Th1/Th2 Imbalance in Peripheral Blood Echoes Microglia State Dynamics in CNS During TLE Progression.

Central and systemic inflammation play pivotal roles in epileptogenesis and proepileptogenesis in temporal lobe epilepsy (TLE). The interplay between peripheral CD4+ T cells and central microglia orchestrates the "systemic-central" immune response in TLE. However, the precise molecular mechanisms linking central and systemic inflammation in TLE remain unknown. This preliminary findings revealed an imbalance in Th1/Th2 subsets in the periphery，accompanied by related cytokines release in TLE patients. they proposed that this peripheral Th1/Th2 imbalance may influence central inflammation by mediating microglial state dynamics within epileptic foci and distant brain regions. In Li-pilocarpine-induced TLE rats, a peripheral Th1/Th2 imbalance and observed corresponding central and systemic responses is confirmed. Notably, CD4+ T cells infiltrated through the compromised blood-brain barrierand are spatially close to microglia around epileptic foci. Intravenous depletion and reinfusion of CD4+ T cells modulated microglia state dynamics and altered neuroinflammatory cytokines secretion. Moreover, mRNA sequencing of the human hippocampus identified Notch1 as a key regulator of Th1/Th2 differentiation, CD4+ T cell recruitment to brain infiltration sites, and the regulation of microglial responses, seizure frequency, and cognition. This study underscores the significance of Th1/Th2 imbalance in modulating the "systemic-central" response in TLE, highlighting Notch1 as a potential therapeutic target.

Assessing the impact of industrial intelligence on urban carbon emission performance: Evidence from China.

With the growing emphasis on sustainable development, there has been increasing attention given to measures aimed at promoting environmental improvements and reducing carbon emissions, including the adoption of intelligent industry. Recent studies have analyzed the influence of industrial intelligence on urban carbon emission performance while ignore the spatial spillover effects and lack in-depth discussion of the mechanisms, which reduces the reliability of the assessment of industrial intelligence's impact on carbon emission performance. To address this issue, the paper examines direct effect, spatial spillover effects, and mechanisms, utilizing a balanced panel data from 2008 to 2019 for 238 Chinese cities. The findings reveal that a 1 % improvement in industrial intelligence results in a 2.747 % enhancement of local carbon emission performance. Moreover, through the spatial spillover analysis, we determined that industrial intelligence has a notable negative impact on the carbon emission performance of surrounding areas. The mechanism analysis demonstrated that industrial intelligence affects the carbon emission performance of local and neighboring areas by influencing the agglomeration of productive services. Furthermore, our study illustrates that the industrial intelligence's enhancement effect on carbon emission performance shows more significantly in eastern, resource-dependent, and ordinary prefecture-level cities. Finally, endogeneity and robustness tests conducted yielded consistent conclusions. Our study provides a new perspective on industrial intelligence's carbon reduction effect and contributes to the development of policies related to industrial upgrading and green development.

Machine Learning Predictive Model for Septic Shock in Acute Pancreatitis with Sepsis.

Objective: Acute pancreatitis (AP) progresses to septic shock can be fatal. Early identification of high-risk patients and timely intervention can prevent and interrupt septic shock. By analyzing the clinical characteristics of AP with sepsis, this study uses machine learning (ML) to build a model for early prediction of septic shock within 28 days of admission, which guided emergency physicians in resource allocation and medical decision-making. Methods: This retrospective cohort study collected data from the emergency departments (EDs) of three tertiary care hospitals in China. The dataset was randomly divided into a training dataset (70%) and a testing dataset (30%). Ten ML classifiers were utilized to analyze characteristics of AP with sepsis in the training dataset upon admission. Results were evaluated through cross-validation analysis. The optimal model was then tested on the testing dataset without any parameter modifications. The ML model was evaluated using the receiver operating characteristic curve (ROC) and compared to scoring systems through the DeLong test. Results: A total of 604 AP patients with sepsis were included in this study. The auto-encoder (AE) model based on mean normalization, Pearson correlation coefficient (PCC), and recursive feature elimination (RFE) selection, achieved the highest Area Under the Curve (AUC) on the validation dataset (AUC 0.900, accuracy 0.868), with the AUC of 0.879 and accuracy of 0.790 on the testing dataset. Compared to the Sequential Organ Failure Assessment (AUC 0.741), quick Sequential Organ Failure Assessment (AUC 0.727), Acute Physiology and Chronic Health Evaluation II (AUC 0.778), and Bedside Index of Severity in Acute Pancreatitis (AUC 0.691), the AE model showed superior performance. Conclusion: The AE model outperforms traditional scoring systems in predicting septic shock in AP patients with sepsis within 28 days of admission. This assists emergency physicians in identifying high-risk patients early and making timely medical decisions.

