Exercise fatigue is a complex physiological and psychological phenomenon that includes peripheral fatigue in the muscles and central fatigue in the brain. Peripheral fatigue refers to the loss of force caused at the distal end of the neuromuscular junction, whereas central fatigue involves decreased motor output from the primary motor cortex, which is associated with modulations at anatomical sites proximal to nerves that innervate skeletal muscle. The central regulatory failure reflects a progressive decline in the central nervous system’s capacity to recruit motor units during sustained physical activity. Emerging evidence highlights the critical involvement of central neurochemical regulation in fatigue development, particularly through neurotransmitter-mediated modulation. Alterations in neurotransmitter release and receptor activity could influence excitatory and inhibitory signal pathways, thus modulating the perception of fatigue and exercise performance. Increased serotonin (5-HT) could increase perception of effort and lethargy, reduce motor drive to continue exercising, and contribute to exercise fatigue. Decreased dopamine (DA) and noradrenaline (NE) neurotransmission can negatively impact arousal, mood, motivation, and reward mechanisms and impair exercise performance. Furthermore, the serotonergic and dopaminergic systems interact with each other; a low 5-HT/DA ratio enhances motor motivation and improves performance, and a high 5-HT/DA ratio heightens fatigue perception and leads to decreased performance. The expression and activity of neurotransmitter receptors would be changed during prolonged exercise to fatigue, affecting the transmission of nerve signals. Prolonged high-intensity exercise causes excess 5-HT to overflow from the synaptic cleft to the axonal initial segment and activates the 5-HT1A receptor, thereby inhibiting the action potential of motor neurons and affecting the recruitment of motor units. During exercise to fatigue, the DA secretion is decreased, which blocks the binding of DA to D1 receptor in the caudate putamen and inhibits the activation of the direct pathway of the basal ganglia to suppress movement, meanwhile the binding of DA to D2 receptor is restrained in the caudate putamen, which activates the indirect pathway of the basal ganglia to influence motivation. Furthermore, other neurotransmitters and their receptors, such as adenosine (ADO), glutamic acid (Glu), and γ‑aminobutyric acid (GABA) also play important roles in regulating neurotransmitter balance and fatigue. The occurrence of central fatigue is not the result of the action of a single neurotransmitter system, but a comprehensive manifestation of the interaction between multiple neurotransmitters. This review explores the important role of neurotransmitters and their receptors in central motor fatigue, reveals the dynamic changes of different neurotransmitters such as 5-HT, DA, NE, and ADO during exercise, and summarizes the mechanisms by which these neurotransmitters and their receptors regulate fatigue perception and exercise performance through complex interactions. Besides, this study presents pharmacological evidence that drugs such as agonists, antagonists, and reuptake inhibitors could affect exercise performance by regulating the metabolic changes of neurotransmitters. Recently, emerging interventions such as dietary bioactive components intake and transcranial electrical stimulation may provide new ideas and strategies for the prevention and alleviation of exercise fatigue by regulating neurotransmitter levels and receptor activity. Overall, this work offers new theoretical insights into the understanding of exercise central fatigue, and future research should further investigate the relationship between neurotransmitters and their receptors and exercise fatigue.

OBJECTIVE To investigate the effects of calcitriol on sepsis-induced immunosuppression and its potential mechanism. METHODS A sepsis-induced immunosuppression mice model was established using cecal ligation and puncture （CLP）. The 7-day survival rate， serum levels of tumor necrosis factor- α （TNF- α）， interleukin-6 （IL-6）， and IL-1β were determined in sham operation group， CLP group and calcitriol group （1 μg/kg）； the morphological changes of lung tissue in mice were observed. Lipopolysaccharide （LPS） tolerance macrophage models （representing sepsis-induced immunosuppression） were established using mice macrophage cell line RAW264.7 cells. The levels of TNF-α and IL-6 in cell supernatants as well as mRNA expressions of IL-1β， nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 （NLRP3）， IL-18 and caspase-1 were assessed in culture medium group， LPS group， LPS tolerance group， and calcitriol （5 μmol/L） group. The following parameters were measured： propidium iodide （PI）-positive cell ratio， caspase-1 activity， lactate dehydrogenase （LDH） release， and Ca2+ levels. RESULTS Compared with CLP group， 7-day survival rate and serum levels of TNF-α， IL-6 and IL-1β were increased significantly in calcitriol group （P＜0.05）. Additionally， pulmonary tissue damage was markedly attenuated in calcitriol group. Compared with LPS tolerance group， the levels of TNF-α and IL-6 in cell supernatants， mRNA expressions of IL- 1β， NLRP3， IL-18 and caspase-1， PI-positive cell ratio， caspase-1 activity， LDH release， and Ca2+ levels were all increased significantly in calcitriol group （P＜0.05）. CONCLUSIONS Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be E-mail：yarfwy@163.com achieved by the binding of calcitriol to vitamin D receptor，which promotes the release of Ca2+ from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway.

