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ObjectivesTo determine risk factors for the occurrence of adverse outcomes in patients with new-onset refractory status epilepsy (NORSE) and to construct a concomitant nomogram.MethodsSeventy-six adult patients with NORSE who were admitted to the Department of Neurology, First Affiliated Hospital of Sun Yat-sen University between January 2016 and December 2022 were enrolled for the study. Participants were divided into two—those with good and poor functional outcomes—and their pertinent data was obtained from the hospital medical recording system. Univariate analysis was used to identify potential causes of poor outcomes in both groups and a multivariate logistic regression model was used to identify risk factors for the occurrence of poor outcomes. Using the R programming language RMS package, a nomogram was created to predict the occurrence of poor outcomes.ResultsThe NORSE risk of adverse outcome nomogram model included four predictors, namely duration of mechanical ventilation (OR = 4.370, 95% CI 1.221–15.640, p = 0.023), antiviral therapy (OR = 0.045, 95% CI 0.005–0.399, p = 0.005), number of anesthetics (OR = 13.428, 95% CI 2.16–83.48, p = 0.005) and neutrophil count/lymphocyte count ratio (NLR) (OR = 5.248, 95% CI 1.509–18.252, p = 0.009). The nomogram had good consistency and discrimination in predicting risk and can thus assist clinical care providers to assess outcomes for NORSE patients. Through ordinary bootstrap analyses, the results of the original set prediction were confirmed as consistent with those of the test set.ConclusionThe nomogram model of risk of adverse outcomes in NORSE adult patients developed in this study can facilitate clinicians to predict the risk of adverse outcomes in NORSE patients and make timely and reasonable interventions for patients at high risk of adverse outcomes.

The digital archive of cultural heritage provides new opportunities for the protection of the cultural heritage and the development of online museums. One of the essential requirements for the digitization is to achieve accurate color reproduction. Taking the Imperial Chinese robes in the Qing Dynasty as an example, this study aims to develop a digital achieve system to digitize the robes using a high-end imaging system and accurately reproduce their color properties on a display. Currently, there has been very limited study focused on the color reproduction of silk fabrics or other textile materials. The conventional color management process using a traditional color chart, however, may not be suitable for the reproduction of silk fabrics because they have very high gloss. To address this difficulty, a unique “Qianlong Palette” color chart, consisting of 210 silk fabric samples, has been specifically produced for optimizing the color reproduction of silk fabrics and a color image reproduction system has been developed for the digitization and archiving of the clothing fabric for the royal court. Color characterization models using both the “Qianlong Palette” color chart and the traditional color chart, and different mapping methods, are compared and the model with highest accuracy used in a self-programmed interface for automatically processing textile images in the future. Finally, the digital archive system has been validated using six garments of silk fabric relics. The color differences after the color image reproduction are all less than 3.00ΔE*ab, indicating acceptable color reproduction of the system. The images after color reproduction have also been evaluated subjectively by experts from the museum and the results are considered satisfactory. Our results show that the newly designed “Qianlong Palette” color chart exhibits superior performance over the conventional color chart in effectively predicting the color of the silk fabrics. The self-programmed graphical user interface for image color management can serve as a powerful tool to truly reproduce the color of various silk fabric relics in museums in the future and digitally archive those valuable cultural relics for different uses.

PurposeIt is crucial to identify biomarkers that influence the aging process and associated health risks, given the growing severity of the global population aging issue. The objectives of our research were to evaluate cardiac metabolic index (CMI) as a novel biomarker for identifying individuals at increased risk of accelerated biological aging and to assess its use in guiding preventive strategies for aging-related health risks.MethodsThe National Health and Nutrition Examination Survey (NHANES) provided cross-sectional data on participants with complete information on CMI, phenotypic age (PA), and other variables. Analyses of variance and weighted χ2 tests were conducted to assess differences between groups. The relationship between CMI and biological aging was investigated using a weighted multivariate logistic regression model, restricted cubic spline (RCS) regression analysis, subgroup analysis, and interaction testing.ResultsA positive correlation between CMI and biological aging was observed in 6,272 participants. RCS regression analysis confirmed the non-linear relationship, identifying significant inflection point at 1.10. In the crude or adjusted models, the OR (95% CI), for the highest group versus the reference were 3.608 (3.108, 4.188), 3.397 (2.920, 3.952), and 1.550 (1.299, 1.850), respectively, when categorizing CMI into different groups. Subgroup analyses and interaction tests indicate that the association between CMI and biological aging remained consistent across different subgroups. Gender, race, education level, marital status, poverty income ratio (PIR), drinking status and diabetes had an interaction with CMI in relation to biological aging.ConclusionAn elevated CMI is linked to increased risk for biological aging. This relationship may inform more effective prevention and treatment strategies for biological aging in the future. CMI be integrated into routine health screenings or aging assessments by healthcare professionals.