Diagnostic value of nerve conduction study in NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND AND AIMS: Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder mainly caused by abnormally expanded GGC repeats within the NOTCH2NLC gene. Most patients with NIID show polyneuropathy. Here, we aim to investigate diagnostic electrophysiological markers of NIID. METHODS: In this retrospective dual-center study, we reviewed 96 patients with NOTCH2NLC-related NIID, 94 patients with genetically confirmed Charcot-Marie-Tooth (CMT) disease, and 62 control participants without history of peripheral neuropathy, who underwent nerve conduction studies between 2018 and 2022. RESULTS: Peripheral nerve symptoms were presented by 53.1% of patients with NIID, whereas 97.9% of them showed peripheral neuropathy according to electrophysiological examinations. Patients with NIID were characterized by slight demyelinating sensorimotor polyneuropathy; some patients also showed mild axonal lesions. Motor nerve conduction velocity (MCV) of the median nerve usually exceeded 35 m/s, and were found to be negatively correlated with the GGC repeat sizes. Regarding the electrophysiological differences between muscle weakness type (n = 27) and non-muscle weakness type (n = 69) of NIID, nerve conduction abnormalities were more severe in the muscle weakness type involving both demyelination and axonal impairment. Notably, specific DWI subcortical lace sign was presented in only 33.3% of muscle weakness type, thus it was difficult to differentiate them from CMT. Combining age of onset, distal motor latency, and compound muscle action potential of the median nerve showed the optimal diagnostic performance to distinguish NIID from major CMT (AUC = 0.989, sensitivity = 92.6%, specificity = 97.4%). INTERPRETATION: Peripheral polyneuropathy is common in NIID. Our study suggest that nerve conduction study is useful to discriminate NIID.

Differences in whole-brain metabolism are associated with the expression of genes related to neurovascular unit integrity and synaptic plasticity in temporal lobe epilepsy.

PURPOSE: Temporal lobe epilepsy (TLE) is a common, polygenic epilepsy syndrome that involves glucose hypometabolism in the epileptogenic zone. However, the transcriptional and cellular signatures underlying the metabolism in TLE remain unclear. METHODS: In this retrospective study, 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) scans of TLE patients (n = 104) who underwent anterior temporal lobectomy were consecutively collected between 2016 and 2021. The transcriptional profiles of TLE risk genes across the brain were identified by the gene expression analyses from six TLE patients and twelve postmortem donors (six from the Allen Human Brain Atlas). Integrating the neuroimaging and transcriptomic data, we examined the relationship between the expression of TLE-associated genes and metabolic alterations in TLE. Furthermore, we performed functional enrichment analyses of the genes with higher weight in partial least squares regression using Metascape. RESULTS: A total of 104 patients with TLE (mean age 29 ± 9 years, 50% male) and 30 healthy controls (HCs) (mean age 31 ± 6 years, 53% male) were enrolled. Compared to that of HCs, patients with TLE showed hypometabolism in the temporal lobes and adjacent structures but hypermetabolism in the thalamus and basal ganglia. The cortical map of inter-group differences in cerebral metabolism was spatially correlated with the expression of a weighted combination of genes enriched in ontology terms and pathways related to neurovascular unit (NVU) integrity and synaptic plasticity. DISCUSSION: Our findings, combined with the analysis of neuroimaging and transcriptional data, suggest that genes related to NVU integrity and synaptic plasticity may drive alterations to brain metabolism that mediate the genetic risk of TLE.

Mechanisms and Functions of Activity-Regulated Cytoskeleton-Associated Protein in Synaptic Plasticity.