Age-related macular degeneration(AMD)is one of the leading causes of blindness in the elderly.Wet AMD(nAMD)accounts for more than 90％of AMD-related vision loss.Pathologically,nAMD is defined by choroidal neovascu-larization(CNV)and chronic retinal inflammation driven by oxidative stress,complement activation,pro-inflammatory cy-tokines,and overexpression of vascular endothelial growth factor(VEGF).Yet anti-VEGF monotherapy often falls short.The nuclear factor kappa-B(NF-κB)signaling cascade,acting through both canonical and non-canonical pathways,or-chestrates the expression of genes governing immunity,inflammation,apoptosis,and angiogenesis.In nAMD,oxidative stress and complement fragments ignite NF-κB,unleashing a repertoire of pro-inflammatory and pro-angiogenic mediators that fuel CNV.Pharmacologic or genetic suppression of NF-κB dampens both inflammation and neovascularization,attenua-ting experimental CNV.Thus,dissecting the molecular machinery of NF-κB signaling in nAMD may uncover novel combina-tion strategies that enhance therapeutic efficacy and curb anti-VEGF resistance.

AIM:Hepatotoxicity of Brucea javani-ca picryl with broad-spectrum anticancer effect in nude mice based on hepatic drug metabolizing en-zyme CYP450 activity.METHODS:Fifty-six nude mice were randomly divided into blank group,Bru-cea javanica low-dose group(2 mg/kg),Brucea ja-vanica high-dose group(4 mg/kg),and cisplatin group(2 mg/kg),with 14 mice in each group.The blank group was injected with the same amount of normal saline every 3 days for 6 weeks.Calculate the mortality rate of nude mice in each group,ob-serve the general growth state of nude mice,re-cord the weight change of nude mice before and af-ter administration,weigh and record the liver weight after taking materials,and calculate the liv-er coefficient(liver weight/weight mass×100％),ob-serve and record the liver color and morphology.Hematoxylin-eosin(HE)staining was used to ob-serve the pathological changes of liver tissue.De-tection of alanine aminotransferase(ALT),aspar-tate aminotransferase(AST),lactate dehydrogenase(LDH),alkaline phosphatase(AKP)and albumin(ALB)levels in serum of nude mice by ELISA.Real-time PCR and Western blot were used to detect the mRNA and protein expression levels of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6 and CYP2C9,which were key enzymes of drug metabolism in nude mice liver.RESULTS:Compared with the blank group,the mortality rate of nude mice in the low-dose Brucea javanica bitter alcohol group was 0,the growth state was good,the diet,movement,and mental state were normal,the weight change and liver coefficient ratio were consistent,the liver color was ruddy,the liver lobule morphology was complete under the microscope,the structure was clear,the liver cells were arranged regularly,and there was no inflammatory cell infiltration.There was no significant difference in the content of ALT,AST,LDH,AKP,and ALB.There was no significant difference in the mRNA and protein expression of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9(all P＞0.05).Compared with the blank group,the mortality rate of nude mice in the high-dose group of Brucea javanica bitter alcohol was 14.3％,the growth state was slightly poor,the diet,movement,and mental state were reduced,the weight growth was slow,the liver coefficient ratio was increased,the liver color was reddish brown,some liver lobule boundaries were unclear,a small number of liver cells were loosely arranged,the contents of ALT,AST,LDH,AKP,and ALB were signif-icantly increased,the mRNA levels of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9 were significantly reduced,and the protein expres-sions of CYP2E1,CYP3A11,CYP1A2,and CYP2D6 were significantly reduced(all P＜0.05 or P＜0.01),but there was no statistical difference in the mRNA and protein expression of CYP2C19,and the pro-tein expression of CYP2C9(P＞0.05).Compared with the blank group,the mortality rate of nude mice in the cisplatin group was 35.7％,the growth state was poor,the diet,action,and mental state were low,the weight gain was less,the liver coefficient ratio was significantly increased,the liver color was dark red,the liver sinusoids and central veins were congested,the hepatocytes were disordered,the nuclei were consolidated and contracted,and the arrangement was loose,the contents of ALT,AST,LDH,AKP,and ALB were significantly increased,and the mRNA and protein expressions of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9 were significantly reduced(all P＜0.05 or P＜0.01).CONCLUSION:The dose of Brucea javanica bitter alcohol is correlated with hepatotoxicity to nude mice.High doses of Brucea javanica bitter alcohol have hepatotoxicity to nude mice,which may be re-lated to reducing serum levels of ALT,AST,LDH,AKP,and ALB,inhibiting the expression of multiple subtypes of enzymes in the key enzyme CYP450 of liver drug metabolism,and then reducing the me-tabolism of toxic substances.

Objective:In order to clarify the ABO phenotype and genotype,and explore the molecular biological mechanism,serological detection,genotyping and gene sequencing were performed on an upper gastrointestinal hemorrhage patient with inconsistent forward and reverse ABO blood typing.Methods:ABO forward and reverse blood typing,H antigen identification,capillary centrifugation test and salivary substance detection were performed by classical serological method,moreover,polymerase chain reaction-sequence specific primer(PCR-SSP)was used for ABO genotyping,ABO gene 1-7 exons were sequenced by Sanger analysis in order to identify mutation.Results:Mixed field agglutination with anti-A,anti-AB and no agglutination with anti-A1 were appeared in the forward typing tests,agglutination with B cells but no agglutination with A1 cells and O cells were appeared in the reverse typing tests.3+agglutination strength was showed with anti-H.In capillary centrifugation experiment,erythrocyte after isolation in proximal part and distal end had same strength of agglutination with anti-A.Substances A and H were detected in saliva.The patient was assigned an A3 phenotype according to serological characteristics.Sequencing results of ABO gene 1-7 exons showed c.261delG,c.467C＞T,c.865A＞G,in which,865A＞G was the first discovered mutation,and this new mutation had been submitted to GenBank with accession number PP187306.Conclusion:A novel site mutation c.865A＞G is reported in this study,and this new mutation can result in a replacement of Met with Val at residue 289(p.Met289Val)and lead to an A3 phenotype.

Objective:In order to clarify the ABO phenotype and genotype,and explore the molecular biological mechanism,serological detection,genotyping and gene sequencing were performed on an upper gastrointestinal hemorrhage patient with inconsistent forward and reverse ABO blood typing.Methods:ABO forward and reverse blood typing,H antigen identification,capillary centrifugation test and salivary substance detection were performed by classical serological method,moreover,polymerase chain reaction-sequence specific primer(PCR-SSP)was used for ABO genotyping,ABO gene 1-7 exons were sequenced by Sanger analysis in order to identify mutation.Results:Mixed field agglutination with anti-A,anti-AB and no agglutination with anti-A1 were appeared in the forward typing tests,agglutination with B cells but no agglutination with A1 cells and O cells were appeared in the reverse typing tests.3+agglutination strength was showed with anti-H.In capillary centrifugation experiment,erythrocyte after isolation in proximal part and distal end had same strength of agglutination with anti-A.Substances A and H were detected in saliva.The patient was assigned an A3 phenotype according to serological characteristics.Sequencing results of ABO gene 1-7 exons showed c.261delG,c.467C＞T,c.865A＞G,in which,865A＞G was the first discovered mutation,and this new mutation had been submitted to GenBank with accession number PP187306.Conclusion:A novel site mutation c.865A＞G is reported in this study,and this new mutation can result in a replacement of Met with Val at residue 289(p.Met289Val)and lead to an A3 phenotype.