Abstract The adverse use of alcohol is a serious global public health problem. Maternal alcohol consumption during pregnancy usually causes prenatal alcohol exposure (PAE) in the developing fetus, leading to a spectrum of disorders known as fetal alcohol spectrum disorders (FASD) and even fetal alcohol syndrome (FAS) throughout the lifelong sufferers. The prevalence of FASD is approximately 7.7 per 1,000 worldwide, and is even higher in developed regions. Generally, Ethanol in alcoholic beverages can impair embryonic neurological development through multiple pathways leading to FASD. Among them, the leading mechanism of FASDs is attributed to ethanol-induced neuroinflammatory damage to the central nervous system (CNS). Although the underlying molecular mechanisms remain unclear, the remaining multiple pathological mechanisms is likely due to the neurotoxic damage of ethanol and the resultant neuronal loss. Regardless of the molecular pathway, the ultimate outcome of the developing CNS exposed to ethanol is almost always the destruction and apoptosis of neurons, which leads to the reduction of neurons and further the development of FASD. In this review, we systematically summarize the current research progress on the pathogenesis of FASD, which hopefully provides new insights into differential early diagnosis, treatment and prevention for patents with FASD.

Abstract Introduction Ferroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to blood–brain barrier (BBB) disruption followed by secondary iron‐loaded transferrin (TF) influx. As a novel and independent cell death pathway, ferroptosis was characterized by iron‐dependent lipid peroxidation, decline of GSH, GPX4, and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke–induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats. Methods We conducted the subcutaneous injection of 1.3 mL/kg CSO every other day for 3 weeks on rats with middle cerebral artery occlusion–reperfusion (MCAO‐R) injury. We used Garcia Test, TTC staining, HE, Nissl and NeuN staining, Evans blue test, 68Ga‐citrate PET, Western blot, immunofluorescence staining, Elisa kits, and transmission electron microscopy to detect the infarct volume, neural injuries, and ferroptosis‐related indexes. Results CSO treatment could significantly ameliorate MCAO‐R‐induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries; protected BBB integrity; reduced the influx of iron ion, TF, and TF receptors; up‐regulated anti‐ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down‐regulating ferroptosis‐related protein ACSL4; increased the activity of GSH and SOD; and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment. Conclusion CSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.

Parkinson’s disease (PD) is one of the most common degenerative diseases. It is most typically characterized by neuronal death following the accumulation of Lewis inclusions in dopaminergic neurons in the substantia nigra region, with clinical symptoms such as motor retardation, autonomic dysfunction, and dystonia spasms. The exact molecular mechanism of its pathogenesis has not been revealed up to now. And there is a lack of effective treatments for PD, which places a burden on patients, families, and society. CRISPR Cas9 is a powerful technology to modify target genomic sequence with rapid development. More and more scientists utilized this technique to perform research associated neurodegenerative disease including PD. However, the complexity involved makes it urgent to organize and summarize the existing findings to facilitate a clearer understanding. In this review, we described the development of CRISPR Cas9 technology and the latest spin-off gene editing systems. Then we focused on the application of CRISPR Cas9 technology in PD research, summarizing the construction of the novel PD-related medical models including cellular models, small animal models, large mammal models. We also discussed new directions and target molecules related to the use of CRISPR Cas9 for PD treatment from the above models. Finally, we proposed the view about the directions for the development and optimization of the CRISPR Cas9 technology system, and its application to PD and gene therapy in the future. All these results provided a valuable reference and enhanced in understanding for studying PD.

