjury. These observations underscore the essential involvement of corneal endothelial and stromal cilia in maintaining corneal homeostasis and provide an innovative strategy for the treatment of corneal injuries and diseases.
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Cílios , Substância Própria , Endotélio Corneano , Homeostase , Animais , Camundongos , Actinas/metabolismo , Cílios/metabolismo , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Lesões da Córnea/terapia , Substância Própria/citologia , Substância Própria/crescimento & desenvolvimento , Substância Própria/metabolismo , Endotélio Corneano/citologia , Endotélio Corneano/crescimento & desenvolvimento , Endotélio Corneano/metabolismo , Homeostase/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Supressoras de Tumor/genética , Ciliopatias/metabolismo , Ciliopatias/patologia , Ciliopatias/terapiaRESUMO
Objective: The study aimed to explore the association between the site of interictal epileptic discharges (IEDs) on postoperative electroencephalogram (EEG) and seizure recurrence after antiepileptic drug (AED) withdrawal. The study hypothesizes that the concordance of IED sites with surgical sites indicates incomplete resection of epileptic focus, while non-concordance of IED sites with surgical sites indicates postoperative changes or cortical stimulation. The former has a higher risk of seizure recurrence. Methods: We retrospectively analyzed the postoperative EEG pattern of 182 consecutive children who underwent resection surgery. To identify the risk factors for seizure recurrence, we compared the attributes of seizure recurred and seizure-free groups by univariate and multivariate analyses. AED tapering was standardized, involving a 25% reduction in the dose of a single type of AED every 2 weeks, independent of the presurgical AED load. Results: We attempted AED withdrawal in 116 (63.7%) children. Twenty-eight (24.1%) children experienced seizure recurrence during or after AED withdrawal. A greater number of AEDs used at the time of surgery (p=0.005), incomplete resection (p=0.001), and presence of IED on postoperative EEG (p=0.011) are predictors of seizure recurrence. The completeness of resection and seizure recurrence after AED withdrawal were related to the presence of IED on the EEG, but not to the concordance of IED with surgical sites. Conclusion: For children with abnormal EEG, the decision to discontinue AED should be made more cautiously, regardless of the relative location of the discharge site and the surgical site.
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BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.
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Catepsina D , Diabetes Mellitus Tipo 2 , Monócitos , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Catepsina D/metabolismo , Catepsina D/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Precursores Enzimáticos , Camundongos Transgênicos , Monócitos/metabolismo , Transcitose/fisiologiaRESUMO
Gut microbiota, widely populating the mammalian gastrointestinal tract, plays an important role in regulating diverse pathophysiological processes by producing bioactive molecules. Extensive detection of these molecules contributes to probing microbiota function but is limited by insufficient identification of existing analytical methods. In this study, a systematic strategy was proposed to detect and annotate gut microbiota-related metabolites on a large scale. A pentafluorophenyl (PFP) column-based liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was first developed for high-coverage analysis of gut microbiota-related metabolites, which was verified to be stable and robust with a wide linearity range, high sensitivity, satisfactory recovery, and repeatability. Then, an informative database integrating 968 knowledge-based microbiota-related metabolites and 282 sample-sourced ones defined by germ-free (GF)/antibiotic-treated (ABX) models was constructed and subsequently used for targeted extraction and annotation in biological samples. Using pooled feces, plasma, and urine of mice for demonstration application, 672 microbiota-related metabolites were annotated, including 21% neglected by routine nontargeted peak detection. This strategy serves as a useful tool for the comprehensive capture of the intestinal flora metabolome, contributing to our deeper understanding of microbe-host interactions.
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Microbioma Gastrointestinal , Metabolômica , Camundongos , Animais , Metabolômica/métodos , Metaboloma , Espectrometria de Massas/métodos , Cromatografia Líquida/métodos , MamíferosRESUMO
OBJECTIVE: People with epilepsy desire to acquire accurate information about epilepsy and actively engage in its management throughout the long journey of living with seizures. ChatGPT is a large language model and we aimed to assess the accuracy and consistency of ChatGPT in responding to the common concerns of people with epilepsy and to evaluate its ability to provide emotional support. METHODS: Questions were collected from the International League against Epilepsy and the China Association against Epilepsy. The responses were independently assessed by two board-certified epileptologists from the China Association against Epilepsy, and a third reviewer resolved disagreements. The reviewers assessed its ability to provide emotional support subjectively. RESULTS: A total of 378 questions related to epilepsy and 5 questions related to emotional support were included. ChatGPT provided "correct and comprehensive" answers to 68.4% of the questions. The model provided reproducible answers for 82.3% questions. The model performed poorly in answering prognostic questions, with only 46.8% of the answers rated as comprehensive. When faced with questions requiring emotional support, the model can generate natural and understandable responses. SIGNIFICANCE: ChatGPT provides accurate and reliable answers to patients with epilepsy and is a valuable source of information. It also provides partial emotional support, potentially assisting those experiencing emotional distress. However, ChatGPT may provide incorrect responses, leading users to inadvertently accept incorrect and potentially dangerous advice. Therefore, the direct use of ChatGPT for medical guidance is not recommended and its primary use at present is in patients education.
