Epilepsy is a chronic brain disorder characterized by abnormal synchronous neuronal discharges in the brain, often accompanied by various complications. The pathogenesis of epilepsy has not yet been fully elucidated. Optogenetics, a cutting-edge technique that integrates optics and genetics, enables precise modulation of specific neurons by regulating light-sensitive proteins. Utilizing optogenetic technology has facilitated the dissection of neural circuits involved in epileptic seizures within brain regions such as the hippocampus, thalamus, hypothalamus. It has also helped identify potential therapeutic targets for epilepsy-related complications, including cognitive impairment, sudden unexpected death in epilepsy and mood disorders.However, in the process of advancing from basic research to clinical treatment, its translational path is profoundly influenced by factors such as stimulation modes (the choice between open-loop and closed-loop systems), key parameters (light frequency), and intervention strategies (unilateral or bilateral target selection). The individualized customization of these factors represents the future direction for overcoming current translational bottlenecks and achieving precise treatment.

Research shows that epileptic seizures are essentially due to abnormal functions of neural circuits. Optogenetics regulates neural circuits by specifically expressing light-sensitive proteins in target neurons, which has now become an important tool in the research of temporal lobe epilepsy. Studies have shown that optogenetics focuses on brain regions such as the hippocampus, medial septal nucleus, cerebellum, and basal ganglia in studying temporal lobe epilepsy. This article reviews the research progress of optogenetics in exploring the pathogenesis and therapeutic targets of temporal lobe epilepsy, aiming to provide new ideas for temporal lobe epilepsy treatment.

Objective:To explore the correlation between the expression of fucosylated proteins in colonic epithelium (abbreviated as colonic fucosylation level) and the clinical efficacy of ustekinumab (UST) in patients with Crohn′s disease (CD).Methods:From January 2022 to November 2023, CD patients who were hospitalized at Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University and received the treatment of UST ≥24 weeks (CD group) and patients with colon polyps (colon polyps control group) were retrospectively enrolled. Baseline data of the patients were collected. Harvey-Bradshaw index for Crohn′s disease (HBI) and simple endoscopic score for Crohn′s disease (SES-CD) were applied to assess clinical and endoscopic disease activities, respectively. The colonic fucosylation level was detected by immunofluorescence staining in the CD group at weeks 0 and 24 after UST treatment and at diagnosis in the colon polyps control group (baseline). The levels of C-reactive protein (CRP) and fecal calprotectin (FC) were also assessed. A linear regression model was performed to analyze the correlation between the baseline colonic fucosylation levels and the clinical characteristics in CD patients. At week 24, the clinical efficacy of UST treatment was evaluated, clinical remission was defined as HBI ≤4, biological remission was defined as CRP<5 mg/L and(or) FC≤250 μg/g, and mucosal healing was defined as SES-CD≤2.Based on the efficacy of UST treatment, the CD group was further divided into clinical remission subgroup and clinical non-remission subgroup, biological remission subgroup and biological non-remission subgroup, and mucosal healing subgroup and mucosal non-healing subgroup. The differences in colonic fucosylation level between the subgroups were compared. Multivariate binary logistic regression model was used to analyze the impacts of the baseline clinical characteristics on clinical efficacy at week 24 of UST treatment in the CD group. Mann-Whitney U test and Wilcoxon matched-pair test were used for statistical analysis. Results:A total of 60 patients in the CD group and 72 patients in the colon polyps control group were enrolled. The baseline colonic fucosylation level of CD group was lower than that of the colon polyps control group (25.81 (15.55, 29.70) vs. 29.57 (27.32, 32.96)), and the difference was statistically significant ( Z=-5.02, P<0.001). The results of multiple linear regression analysis showed that the baseline colonic fucosylation level of the CD group was negatively correlated with the baseline FC level ( β=-13.80, 95% confidence interval (95% CI): -20.59 to -7.00, P<0.001). The colonic fucosylation level at week 24 of the CD group was higher than that at week 0 (28.53 (24.54, 32.32) vs. 25.81 (15.55, 29.70)), and the difference was statistically significant ( Z=4.75, P<0.001). The colonic fucosylation levels at week 24 of the clinical remission subgroup, the biological remission subgroup, and the mucosal healing subgroup were higher than those of the clinical non-remission subgroup, the biological non-remission subgroup, and the mucosal non-healing subgroup, respectively (29.1 (27.9, 33.0) vs. 19.6 (16.3, 31.9), 29.5 (27.3, 33.0) vs. 19.6 (17.5, 27.5), 29.6 (28.4, 33.0) vs. 23.4 (17.5, 28.4)), and the differences were statistically significant ( Z=3.35, 3.78, 4.63; all P<0.001). The results of multivariate binary logistic regression analysis showed that the baseline colonic fucosylation level was the independent influencing factor of the rate of clinical remission, biological remission and mucosal healing at week 24 after UST treatment in the CD group ( OR=1.30 (95% CI: 1.05 to 1.61), 1.24 (95% CI: 1.01 to 1.52), 1.57 (95% CI: 1.16 to 2.12); P=0.018, 0.037 and 0.003). Conclusion:The baseline level of colonic fucosylation in CD patients is correlated with the clinical efficacy at week 24 of UST treatment, suggesting its potential utility in predicting the efficacy of UST treatment in CD patients.