Amyotrophic lateral sclerosis (ALS) is a deadly neurological disease with a complicated and variable pathophysiology yet to be fully understood. There is currently no effective treatment available to either slow or terminate it. However, recent advances in ALS genomics have linked genes to phenotypes, encouraging the creation of novel therapeutic approaches and giving researchers more tools to create efficient animal models. Genetically engineered rodent models replicating ALS disease pathology have a high predictive value for translational research. This review addresses the history of the evolution of gene editing tools, the most recent ALS disease models, and the application of CRISPR/Cas9 against ALS disease.

BackgroundDiabetes mellitus (DM) has been reported to be associated with perioperative stroke, but the effects of preoperative hyperglycemia on the risk of perioperative stroke in diabetic patients undergoing non-cardiovascular surgery remain unclear. This study investigated the association between preoperative hyperglycemia and the risk of perioperative ischemic stroke in type 2 diabetic patients undergoing non-cardiovascular surgery.MethodsThis retrospective cohort study screened 27,002 patients with type 2 DM undergoing non-cardiovascular surgery with general anesthesia between January 2008 and August 2019 at The First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital. The exposure of interest was preoperative hyperglycemia, defined as a fasting plasma glucose (FPG) ≥ 7 mmol/L. The outcome of interest was a new diagnosis of perioperative ischemic stroke within 30 days after surgery. Residual confounding was minimized by controlling for observable patient and intraoperative factors. Logistic regression was conducted in the total and propensity score matched cohorts. In addition, we stratified patients into six subgroups to investigate whether the association between preoperative hyperglycemia and perioperative ischemic stroke differs in these subgroups.ResultsThe overall incidence of perioperative ischemic stroke was 0.53% (n = 144) in the current cohort. The odds of perioperative ischemic stroke were significantly increased for patients with preoperative hyperglycemia after adjusting for patient- related variables (OR: 1.95; 95% CI: 1.39–2.75; p < 0.001), surgery-related variables (OR: 2.1; 95% CI: 1.51–2.94; p < 0.001), and all confounding variables (OR: 1.78; 95% CI: 1.26–2.53; p < 0.001). The risk of perioperative stroke was significantly increased in patients with preoperative hyperglycemia (OR: 2.51; 95% CI: 1.66–3.9; p < 0.001) in the propensity score matched cohort. Preoperative hyperglycemia was associated with the outcome for all the subgroups except for patients undergoing neurosurgery.ConclusionPreoperative hyperglycemia is associated with an elevated risk of perioperative stroke in patients with type 2 DM undergoing non-cardiovascular surgery. The effect could be eliminated for patients undergoing neurosurgery, during which specific risk factors should be considered.

Due to the high clinical heterogeneity of neuronal intranuclear inclusion disease (NIID), it is easy to misdiagnose this condition and is considered to be a rare progressive neurodegenerative disease. More evidence demonstrates that NIID involves not only the central nervous system but also multiple systems of the body and shows a variety of symptoms, which makes a clinical diagnosis of NIID more difficult. This review summarizes the clinical symptoms in different systems and demonstrates that NIID is a multiple-system intranuclear inclusion disease. In addition, the core triad symptoms in the central nervous system, such as dementia, parkinsonism, and psychiatric symptoms, are proposed as an important clue for the clinical diagnosis of NIID. Recent studies have demonstrated that expanded GGC repeats in the 5′-untranslated region of the NOTCH2NLC gene are the cause of NIID. The genetic advances and possible underlying mechanisms of NIID (expanded GGC repeat-induced DNA damage, RNA toxicity, and polyglycine-NOTCH2NLC protein toxicity) are briefly summarized in this review. Interestingly, inflammatory cell infiltration and inflammation were observed in the affected tissues of patients with NIID. As a downstream pathological process of NIID, inflammation could be a therapeutic target for NIID.