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Epilepsia , Humanos , Epilepsia/terapia , Convulsões , Certificação , China , IdiomaRESUMO
OBJECTIVE: The timing of antiseizure medication (ASM) withdrawal in children after epilepsy surgery remains controversial and lacks recognized standards. Given the various negative effects of ASM on development in children, this study aimed to evaluate the safety and feasibility of early ASM withdrawal after epileptic resection surgery. METHODS: We retrospectively assessed the seizure outcomes and ASM profiles of children who had undergone epileptic resection surgery between August 2015 and August 2020 and attempted ASM reduction in the early postoperative phase. Tapering the dose of ASM was attempted when children were seizure-free with no interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) for at least 6 months postoperatively. RESULTS: This study included 145 children with a median follow-up duration of 40 months. Early ASM tapering was attempted postoperatively in 99 (68.3 %) children. Postoperative ASM discontinuation was attempted in 87 (60.0 %) children. Nine (9.1 %) children experienced seizure recurrence during the ASM reduction stage, and 10 (11.5 %) experienced recurrence after ASM discontinuation. Incomplete resection (P = 0.003) and postoperative seizures before ASM tapering (P = 0.003) were independent predictors of seizure recurrence during and after early ASM withdrawal. SIGNIFICANCE: ASM withdrawal is viable and safe to be initiated in children who are seizure-free postoperatively and have no IEDs on the scalp EEG for at least 6 months. Children with incomplete resection and postoperative seizures before ASM withdrawal are at a higher risk of seizure recurrence and may need to continue ASM for a longer period.
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Epilepsia , Síndrome de Abstinência a Substâncias , Criança , Humanos , Estudos Retrospectivos , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/cirurgia , Convulsões/tratamento farmacológico , Convulsões/etiologia , Eletroencefalografia , Síndrome de Abstinência a Substâncias/etiologia , RecidivaRESUMO
Tumor mutational signatures have the potential to inform cancer diagnosis and treatment. However, their detection in targeted sequenced tumors is hampered by sparse mutations and variability in targeted gene panels. Here we present SATS, a scalable mutational signature analyzer addressing these challenges by leveraging tumor mutational burdens from targeted gene panels. Through analyzing simulated data, pseudo-targeted sequencing data generated by down-sampling whole exome and genome data, and samples with matched whole genome sequencing and targeted sequencing, we showed that SATS can accurately detect common mutational signatures and estimate signature burdens. Applying SATS to 111,711 targeted sequenced tumors from the AACR Project GENIE, we generated a pan-cancer catalogue of mutational signatures tailored to targeted sequencing, enabling estimation of signature burdens within individual tumors. Integrating signatures with clinical data, we demonstrated SATS's clinical utility, including identifying signatures enriched in early-onset hypermutated colorectal cancers and signatures associated with cancer prognosis and immunotherapy response.
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As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Receptores Citoplasmáticos e NuclearesRESUMO
Cardiac fibrosis is associated with aging, for which no targeted therapies are available. With aging, the levels of nerve growth factor-induced gene B (Nur77) are reduced during cardiac remodelling; however, its role in cardiac fibrosis in aging remains unclear. Here, we found that Nur77 knockout increased cardiac structure abnormalities, systolic and diastolic dysfunction, cardiac hypertrophy, and fibrotic marker expression in 15-month-old mice. Furthermore, Nur77 deficiency induced collagen type I (Col-1) and α-smooth muscle actin overproduction in transforming growth factor beta (TGF-ß) treated H9c2 cells, whereas Nur77 overexpression attenuated this effect. Nur77 deficiency in vivo and in vitro downregulated glycogen synthase kinase (GSK)-3ß expression and increased ß-catenin activity, while its overexpression increased GSK-3ß expression. GSK-3ß knockdown counteracted the anti-fibrotic effect of Nur77 on TGF-ß-treated H9c2 cells. Chromatin immunoprecipitation and luciferase reporter assay results suggested GSK-3ß as the direct target of Nur77. Our findings suggest that Nur77 directly initiates GSK-3ß transcription and age-related cardiac fibrosis partly through the GSK-3ß/ß-catenin pathway. This study proposes a novel mechanism for Nur77 regulating cardiac fibrosis and suggests Nur77 as a target for the prevention and treatment of aging-associated cardiac fibrosis and heart failure.
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Coração , beta Catenina , Animais , Camundongos , beta Catenina/metabolismo , Fibrose , Glicogênio Sintase Quinase 3 beta , Fator de Crescimento Transformador betaRESUMO
Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics.