Although global brain science research has progressed rapidly in recent decades, several fundamental questions in neuroscience remain unresolved. In particular, the physical mechanism underlying neural signal transmission remains controversial, and the carriers responsible for neural information storage and retrieval have not yet been fully clarified. These unresolved issues motivate us to re-examine the processes of neural information generation, transmission, integration, storage, and retrieval from multiple perspectives. A key observation is that neural electromagnetic activities are closely associated with time. Their duration, temporal structure, and dynamic evolution play crucial roles in neural information processing. In this work, we analyze neural electromagnetic activities from the perspective of temporal scales (referred to here as the “time course”). By reviewing and integrating findings from previous studies, we examine the characteristic time requirements and dynamic features of neural processes occurring at different stages of information processing. These stages include neural signal generation, signal transmission along axons, synaptic integration, synaptic plasticity, and memory formation and retrieval. Based on this temporal analysis, we outline a framework describing neural electromagnetic activities across a wide range of time scales, spanning from microseconds to minutes, hours, or even longer periods associated with long-term memory, which suggests that neural information processing involves multiple physical processes operating at different time levels. Rapid electromagnetic events may occur on microsecond scales, whereas electrophysiological phenomena such as action potentials typically last on the order of milliseconds. Longer time scales are associated with synaptic plasticity and memory-related processes. From this perspective, we propose that the physical carrier of neural information may be transient electromagnetic pulses with durations on the microsecond scale. In this framework, action potentials can be interpreted as the macroscopic electrophysiological manifestation of underlying electromagnetic processes triggered by ionic currents across neuronal membranes. Rather than being the fundamental neural signal itself, the action potential may represent a measurable membrane-level response associated with the successful activation of these electromagnetic events. Moreover, we discuss a possible mechanism for long-term memory storage. Considering the apparent temporal contradiction between the millisecond-scale excitation of neurons and the long-term persistence of memories, we believe that long-term memory information may be stored within neural network topologies formed by electrical synapse coupling. Such structures, referred to as electrically coupled memory networks (ECMNs), may enable neurons within the same network to respond rapidly and synchronously to stimuli, thereby facilitating efficient memory retrieval. Overall, this study emphasizes the importance of considering the temporal organization of neural electromagnetic activities when interpreting neural signaling mechanisms. It may provide new insights into the physical nature of neural information carriers and the mechanisms of memory storage and retrieval. Furthermore, highlighting the potential role of electromagnetic interactions in neural activity may contribute to the development of new theoretical frameworks and experimental approaches in neuroscience. Such perspectives may also offer valuable references for future research on neural coding, brain function mechanisms, and neuromodulation technologies.

ObjectiveTo investigate the changing trend of hemoglobin （Hb） and related influencing factors in patients with liver failure after artificial liver support system （ALSS） therapy. MethodsA total of 106 patients with liver failure who were hospitalized and received ALSS therapy in our hospital from January to December 2018 were enrolled and analyzed in terms of clinical data and red blood cell parameters such as Hb， mean corpuscular volume （MCV）， mean corpuscular hemoglobin （MCH）， mean corpuscular hemoglobin concentration （MCHC）， and red blood cell distribution width-coefficient of variation （RDW-CV）. A one-way repeated-measures analysis of variance was used for comparison of continuous data with repeated measurement between groups， and the paired t-test was used for comparison between two groups. The Kruskal-Wallis H test was used for comparison of continuous data with skewed distribution between multiple groups， the Mann-Whitney U test was used for further comparison between two groups. Univariate and multivariate linear regression analyses were used to identify the influencing factors for the reduction in Hb after ALSS therapy. ResultsThe 106 patients with liver failure received 606 sessions of ALSS therapy， and Hb was measured for 402 sessions before and after treatment. There was a significant reduction in Hb after ALSS therapy in the patients with liver failure （97.49±20.51 g/L vs 109.38±20.22 g/L， t=32.764， P<0.001）. Longitudinal observation was further performed for 14 patients with liver failure， and the results showed that the level of Hb was 108.50±21.61 g/L before the last session of ALSS therapy， with certain recovery compared with the level of Hb （103.14±19.15 g/L） on the second day after ALSS， and there was an increase in Hb on day 3 （102.57±21.73 g/L） and day 7 （105.57±22.04 g/L） after surgery. The level of Hb in patients with liver failure on the second day after ALSS decreased with the increase in the number of ALSS sessions （F=8.996， P<0.001）， while MCV and MCH gradually increased with the increase in the number of ALSS sessions （F=9.154 and 13.460， P=0.004 and P<0.001）， and RDW-CV first gradually increased and then gradually decreased （F=4.520， P=0.032）； MCHC showed fluctuations with no clear trend （F=0.811， P=0.494）. The multivariate linear regression analysis showed that the duration of ALSS therapy， the mode of ALSS therapy， and initial treatment were independent risk factors for the reduction in Hb after ALSS therapy. ConclusionALSS therapy can influence the level of peripheral blood Hb in patients with liver failure， and patient blood management should be strengthened for patients with liver failure who are receiving ALSS therapy.