Activity-regulated cytoskeleton-associated protein (Arc) is one of the most important regulators of cognitive functions in the brain regions. As a hub protein, Arc plays different roles in modulating synaptic plasticity. Arc supports the maintenance of long-term potentiation (LTP) by regulating actin cytoskeletal dynamics, while it guides the endocytosis of AMPAR in long-term depression (LTD). Moreover, Arc can self-assemble into capsids, leading to a new way of communicating among neurons. The transcription and translation of the immediate early gene Arc are rigorous procedures guided by numerous factors, and RNA polymerase II (Pol II) is considered to regulate the precise timing dynamics of gene expression. Since astrocytes can secrete brain-derived neurotrophic factor (BDNF) and L-lactate, their unique roles in Arc expression are emphasized. Here, we review the entire process of Arc expression and summarize the factors that can affect Arc expression and function, including noncoding RNAs, transcription factors, and posttranscriptional regulations. We also attempt to review the functional states and mechanisms of Arc in modulating synaptic plasticity. Furthermore, we discuss the recent progress in understanding the roles of Arc in the occurrence of major neurological disorders and provide new thoughts for future research on Arc.

Clinical Reasoning: A 14-Year-Old Girl With Reversible Peripheral Neuropathy and Encephalopathy.

A 14-year-old girl presented with acute ascending, symmetric numbness, and flaccid paralysis 3 weeks after a suspected gastrointestinal infection. She had experienced anorexia since this gastrointestinal episode. EMG showed a sensorimotor axonal polyneuropathy. Routine CSF analysis and serum-specific antibodies (antiganglioside and node of Ranvier-associated antibodies) were all negative. Laboratory investigations for possible etiologies revealed only mild metabolic perturbations. During her hospitalization, she developed mild cognitive deficits. Brain MRI showed bilateral symmetric basal ganglia lesions with hyperintensity on T2 fluid-attenuated inversion recovery, diffusion-weighted imaging hyperintensity, and corresponding apparent diffusion coefficient hypointensity, but without contrast enhancement. A more thorough and detailed history indicated exercise intolerance, and specific examinations subsequently revealed an underlying etiology. This case presentation discusses specific etiology of an acute-onset diffuse and symmetric neuropathy after an acquired injury in a teenager, emphasizing the need of a broad differential diagnosis in this condition.

How Does Environmental Information Disclosure Affect Public Health? Evidence from the New Ambient Air Quality Standards.

Using a quasi-natural experiment of the implementation of the new Ambient Air Quality Standards in China, this paper assessed the impact of environmental information disclosure on public health. Our empirical results showed that environmental information disclosure (EID) largely improved both physical health and mental health. Moreover, we further investigated the air pollution channel, and the empirical results showed that EID could reduce the concentration of PM2.5, which could cause an increase in public health as the concentration of PM2.5 decreases. In addition, in terms of individual characteristics, the impact of EID was larger for men, people living in the countryside and people older than 60. In terms of the heterogeneity of cities, the impact of EID was larger in cities with higher public environmental concerns, and the impact of EID was more pronounced in core cities. For regional heterogeneity, the impact of EID on physical health was more pronounced in more developed regions, whereas the impact EID on mental health was higher in less developed regions.

Altered cerebellar-motor loop in benign adult familial myoclonic epilepsy type 1: The structural basis of cortical tremor.

OBJECTIVE: Cortical tremor/myoclonus is the hallmark feature of benign adult familial myoclonic epilepsy (BAFME), the mechanism of which remains elusive. A hypothesis is that a defective control in the preexisting cerebellar-motor loop drives cortical tremor. Meanwhile, the basal ganglia system might also participate in BAFME. This study aimed to discover the structural basis of cortical tremor/myoclonus in BAFME. METHODS: Nineteen patients with BAFME type 1 (BAFME1) and 30 matched healthy controls underwent T1-weighted and diffusion tensor imaging scans. FreeSurfer and spatially unbiased infratentorial template (SUIT) toolboxes were utilized to assess the motor cortex and the cerebellum. Probabilistic tractography was generated for two fibers to test the hypothesis: the dentato-thalamo-(M1) (primary motor cortex) and globus pallidus internus (GPi)-thalamic projections. Average fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of each tract were extracted. RESULTS: Cerebellar atrophy and dentate nucleus alteration were observed in the patients. In addition, patients with BAFME1 exhibited reduced AD and FA in the left and right dentato-thalamo-M1 nondecussating fibers, respectively false discovery rate (FDR) correction q < .05. Cerebellar projections showed negative correlations with somatosensory-evoked potential P25-N33 amplitude and were independent of disease duration and medication. BAFME1 patients also had increased FA and decreased MD in the left GPi-thalamic projection. Higher FA and lower RD in the right GPi-thalamic projection were also observed (FDR q < .05). SIGNIFICANCE: The present findings support the hypothesis that the cerebello-thalamo-M1 loop might be the structural basis of cortical tremor in BAFME1. The basal ganglia system also participates in BAFME1 and probably serves a regulatory role.

Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China. METHODS: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy. RESULTS: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission. CONCLUSIONS: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Cohen syndrome in two patients from China.

BACKGROUND: Cohen syndrome (CS; OMIM 216550) is a rare syndrome with evident clinical heterogeneity. The diverse phenotype comprises early-onset hypotonia and developmental delays, intellectual disabilities, microcephaly, hypermobile joints, neutropenia, myopia, and characteristic facial features. The disease is rarely reported. Vacuolar Protein Sorting 13 Homolog B (VPS13B; OMIM 607817) is the only causative gene of CS. METHODS: Blood samples sourced from both siblings and parents were sent to identify mutations by trio-WES, and changes in the patient's condition were understood through consultation data and follow-up. RESULTS: We reported two siblings affected by developmental delay, microcephaly, intellectual disability, and facial features. The siblings' WES detected compound heterozygous variants in the exon region of VPS13B (NM_017890): c.9337A>T and c.8551A>C. CONCLUSION: Two individuals were diagnosed with CS by genetic testing and clinical features. In addition, we conduct a brief review of the reports on the Chinese population with CS and reinforce the understanding of the correlation between genotype-phenotype.

A de novo inframe deletion variant in CAPZA2 tentacle domain with global developmental delay and secondary microcephaly.

(A) Sanger sequencing confirmation and family pedigree for the patient. (B) A schematic representation of transcript and translation showing the positions of all CAPZA2 variants identified.

DNAH14 variants are associated with neurodevelopmental disorders.

Neurodevelopmental disorders (NDD) are complex and multifaceted diseases involving genetic and environmental sciences. Rapid developments in sequencing techniques have made it possible to identify new disease-causing genes. Our study aimed to identify novel genes associated with NDDs. Trio whole-exome sequencing was performed to evaluate potential NDD variants. We identified three unrelated patients with compound heterozygous DNAH14 variants. The detailed clinical information and genetic results of the recruited patients were obtained and systematically reviewed. Three compound heterozygous DNAH14 variants were identified as follows: c.6100C > T(p.Arg2034Ter) and c.5167A > G(p.Arg1723Gly), c.12640_12641delAA(p.Lys4214Valfs*7) and c.4811T > A(p.Leu1604Gln), andc.7615C > A(p.Pro2539Thr) and c.11578G > A(p.Gly3860Ser), including one nonsense, one frameshift, and four missense variants, which were not existent or with low minor allele frequencies based on the gnomAD database. The missense variants were assumed to be damaging or probably damaging by using multiple bioinformatics tools. Four of these variants were located in the AAA+ ATPase domain, while two were located in the C-terminal domain. Most affected amino acids were highly conserved in various species. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia. Thus, our findings indicate that variants of DNAH14 could lead to previously unrecognized NDDs.

Subcellular-Targeted Near-Infrared-Responsive Nanomedicine with Synergistic Chemo-photothermal Therapy against Multidrug Resistant Cancer.

Multidrug resistance (MDR) is a major obstacle to effective cancer treatment. Therefore, developing effective approaches for overcoming the limitation of MDR in cancer therapy is very essential. Chemotherapy combined with photothermal therapy (PTT) is a potential therapeutic option against MDR. Herein, we developed a subcellular-targeted near-infrared (NIR)-responsive nanomedicine (Fe3O4@PDA-TPP/S2-PEG-hyd-DOX, abbreviated as Fe3O4-ATSPD) as a new photothermal agent with improved photothermal stability and efficiency. This system demonstrates high stability in blood circulation and can be accumulated at the tumor site by magnetic targeting enhanced permeability and retention effect (EPR). Near-infrared (NIR) irradiation at the tumor site generates a photothermal effect from the photosensitizer Fe3O4@PDA, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the conjugated drugs released under low pH condition in endosomes or lysosomes cause nucleus DNA damage and cell apoptosis. This subcellular-targeted NIR-responsive nanomedicine with efficient integration of diagnosis and therapy could significantly enhance MDR cancer treatment by combination of chemotherapy and PTT.

Regional integration and public healthcare environment: Evidence from China.