Temporal lobe epilepsy(TLE)is the most common form of focal epilepsy in adults,characterized by spontaneous recurrent seizures,with most patients experiencing drug resistance and cognitive dysfunction.MicroRNAs(miRNAs)play a critical role in the pathological process of TLE through their regulation of post-transcriptional gene expression.The pathogenesis of TLE has not been fully elucidated,lacking effective clinical therapeutic targets and prognostic markers.This review sum-marized the expression changes of miRNAs in TLE and their research progress as potential biomarkers,aiming to provide new insights into the early diagnosis,prognosis evaluation,and pathogenic mecha-nisms of TLE.

Objective:To explore the correlation between the expression of fucosylated proteins in colonic epithelium (abbreviated as colonic fucosylation level) and the clinical efficacy of ustekinumab (UST) in patients with Crohn′s disease (CD).Methods:From January 2022 to November 2023, CD patients who were hospitalized at Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University and received the treatment of UST ≥24 weeks (CD group) and patients with colon polyps (colon polyps control group) were retrospectively enrolled. Baseline data of the patients were collected. Harvey-Bradshaw index for Crohn′s disease (HBI) and simple endoscopic score for Crohn′s disease (SES-CD) were applied to assess clinical and endoscopic disease activities, respectively. The colonic fucosylation level was detected by immunofluorescence staining in the CD group at weeks 0 and 24 after UST treatment and at diagnosis in the colon polyps control group (baseline). The levels of C-reactive protein (CRP) and fecal calprotectin (FC) were also assessed. A linear regression model was performed to analyze the correlation between the baseline colonic fucosylation levels and the clinical characteristics in CD patients. At week 24, the clinical efficacy of UST treatment was evaluated, clinical remission was defined as HBI ≤4, biological remission was defined as CRP<5 mg/L and(or) FC≤250 μg/g, and mucosal healing was defined as SES-CD≤2.Based on the efficacy of UST treatment, the CD group was further divided into clinical remission subgroup and clinical non-remission subgroup, biological remission subgroup and biological non-remission subgroup, and mucosal healing subgroup and mucosal non-healing subgroup. The differences in colonic fucosylation level between the subgroups were compared. Multivariate binary logistic regression model was used to analyze the impacts of the baseline clinical characteristics on clinical efficacy at week 24 of UST treatment in the CD group. Mann-Whitney U test and Wilcoxon matched-pair test were used for statistical analysis. Results:A total of 60 patients in the CD group and 72 patients in the colon polyps control group were enrolled. The baseline colonic fucosylation level of CD group was lower than that of the colon polyps control group (25.81 (15.55, 29.70) vs. 29.57 (27.32, 32.96)), and the difference was statistically significant ( Z=-5.02, P<0.001). The results of multiple linear regression analysis showed that the baseline colonic fucosylation level of the CD group was negatively correlated with the baseline FC level ( β=-13.80, 95% confidence interval (95% CI): -20.59 to -7.00, P<0.001). The colonic fucosylation level at week 24 of the CD group was higher than that at week 0 (28.53 (24.54, 32.32) vs. 25.81 (15.55, 29.70)), and the difference was statistically significant ( Z=4.75, P<0.001). The colonic fucosylation levels at week 24 of the clinical remission subgroup, the biological remission subgroup, and the mucosal healing subgroup were higher than those of the clinical non-remission subgroup, the biological non-remission subgroup, and the mucosal non-healing subgroup, respectively (29.1 (27.9, 33.0) vs. 19.6 (16.3, 31.9), 29.5 (27.3, 33.0) vs. 19.6 (17.5, 27.5), 29.6 (28.4, 33.0) vs. 23.4 (17.5, 28.4)), and the differences were statistically significant ( Z=3.35, 3.78, 4.63; all P<0.001). The results of multivariate binary logistic regression analysis showed that the baseline colonic fucosylation level was the independent influencing factor of the rate of clinical remission, biological remission and mucosal healing at week 24 after UST treatment in the CD group ( OR=1.30 (95% CI: 1.05 to 1.61), 1.24 (95% CI: 1.01 to 1.52), 1.57 (95% CI: 1.16 to 2.12); P=0.018, 0.037 and 0.003). Conclusion:The baseline level of colonic fucosylation in CD patients is correlated with the clinical efficacy at week 24 of UST treatment, suggesting its potential utility in predicting the efficacy of UST treatment in CD patients.