Objective:To investigate the effects of metformin on esophageal squamous cell carcinoma cell growth, migration and angiogenesis by regulating the expression of ALKBH3.Methods:Human esophageal cancer TE-1 cells were treated with different concentrations (0, 0.5, 1.0, 2.0, 4.0, 8.0 mmol/L) of metformin, and they were divided into a blank control group, low- (0.5 mmol/L), medium- (1.0 mmol/L), and high- (2.0 mmol/L) concentration metformin groups, a metformin (2.0 mmol/L) +pcDNA-NC group, and a metformin (2.0 mmol/L) +pcDNA-ALKBH3 group. The cell viability was determined by the CCK-8 method. The cell proliferation ability was detected by the clone formation assay. The cell migration and invasion abilities were examined by the Transwell assay. The cell apoptosis was detected by flow cytometry. The tube formation ability of cells was detected by the angiogenesis assay. A xenograft tumor model was constructed using 4- to 6-week-old male BALB/c thymus-less nude mice, which were divided into a model control group, a metformin group, a metformin+pcDNA-NC group, and a metformin+pcDNA-ALKBH3 group using a random number table method, and with six in each group. And the volume and weight of the tumor were measured. The protein expression levels of apoptosis-related proteins Bcl-2, Bax, ALKBH3 and vascular endothelial growth factor A (VEGF-A) were detected by Western blotting. The expression of CD31 protein was detected by immunohistochemistry.Results:After treating TE-1 cells with 0, 0.5, 1.0, 2.0, 4.0, and 8.0 mmol/L metformin for 48 hours, the cell viability was (100.00±0.00) %, (90.31±5.23) %, (81.25±8.65) %, (63.52±6.80) %, (54.64±5.35) %, and (31.48±4.21) %, respectively, with a statistically significant difference ( F=98.11, P<0.001). There were statistically significant differences in cell viability between 0.5, 1.0, 2.0, 4.0, 8.0 mmol/L and 0 mmol/L (all P<0.05). The IC 50 of metformin for TE-1 cells was 4.46 mmol/L. The numbers of colony formations of TE-1 cells in the blank control group, low-, medium-, and high-concentration metformin groups, metformin+pcDNA-NC group, and metformin+pcDNA-ALKBH3 group were 153.15±13.55, 134.80±11.62, 116.24±10.43, 93.17±8.85, 89.39±8.46, 110.26±7.21, respectively, with a statistically significant difference ( F=34.28, P<0.001); the numbers of colony formations of TE-1 cells in the metformin groups at different concentrations decreased significantly with the increase in metformin concentration (both P<0.05); compared with the metformin+pcDNA-NC group, the number of colony formations of cells in the metformin+pcDNA-ALKBH3 group increased ( P<0.05). The numbers of migration of TE-1 cells of 6 groups were 152.13±13.40, 133.85±10.72, 115.28±8.64, 91.16±7.89, 85.39±7.23, 116.85±8.36, the numbers of invasion were 135.22±10.77, 112.07±9.53, 86.30±7.45, 69.53±6.74, 65.81±5.65, 79.80±6.32, respectively, with statistically significant differences ( F=41.35, P<0.001; F=69.06, P<0.001); the numbers of migrated and invaded cells in the metformin groups at different concentrations decreased significantly with the increase in metformin concentration (all P<0.05); compared with the metformin+pcDNA-NC group, the numbers of migrated and invaded cells in the metformin+pcDNA-ALKBH3 group increased significantly (both P<0.05). The apoptosis rates of TE-1 cells in 6 groups were (3.22±1.13) %, (13.82±1.90) %, (22.67±2.53) %, (29.18±3.24) %, (26.84±2.75) %, and (16.36±1.63) %, respectively, with a statistically significant difference ( F=103.66, P<0.001); the apoptosis rates of cells in the metformin groups at different concentrations gradually increased with the increase in metformin concentration (both P<0.05); compared with the metformin+pcDNA-NC group, the apoptosis rate of cells in the metformin+pcDNA-ALKBH3 group was relatively lower ( P<0.05). The tubular structure of cells in blank control group was intact, and there were different degrees of damage to the tubular structure of cells in the low-, medium-, high- concentration metformin groups, the degree of damage to the tubular structure of cells in the metformin+pcDNA-ALKBH3 group was reduced. The numbers of cellular tubular structures of TE-1 cells in the 6 groups were 38.35±3.20, 27.15±2.64, 15.92±3.14, 7.39±1.50, 8.61±1.37, and 29.33±4.20, respectively, with a statistically significant difference ( F=113.92, P<0.001); the number of cellular tubular structures in the low-, medium-, and high- concentration metformin groups gradually decreased (both P<0.05); the number of cellular tubular structures in the metformin+pcDNA-ALKBH3 group was more than that in the metformin+pcDNA-NC group ( P<0.05). There were statistically significant differences in the protein expressions of Bcl-2, Bax, ALKBH3, and VEGF-A in TE-1 cells among 6 groups ( F=56.36, P<0.001; F=57.26, P<0.001; F=159.30, P<0.001; F=132.89, P<0.001); compared with the blank control group, the protein expressions of Bcl-2, ALKBH3, and VEGF-A in the metformin groups at different concentrations decreased, while the protein expression of Bax increased (all P<0.05); compared with the metformin+pcDNA-NC group, the protein expressions of Bcl-2, ALKBH3, and VEGF-A in the metformin+pcDNA-ALKBH3 group increased, and the expression level of Bax decreased (all P<0.05). The weights of tumors in the model control group, metformin group, metformin+pcDNA-NC group, and metformin+pcDNA-ALKBH3 group were (1.16±0.12), (0.46±0.05), (0.50±0.06), (1.19±0.14) g, the volumes of tumors were (878.36±108.93), (413.59±50.23), (439.78±51.39), (793.75±96.98) mm 3, with statistically significant differences ( F=96.61, P<0.001; F=51.90, P<0.001); the weight of tumors were lower and the volume of tumors were smaller in the metformin group than those in the model control group (both P<0.05), the weight of tumors were higher and the volume of tumors were bigger in the metformin+pcDNA-ALKBH3 group than those in the metformin group and the metformin+pcDNA-NC group (all P<0.05). CD31 was mainly distributed in the cytoplasm and cell membrane of tumor cells. There were statistically significant differences in the positive rates of CD31 and the protein expression levels of VEGF-A in transplanted tumor tissues among 4 groups ( F=7.12, P=0.002; F=48.81, P<0.001); the positive rate of CD31 and the protein expression level of VEGF-A in the metformin group were lower than those in the model control group; the positive rate of CD31 and the protein expression level of VEGF-A in the metformin+pcDNA-ALKBH3 group were higher than those in the metformin group and the metformin+pcDNA-NC group (all P<0.05) . Conclusions:Metformin may inhibit the proliferation, migration, and tumor angiogenesis of esophageal squamous cell carcinoma by reducing ALKBH3 expression.