Introduction: Existing studies have focused on the impact of economic development and urban expansion on public healthcare environment but has ignored the importance of regional integration. Regional integration reflects the spatial distribution of the labor force, which significantly affects healthcare workforce and healthcare infrastructure development. Methods: Based on panel nested data for 137 cities in 16 major city clusters in China from 2001 to 2019, this paper assesses the impact of regional integration on the public healthcare environment through a hierarchical linear model (HLM). Results: Our findings indicate that a 1% increase in regional integration leads to a 6.6 and 1.9% improvement in healthcare workforce and healthcare infrastructure. The results of the mechanism analysis indicate that regional integration affects the public healthcare environment through improving transportation infrastructure and industrial upgrading. In addition, regional integration has a stronger effect on cities with lower levels of economic development and healthcare environments. Finally, the endogeneity test based on the difference-in-difference (DID) model and the robustness test based on high-dimensional fixed effects model conduct the consistent conclusions. Discussion: Policies to improve the public healthcare environment through promoting regional integration are proposed. Government should develop a more comprehensive regional cooperation plan to improve the public healthcare environment. Also, financial spending on improving the healthcare environment in peripheral cities should be increased. In addition, regional integration policy development needs to consider differences across regions.

The second DDOST-CDG patient with lactose intolerance, developmental delay, and situs inversus totalis.

Congenital disorders of glycosylation (CDGs) are inherited metabolic diseases affecting protein and lipid glycosylation. DDOST-CDG is a rare, newly identified type of CDGs, with only one case reported so far. In this study, we report a Chinese patient with a homozygous pathogenic variant in DDOST (c.1187G>A) and who presented with feeding difficulty, lactose intolerance, facial dysmorphism, failure to thrive, strabismus, high myopia, astigmatism, hypotonia, developmental delay and situs inversus totalis. Serum transferrin isoelectrofocusing demonstrated defective glycosylation in our patient. This finding further identifies DDOST as a genetic cause of CDGs and expands the clinical phenotype of DDOST-CDG.

Genome-Wide DNA Methylation Pattern in Whole Blood Associated With Primary Intracerebral Hemorrhage.

Primary intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality throughout the world. ICH is a multifactorial disease that emerges from interactions among multiple genetic and environmental factors. DNA methylation plays an important role in the etiology of complex traits and diseases. We used the Illumina Infinium Human Methylation 850k BeadChip to detect changes in DNA methylation in peripheral blood samples from patients with ICH and healthy controls to explore DNA methylation patterns in ICH. Here, we compared genomic DNA methylation patterns in whole blood from ICH patients (n = 30) and controls (n = 34). The ICH and control groups showed significantly different DNA methylation patterns at 1530 sites (p-value < 5.92E-08), with 1377 hypermethylated sites and 153 hypomethylated sites in ICH patients compared to the methylation status in healthy controls. A total of 371 hypermethylated sites and 35 hypomethylated sites were in promoters, while 738 hypermethylated sites and 67 hypomethylated sites were in coding regions. Furthermore, the differentially methylated genes between ICH patients and controls were largely related to inflammatory pathways. Abnormalities in the DNA methylation pattern identified in the peripheral blood of ICH patients may play an important role in the development of ICH and warranted further investigation.

Case Report: Aicardi-Goutières Syndrome and Singleton-Merten Syndrome Caused by a Gain-of-Function Mutation in IFIH1.

The IFIH1 gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the IFIH1 gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the IFIH1 gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the IFIH1 gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by IFIH1 gain-of-function mutation.

Novel PRRT2 gene variants identified in paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy in Chinese families.

The present study was performed to investigate the clinical manifestations and pathogenic variants in three large families with autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) and/or benign familial infantile epilepsy (BFIE) in China. Detailed clinical data and family history were collected. Genomic DNA was isolated from the peripheral blood samples of all available members. The genetic diagnosis was made by whole-exome sequencing on the three probands and the candidate variants were verified by PCR-Sanger sequencing. The pathogenicity of variants was predicted by bioinformatics analyses and classified according to the American College of Medical Genetics criteria. A total of three causative heterozygous variants were identified in the proline-rich transmembrane protein 2 (PRRT2) gene by DNA sequencing: A novel c.324_334del(p.Val109Argfs*21) deletion variant in Family A, as well as the previously known c.510_513del(p.Ser172Argfs*3) deletion variant in Family B and c.649dupC(p.Arg217Profs*8) duplication variant in Family C. The three variants of PRRT2 co-segregated with the phenotype and genotype in the family members. The present results deepen the current understanding of PKD/BFIE and extend the genotypic-phenotypic spectrum of PKD/BFIE.