Abstract Stress activates the nuclear translocation of glucocorticoid receptors (GR) to trigger gene expression. Abnormal GR levels can alter the stress responses in animals and therapeutic effects of antidepressants. Here, we reported that stress-mediated nuclear translocation of GR reduced Ahi1 in the stressed cells and mouse brains. Ahi1 interacts with GR to stabilize each other in the cytoplasm. Importantly, Ahi1 deficiency promotes the degradation of GR in the cytoplasm and reduced the nuclear translocation of GR in response to stress. Genetic depletion of Ahi1 in mice caused hyposensitivity to antidepressants under the stress condition. These findings suggest that AHI1 is an important regulator of GR level and may serve as a therapeutic target for stress-related disorders.

Abstract Background The rapidly increasing case reports revealed that neuronal intranuclear inclusion disease (NIID) had concomitant other system symptoms besides nervous system symptoms. In this study, we systematically evaluated the symptoms, signs, auxiliary examination, and pathological changes in different systems in NIID patients. Methods NIID patients were confirmed by examining GGC repeats in the NOTCH2NLC gene. Clinical data of NIID patients including symptoms, signs, and auxiliary examinations were collected for analysis. Ubiquitin and p62 were detected in different tissues from previous surgical samples. Results Fifty‐one NIID patients from 17 families were included in this study. Except neurological symptoms, clinical manifestations from other systems were very notable and diverse. The proportions of different system symptoms were 88.2% in nervous system, 78.4% in respiratory system, 72.5% in circulatory system, 72.5% in locomotor system, 66.7% in urinary system, 64.7% in digestive system, 61.5% in reproductive system, and 50.0% in endocrine system. In addition, other common symptoms included sexual dysfunction (43.1%), pupil constriction (56.9%), blurred vision (51.0%), and hearing loss (23.5%). Ubiquitin and p62‐positive cells were found in different tissues and systems in 24 NIID patients with previous surgery. Initial symptoms of NIID and median onset age in different systems also revealed system heterogeneity of NIID. Interpretation For the first time, we systematically demonstrated that NIID is a heterogeneous and systemic neurodegenerative disease by providing clinical and pathological evidence. In addition to the nervous system, the clinical symptomatic and pathological spectrum of NIID has been extended to almost all systems.

Objective: Diabetes mellitus (DM) has been critically associated with unfavorable outcomes in the general population. We aimed to investigate the association between type 2 DM and long-term survival outcomes for postoperative ischemic stroke in patients who underwent non-cardiac surgery.Research Design and Methods: This was a retrospective cohort study of patients with non-cardiac surgery who had suffered from postoperative ischemic stroke between January 2008 and August 2019. Diabetic individuals were included in postoperative ischemic stroke patients with the DM group. The outcome of interest was long-term overall survival (OS). We conducted propensity score matching (PSM) and inverse probability treatment weighting (IPTW) to adjust for baseline characteristic differences between groups. Multivariate Cox regression analysis with stepwise selection was used to calculate the adjusted hazard ratio (HR) of OS and type 2 DM.Results: During a median follow-up of 46.2 month [interquartile range (IQR), 21.1, 84.2], 200 of 408 patients (49.0%) died. The OS rates at 3, 5, and 10 years were significantly lower for postoperative ischemic stroke patients with DM than those without DM (3 years OS: 52.2 vs. 69.5%, p < 0.001; 5 years OS: 41.6 vs. 62.4%, p < 0.001; 10 years OS: 37.2 vs. 56.6%, p < 0.001). All covariates were between-group balanced after using PSM or IPTW. The postoperative ischemic stroke patients with type 2 DM had a shortened OS in primary analysis (HR: 1.947; 95% CI: 1.397–2.713; p < 0.001), PSM analysis (HR: 2.190; 95% CI: 1.354–3.540; p = 0.001), and IPTW analysis (HR: 2.551; 95% CI: 1.769–3.679; p < 0.001).Conclusion: Type 2 DM was associated with an unfavorable survival outcome for postoperative ischemic stroke in patients who underwent non-cardiac surgery. When postoperative ischemic stroke co-occurred with type 2 DM, the potential synergies would have multiplicative mortality risk. Further research to assess the adverse effects of type 2 DM on long-term survival may be warranted.