OBJECTIVE To explore the in vitro and in vivo inhibitory effects and mechanism of metformin on the malignant biological behavior of esophageal squamous cell carcinoma （ESCC） cells by the hypoxia inducible factor-1α （HIF-1α）/interleukin-8 （IL-8） signaling pathway. METHODS Human ESCC TE1 cells were assigned into blank group， metformin low-， medium-， and high-dose groups （0.5， 1， 2 mmol/L）， IDF-11774 （HIF-1α inhibitor） group （20 μmol/L）， and high-dose metformin+HIF-1α activator dimethyloxalylglycine （DMOG） group. After 24 h treatment， cell proliferation [measured by the positive rate of 5-ethynyl- 2′-deoxyuridine （EdU） and optical density at 450 nm （OD450 value）]， apoptosis， invasion and migration as well as mRNA expressions of proliferating cell nuclear antigen （PCNA）， Bcl-2 interacting mediator of cell death （Bim）， migration and invasion enhancer 1 （MIEN1）， and matrix metalloproteinase-9 （MMP-9）， and protein expressions of HIF-1α and IL-8 in the cells were detected. The xenograft tumor model of nude mice was established. Thirty nude mice were randomly divided into blank group， metformin low-， medium-， and high-dose groups （i.g. administration of metformin 62.5， 125， 250 mg/kg+i.p. administration of equal volume of normal saline）， IDF-11774 group （i.g. administration of 50 mg/kg IDF-11774+i.p. administration of equal volume of normal saline） and high-dose metformin+DMOG group （i.g. administration of metformin 250 mg/kg+i.p. administration of DMOG 250 mg/kg）， with 5 mice in each group. They were given relevant medicine， once a day， for 4 consecutive weeks； the mass and volume of the tumor and protein expressions of HIF-1α and IL-8 in the tumor tissue were determined. RESULTS The EdU positive rate， OD450 value， cell invasion number， scratch healing rate， mRNA expressions of PCNA， MIEN1 and MMP-9， protein expressions of HIF-1α and IL-8， as well as the mass and volume of transplanted tumors and protein expressions of HIF-1α and IL-8 in tumor tissues were decreased by metformin in concentration/dose-dependent manner （P＜0.05）. Additionally，metformin increased the apoptosis rate and mRNA expression of Bim in cells （P＜0.05）. The trend of changes in corresponding indicators in the IDF-11774 group was consistent with that in the metformin groups， whereas DMOG could significantly attenuate the aforementioned effects of high-concentration/high-dose metformin （P＜0.05）. CONCLUSIONS Metformin can inhibit the proliferation， invasion， migration of TE1 cells， and tumor growth of nude mice， and induce cell apoptosis， the mechanism of which may be related to the inhibition of HIF-1α/IL-8 signaling pathway.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

OBJECTIVES: To summarize the clinical and genetic characteristics of epilepsy with intellectual disability caused by SETD1B gene variants in children. METHODS: A retrospective analysis was conducted on the clinical data of three children with SETD1B gene variants diagnosed and treated at the Department of Pediatric Neurology of Xiangya Hospital of Central South University. Relevant literature was reviewed to summarize the clinical characteristics of this condition. RESULTS: All three children presented with symptoms during infancy or early childhood, including mild intellectual disability and myoclonic seizures, with two cases exhibiting eyelid myoclonia. After treatment with three or more antiepileptic drugs, two cases achieved seizure control or partial control, while one case remained refractory. Each of the three children was found to have a heterozygous variant in the SETD1B gene (one deletion, one frameshift, and one missense variant). To date, 54 cases with SETD1B gene variants have been reported, involving a total of 56 variants, predominantly missense variants (64%, 36/56). The main clinical manifestations included varying degrees of developmental delay (96%, 52/54) and seizures (81%, 44/54). Among the 44 patients with seizures, myoclonic (20%, 9/44) and absence seizures (34%, 15/44) were common, with eyelid myoclonia reported in six cases. Approximately one-fifth of these patients had poorly controlled seizures. CONCLUSIONS The primary phenotypes associated with SETD1B gene variants are intellectual disability and seizures, and seizures exhibit distinct characteristics. Eyelid myoclonia is not uncommon.
Humans ; Intellectual Disability/complications* ; Epilepsy/complications* ; Male ; Female ; Histone-Lysine N-Methyltransferase/genetics* ; Child, Preschool ; Child ; Retrospective Studies

The triterpenoid saponins of Centella asiatica, including asiaticoside, madecassoside, asiatic acid, and madecassic acid, are pivotal bioactive compounds of the plant. These constituents exhibit a spectrum of pharmacological activities, such as antioxidant, antitumor, and antidepressant effects, promotion of wound healing, and enhancement of microcirculation. Owing to these therapeutic properties, C. asiatica is widely employed in pharmaceutical and cosmetic industries. However, the escalating global demand for its extracts has led to potential supply shortages, prompting researchers to use multiple strategies such as multi-omics, molecular biology, and synthetic biology to conduct extensive studies. These studies encompass the elucidation of the biosynthetic pathways of triterpenoid saponins in C. asiatica, metabolic regulation, the hormonal induction of secondary metabolite synthesis, and the application of biotechnological strategies for natural product production to increase the yield of secondary metabolites in C. asiatica, or to produce active components via microbial chassis, thus satisfying market demands and promoting the sustainable exploitation of wild C. asiatica resources. This article first introduced the triterpenoid saponins of C. asiatica and their biological activities, then summarized the latest research advancements in their biosynthetic pathways, metabolic regulation, and heterologous biosynthesis, and provided an outlook on future development directions, with the aim of providing reference for comprehensive resource development and biotechnological synthesis of active components from C. asiatica.