Epilepsy is a chronic brain disorder characterized by abnormal synchronous neuronal discharges in the brain, often accompanied by various complications. The pathogenesis of epilepsy has not yet been fully elucidated. Optogenetics, a cutting-edge technique that integrates optics and genetics, enables precise modulation of specific neurons by regulating light-sensitive proteins. Utilizing optogenetic technology has facilitated the dissection of neural circuits involved in epileptic seizures within brain regions such as the hippocampus, thalamus, hypothalamus. It has also helped identify potential therapeutic targets for epilepsy-related complications, including cognitive impairment, sudden unexpected death in epilepsy and mood disorders.However, in the process of advancing from basic research to clinical treatment, its translational path is profoundly influenced by factors such as stimulation modes (the choice between open-loop and closed-loop systems), key parameters (light frequency), and intervention strategies (unilateral or bilateral target selection). The individualized customization of these factors represents the future direction for overcoming current translational bottlenecks and achieving precise treatment.

Research shows that epileptic seizures are essentially due to abnormal functions of neural circuits. Optogenetics regulates neural circuits by specifically expressing light-sensitive proteins in target neurons, which has now become an important tool in the research of temporal lobe epilepsy. Studies have shown that optogenetics focuses on brain regions such as the hippocampus, medial septal nucleus, cerebellum, and basal ganglia in studying temporal lobe epilepsy. This article reviews the research progress of optogenetics in exploring the pathogenesis and therapeutic targets of temporal lobe epilepsy, aiming to provide new ideas for temporal lobe epilepsy treatment.

Background::Scleroderma is characterized by inflammation and fibrosis, predominantly occurring in the skin and extending to various parts of the body. The pathophysiology of scleroderma is multifaceted, with the current understanding including endothelial damage, inflammatory cell infiltration, and fibroblast activation in its progression. Nonetheless, the mechanism of cellular interactions and the precise spatial distribution of these cellular events within the fibrotic tissues remain elusive, highlighting a critical gap in our comprehensive understanding of scleroderma’s pathogenesis.Methods::In this study, we administered bleomycin intradermally to the dorsal skin of four individual murine models. Subsequently, skin tissues were harvested at predetermined intervals for comprehensive spatial transcriptomic analysis to determine the spatial dynamics influencing scleroderma pathogenesis. To validate the possible results from bioinformatic analysis, further in vitro and in vivo experiments were conducted. Results::Analysis of the spatial transcriptome revealed significant alterations in cell clusters during the progression of scleroderma. Gene Ontology analysis identified disruptions in lipid metabolism as the disease advanced. Pseudotime analysis provided evidence for a phenotypic transition from adipocytes to fibroblasts. In vitro studies demonstrated increased expression of Col1a1 and α-SMA as the disease progressed. These fibroblasts have been identified as key contributors to the increasing inflammation. Co-culturing TGF-β induced adipocytes with RAW264.7 cells resulted in overexpression of pro-inflammatory cytokines in the RAW264.7 cells. Both in vitro and in vivo experiments confirmed adipocyte loss and fibroblast formation, with transformed fibroblasts showing pronounced pro-inflammatory characteristics, highlighting their crucial role in the disease mechanism. Conclusions::Our study showed the spatial distribution and dynamic alterations of various cell types during scleroderma progression. Crucially, we identified the transformation of adipocytes into fibroblasts as a key factor promoting disease advancement. These emergent fibroblasts intensify inflammation, indicating that research on these cell clusters could reveal key scleroderma mechanisms and guide future therapies.