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder clinically characterized by cognitive impairment, abnormal behavior, and social deficits, which is intimately linked with excessive β-amyloid (Aβ) protein deposition along with many other misfolded proteins, neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates, and mitochondrial damage in neurons, leading to neuron loss. Currently, research on the pathological mechanism of AD has been elucidated for decades, still no effective treatment for this complex disease was developed, and the existing therapeutic strategies are extremely erratic, thereby leading to irreversible and progressive cognitive decline in AD patients. Due to gradually mental dyscapacitating of AD patients, AD not only brings serious physical and psychological suffering to patients themselves, but also imposes huge economic burdens on family and society. Accordingly, it is very imperative to recapitulate the progress of gene editing-based precision medicine in the emerging fields. In this review, we will mainly focus on the application of CRISPR/Cas9 technique in the fields of AD research and gene therapy, and summarize the application of CRISPR/Cas9 in the aspects of AD model construction, screening of pathogenic genes, and target therapy. Finally, the development of delivery systems, which is a major challenge that hinders the clinical application of CRISPR/Cas9 technology will also be discussed.

Background Stroke is a sexually dimorphic disease and a leading cause of death and disability. Estrogen replacement therapy (ERT) confers beneficial neuroprotective effects if administered within a widely accepted time window called the “critical period.” However, very few studies have explored the idea of modulating the critical period to enable long‐term post‐menopausal women to regain more benefits from estrogen therapy. Here, motivated by previous findings that electroacupuncture could both alter estrogen metabolism and induce significant tolerance against stroke, it was explored whether EA could restore estrogen's neuroprotection against cerebral ischemia in long‐term ovariectomized (OVX) rats. Methods We implemented 1 week(w)‐EA pretreatment on OVX‐10w or OVX‐20w rats, and tested the expression of estrogen receptors, and detected the ERT's neuroprotection against stroke induced by middle cerebral artery occlusion (MCAO). Results We found that the expression levels of phospho‐ERα‐S118 and estrogen receptor β (ERβ) in the striatum of OVX‐10w rats were significantly decreased and ERT's neuroprotection was abolished in the OVX‐10w rats. However, EA‐1w pretreatment could significantly recover the expression levels of phospho‐ERα‐S118 and ERβ, and also restored the neuroprotective effects of ERT in OVX‐10w rats. However, EA‐1w pretreatment could not restore the expression of estrogen receptors and ERT's neuroprotection in OVX‐20w rats. Conclusion Taken together, our study indicates that EA may be an easy intervention that can restore the efficacy of estrogen therapy during the “critical period,” which has the potential to improve the stroke outcomes of an enormous number of long‐term post‐menopausal women. However, the time‐sensitive influences for how EA and estrogen metabolism interact with each other should be considered.

The fetal origins of adult disease (FOAD) hypothesis, which was proposed by David Barker in the United Kingdom in the late 1980s, posited that adult chronic diseases originated from various adverse stimuli in early fetal development. FOAD is associated with a wide range of adult chronic diseases, including cardiovascular disease, cancer, type 2 diabetes and neurological disorders such as schizophrenia, depression, anxiety, and autism. Intrauterine hypoxia/prenatal hypoxia is one of the most common complications of obstetrics and could lead to alterations in brain structure and function; therefore, it is strongly associated with neurological disorders such as cognitive impairment and anxiety. However, how fetal hypoxia results in neurological disorders remains unclear. According to the existing literature, we have summarized the causes of prenatal hypoxia, the effects of prenatal hypoxia on brain development and behavioral phenotypes, and the possible molecular mechanisms.

The processing of amyloid precursor protein (APP) into β-amyloid peptide (Aβ) is a key step in the pathogenesis of Alzheimer’s disease (AD), and trafficking dysregulations of APP and its secretases contribute significantly to altered APP processing. Here we show that the cell polarity protein Par3 plays an important role in APP processing and trafficking. We found that the expression of full length Par3 is significantly decreased in AD patients. Overexpression of Par3 promotes non-amyloidogenic APP processing, while depletion of Par3 induces intracellular accumulation of Aβ. We further show that Par3 functions by regulating APP trafficking. Loss of Par3 decreases surface expression of APP by targeting APP to the late endosome/lysosome pathway. Finally, we show that the effects of Par3 are mediated through the endocytic adaptor protein Numb, and Par3 functions by interfering with the interaction between Numb and APP. Together, our studies show a novel role for Par3 in regulating APP processing and trafficking.