Objective:To analyze the human immunodeficiency virus (HIV) screening status and the resulting residual risk (RR) among blood donors across 17 provincial blood centers in China.Methods:This study used a cross-sectional study. Data on HIV infection markers per 100 000 first-time donors (FD) and repeat donors (RD) from January 2015 to December 2024 were extracted from the National Blood Establishment Performance Comparison Information Management System. Questionnaires were used to collect each center′s HIV screening strategy, algorithm, serological test (ST) kit manufacturers, gray-zone setting for ST, and nucleic acid test (NAT) modality, method, and platform. The incidence-window-period model was used to calculate the residual risk for first-time donors (RR FD), repeat donors (RR RD), and total donors (RR TD) at each center. Horizontal and vertical analysis of RR FD, RR RD, and RR TD across centers and years were performed. Results:All 17 centers applied the same HIV screening strategy which was two rounds of ST followed by one round of NAT. Eight of them operated a single screening algorithm, six employed two algorithms and three used three. Eleven centers used both imported and domestic ST kits, five relied on domestic ST kits only, and one used imported ST kits only, while four centers never set a grey zone for ST throughout the decade. For NAT modalities, eight centers adopted both individual nucleic acid test (ID-NAT) and minipool nucleic acid test (MP-NAT), eight used MP-NAT only and one used ID-NAT only. Seven centers combined transcription mediated amplification (TMA) and polymerase chain reaction (PCR), nine used PCR only and one used TMA only, and fourteen centers ran both imported and domestic NAT systems, two used imported systems only and one used a domestic system only. Over the ten-year period, the mean RR FD across the centers ranged from 2.22 to 12.33 per 10 6 person-years, RR RD from 0.83 to 3.29 per 10 6 person-years and RR TD from 1.59 to 9.29 per 10 6 person-years, with center Z4 consistently showing the lowest values for all three metrics and center U4 recording the highest RR FD and RR TD, while center D2 had the highest RR RD. In 2024 compared with 2015, eleven centers achieved a lower RR FD and ten centers achieved lower RR RD and RR TD. The RR FD and RR TD of centers W2 and U4 displayed pronounced fluctuations and an upward trend in recent years. Conclusions:The 17 provincial blood centers maintain consistent HIV screening strategies, while demonstrating variations in screening algorithm, ST kit manufacturers, NAT modalities, methods, and platform. And the RR FD, RR RD, and RR TD differ across centers. Although most centers show declining trend in RR over the ten-year period, some centers exhibite data fluctuations with a rising trend, suggesting potential for further optimization of HIV screening protocols.

Objective:To characterize the epidemiology, antimicrobial susceptibility, and molecular mechanisms of carbapenem-resistant Enterobacterales (CRE) carrying multiple carbapenemase genes in China, and to provide evidence for infection control and antibiotic stewardship.Methods:From 2016 to 2023, 115 CRE isolates harboring at least two carbapenemase genes were collected from 41 hospitals in 18 provinces across China. Species identification, antimicrobial susceptibility testing, and whole-genome sequencing were performed. Multilocus sequence typing (MLST) and capsular typing were conducted using Kleborate, plasmid replicon types were identified with PlasmidFinder, and a core genome phylogenetic tree was constructed.Results:The majority of isolates belonged to Klebsiella spp. (80.0%, 92/115), followed by E. cloacae (8.7%, 10/115) and E. coli (6.1%, 7/115). The isolates were mainly from Hebei, Beijing, Shandong, and Hunan (60.9%, 70/115), and sputum was the predominant specimen (43.5%, 50/115). The most common genotype was bla KPC+bla NDM (73.0%, 84/115), primarily in Klebsiella spp. (79.8%, 67/84), followed by bla NDM+bla IMP (15.7%, 18/115). The prevalent plasmid replicon types were IncFII (77.5%, 86/111), IncFIB (68.5%, 76/111), IncR (51.4%, 57/111), and IncX3 (20.7%, 23/111). Notably, 88.6% (31/35) of ST11-KL64 K. pneumoniae strains co-harbored IncFII, IncFIB, and IncR plasmids simultaneously. Between 2016 and 2022, the dominant subtype among Klebsiella spp. isolates was bla KPC-2+bla NDM-1 (56.2%, 36/64). In 2023, the bla KPC-2+bla NDM-13 subtype (29.5%, 19/64) emerged and exhibited clonal transmission (single nucleotide polymorphism 2?74 bp) in Hebei, Beijing, and Jilin. Susceptibility testing showed widespread resistance to β-lactams (90.2%-100%). Aztreonam-avibactam, tigecycline, and colistin retained high activity, with susceptibility rates of 90.16%-98.36%. Conclusions:In China, the majority of clinical Enterobacteriaceae strains that harbor multiple carbapenemases are Klebsiella spp. co-producing KPC and NDM enzymes. Dissemination is driven by both clonal expansion of ST11-KL64 and horizontal transfer of IncFII, IncFIB, and IncR plasmids. The recent emergence and regional clonal spread of the bla KPC-2+bla NDM-13 genotype underscore the urgent need for strengthened surveillance and containment measures.