BACKGROUND:Studies have shown that imbalance of bone metabolism during glucocorticoid-induced osteonecrosis of the femoral head necrosis is closely related to oxidative stress. OBJECTIVE:To investigate the pathological mechanism by which oxidative stress-induced ferroptosis promote apoptosis in osteoblasts involved in steroid-induced osteonecrosis of the femoral head. METHODS:General data and serum specimens were collected from 47 patients with steroid-induced osteonecrosis of the femoral head.In addition,six femoral head specimens were collected from these patients.According to the Association Research Circulation Osseous(ARCO)staging system,serum specimens were grouped into ARCO Ⅱ,Ⅲ,and IV,while femoral head specimens were classified into ARCO Ⅲ and IV.Serum levels of malondialdehyde and superoxide dismutase 1 were measured.The protein expression of superoxide dismutase 1,glutathione peroxidase 4,Bcl-2 in the femoral head was detected and verified by Data independent acquisition(DIA)for quantitative sequencing,western blot and alkaline phosphate detection. RESULTS AND CONCLUSION:The ARCO stage of patients with steroid-induced osteonecrosis of the femoral head was independent of age,sex and necrotic side.The serum levels of malondialdehyde and superoxide dismutase 1 were higher in patients with ARCO stage Ⅲ compared with those with ARCO stage Ⅱ and IV.The results of DIA protein quantification showed that the function of differential proteins was mainly related to redox.The levels of superoxide dismutase 1,glutathione peroxidase 4,and Bcl-2 in the necrotic region were lower than in the normal region,as well as lower in ARCO stage IV than in ARCO stage Ⅲ.Western blot verified the results of DIA protein quantification.The alkaline phosphatase activity was lower in the necrotic region than in the normal region,as well as lower in ARCO stage IV than in ARCO stage Ⅲ.In the necrotic and sclerotic regions,the function of differential proteins was also related to redox,and superoxide dismutase 1,glutathione peroxidase 4,Bcl-2 protein expression and alkaline phosphatase activity were lower in the necrotic area than in the sclerotic region,as well as lower in ARCO stage IV than in ARCO stage Ⅲ.To conclude,glucocorticoids can influence the progression of steroid-induced osteonecrosis of the femoral head by upregulating oxidative stress levels,inducing osteoblast ferroptosis,and inhibiting osteogenic function.

Objective To reveal the physiological function of H1 linker histone gene (hil-1) and its molecular mechanism for regulating the lifespan in Caenorhabditis elegans (C. elegans).MethodsC. elegans was used as a model organism and hil-1 gene was knock-down, knock-out and over-expressed via RNA interference technology, hil-1(gk229) mutants backcross purification and microinjection technology. Then the survival and oviposition of C. elegans were observed. Physiological tests including heat shock test, paraquat stress test and heavy metal Cr⁶⁺ stress test were conducted to evaluate the stress resistance of hil-1 mutants. After constructing a dual mutant nematode, real-time fluorescence quantitative PCR (RT-qPCR) was used to further identify the signaling pathways and target sites associated with hil-1 gene regulatory lifespan.ResultsCompared with wild-type N2 worms, the lifespan of C. elegans of RNA interference and hil-1(gk229) mutants were significantly shortened (P<0.001), while overexpression of hil-1 in the whole body increased lifespan (P<0.05). The tolerance of hil-1(gk229) mutants to heat stress and oxidative stress was significantly decreased (P<0.001, P<0.05), but the tolerance to heavy metals was not different compared to wild-type N2 worms (P>0.05). In addition, the developmental cycle of hil-1(gk229) mutants was shortened and the time of oviposition was advanced (P<0.001), but there was no significant change in total number of oviposition (P>0.05). After feeding hil-1 RNA interference bacteria to eat-2(ad465) mutants, the down-regulation of hil-1 expression did not affect the lifespan of eat-2(ad465) mutants (P>0.05). Compared with wild-type N2 worms, the expression level of daf-16 in hil-1(gk229) mutants was significantly down-regulated (P<0.001), and the expressions of downstream genes, mtl-1 and ctl-1, were also down-regulated (P<0.05, P<0.001). Compared with daf-2(e1370) mutants, the lifespan of daf-2 (e1370); hil-1(gk229) mutants did not shortened (P>0.05). Compared with daf-16(mu86) mutants, the lifespan of daf-16(mu86); hil-1(gk229) mutants was significantly shortened (P<0.001). The knockdown of hil-1 via RNA interference technology, specifically in epidermis and intestine, was sufficient for lifespan reduction (P<0.001).Conclusion The deletion of hil-1 gene significantly shortened the lifespan of C. elegans and decreased the tolerance to heat and oxidative stress. The hil-1 gene regulates the lifespan of C. elegans via dietary restriction pathway and acts mostly in epidermis and intestine.