Centella/genetics* ; Triterpenes/chemistry* ; Biosynthetic Pathways ; Humans ; Drugs, Chinese Herbal/chemistry* ; Plant Extracts

The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.

Aim To investigate the intestinal protection and possible mechanism of magnolol(MG)in newborn rats with necrotizing enterocolitis(NEC).Methods The rats were randomly divided into control group(Ctrl group),model group(NEC group)and treatment group(MG group).The NEC model was induced by hypoxia,cold stimulation,deep formula milk and LPS intragastric administration in 7-day-old rats for four days.They were killed after five days of treatment with MG(20 mg·kg-1).HE staining was used to observe the intestinal pathological injury.Western blot was used to detect the expressions of IL-1 β,TNF-α,NL-RP3,ASC,caspase-1 and tight junction protein in the distal ileum of rats.Colon contents were collected for 16S rDNA sequencing to understand the gut microbio-ta.Results MG improved the body mass and intesti-nal injury of NEC neonatal rats.The expressions of in-testinal IL-1β,TNF-α,NLRP3,ASC and caspase-1 proteins were down-regulated,and the expressions of Claudin,Occludin and ZO-1 proteins were up-regula-ted.16S rDNA showed that MG increased the diversity of intestinal flora,and at the phylum level,MG in-creased the abundance of firmicutes and bacteroides in NEC model,and decreased the abundance of pro-teobacteria.At the genus level,MG treatment in-creased the abundance of Lactobacillus,unclassified_Muribaculaceae,Racteroides,but decreased the abun-dance of Escherichia_Shigella,Rodentibacter and Fuso-bacterium.Conclusion MG intervention can protect the intestinal tract of NEC rats by potentially improving barrier function,and regulating the intestinal microbiota through the NLRP3/ASC/caspase-1 signaling pathway.

Icaritin(ICT)is an 8-isopentenylflavonoid,which is the main effective component of the tra-ditional Chinese medicine Epimedium.Previously,we found that Icaritin inhibits the growth of glioblasto-ma(GBM)cells.Herein we aim to study the in vivo anti-GBM effectiveness of Icaritin and explore its mechanism.The results of MTT assay,flow cytometry,comet assay and cellular immunofluorescence as-say in vitro showed that ICT inhibited the proliferation of four kinds of GBM cells,U87,U251,U118 and A172,induced early apoptosis(P＜0.001)and late apoptosis(P＜0.05)in U87 cells,induced DNA damage in U87 cells,and blocked the growth of U87 cells at the G0/G1 phase(P＜0.0001)in a concen-tration-time-dependent manner.In vivo subcutaneous tumor transplantation tumor experiments showed that feeding 200 mg/kg(P＜0.01)and 400 mg/kg(P＜0.001)ICT had a significant inhibitory effect on the growth of GBM subcutaneous tumors,and had no significant toxic effects on heart,liver,spleen,lung and kidney tissues.The results of network pharmacological analysis,molecular docking and cellular thermodynamic experiments showed that there were 26 possible target proteins between ICT and GBM,a-mong which the expression of p53 in GBM tissues was significantly(P＜0.001)higher than in normal tis-sues,and the binding energy of ICT and p53 was lower;cellular thermodynamic experiments verified that ICT significantly enriched the level of p53 in the living cells of GBM,which indicated that ICT could tar-get p53.The expression of key proteins in the DNA damage repair and apoptosis-associated FOXO signa-ling pathway was detected by ICT.The results showed that the expression of ATR(P＜0.01),P53(P＜0.001),P21(P＜0.05)and γ-H2AX(P＜0.05)was up-regulated,whereas the expression of Cyc-lin E1(P＜0.01),E2F1(P＜0.05),CDK2(P＜0.01),Rb(P＜0.001),p-Rb(P＜0.0001)and WRN(P＜0.0001)expression were down-regulated.There was no significant change in the expres-sion of FOXO 1 in the FOXO pathway or a significant down-regulation of its phosphorylation level.This study demonstrated that ICT could effectively inhibit the growth of GBM cells in vivo.It targets p53 to regulate the DNA damage repair pathway and FOXO signaling pathway to induce GBM cell cycle arrest and apoptosis.