The clinical characteristics of a neonatal patient with movement disorder and arthrogryposis (NDEEMA) caused by gain-of-function mutation of the SCN1A gene were reported in this article. The 1-year-and-9-month-old boy started seizures since 2 hours after birth. He had funnel-breast, dislocation of the hip, and bipedal varus. Genetic testing showed SCN1A gene de novo missense mutation c.706A>G(p.Ile236Val), causing overall gain-of-function effect. The frequency of seizures decreased significantly after treatment of oxcarbazepine.

AIM:Hepatotoxicity of Brucea javani-ca picryl with broad-spectrum anticancer effect in nude mice based on hepatic drug metabolizing en-zyme CYP450 activity.METHODS:Fifty-six nude mice were randomly divided into blank group,Bru-cea javanica low-dose group(2 mg/kg),Brucea ja-vanica high-dose group(4 mg/kg),and cisplatin group(2 mg/kg),with 14 mice in each group.The blank group was injected with the same amount of normal saline every 3 days for 6 weeks.Calculate the mortality rate of nude mice in each group,ob-serve the general growth state of nude mice,re-cord the weight change of nude mice before and af-ter administration,weigh and record the liver weight after taking materials,and calculate the liv-er coefficient(liver weight/weight mass×100％),ob-serve and record the liver color and morphology.Hematoxylin-eosin(HE)staining was used to ob-serve the pathological changes of liver tissue.De-tection of alanine aminotransferase(ALT),aspar-tate aminotransferase(AST),lactate dehydrogenase(LDH),alkaline phosphatase(AKP)and albumin(ALB)levels in serum of nude mice by ELISA.Real-time PCR and Western blot were used to detect the mRNA and protein expression levels of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6 and CYP2C9,which were key enzymes of drug metabolism in nude mice liver.RESULTS:Compared with the blank group,the mortality rate of nude mice in the low-dose Brucea javanica bitter alcohol group was 0,the growth state was good,the diet,movement,and mental state were normal,the weight change and liver coefficient ratio were consistent,the liver color was ruddy,the liver lobule morphology was complete under the microscope,the structure was clear,the liver cells were arranged regularly,and there was no inflammatory cell infiltration.There was no significant difference in the content of ALT,AST,LDH,AKP,and ALB.There was no significant difference in the mRNA and protein expression of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9(all P＞0.05).Compared with the blank group,the mortality rate of nude mice in the high-dose group of Brucea javanica bitter alcohol was 14.3％,the growth state was slightly poor,the diet,movement,and mental state were reduced,the weight growth was slow,the liver coefficient ratio was increased,the liver color was reddish brown,some liver lobule boundaries were unclear,a small number of liver cells were loosely arranged,the contents of ALT,AST,LDH,AKP,and ALB were signif-icantly increased,the mRNA levels of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9 were significantly reduced,and the protein expres-sions of CYP2E1,CYP3A11,CYP1A2,and CYP2D6 were significantly reduced(all P＜0.05 or P＜0.01),but there was no statistical difference in the mRNA and protein expression of CYP2C19,and the pro-tein expression of CYP2C9(P＞0.05).Compared with the blank group,the mortality rate of nude mice in the cisplatin group was 35.7％,the growth state was poor,the diet,action,and mental state were low,the weight gain was less,the liver coefficient ratio was significantly increased,the liver color was dark red,the liver sinusoids and central veins were congested,the hepatocytes were disordered,the nuclei were consolidated and contracted,and the arrangement was loose,the contents of ALT,AST,LDH,AKP,and ALB were significantly increased,and the mRNA and protein expressions of CYP2E1,CYP3A11,CYP2C19,CYP1A2,CYP2D6,and CYP2C9 were significantly reduced(all P＜0.05 or P＜0.01).CONCLUSION:The dose of Brucea javanica bitter alcohol is correlated with hepatotoxicity to nude mice.High doses of Brucea javanica bitter alcohol have hepatotoxicity to nude mice,which may be re-lated to reducing serum levels of ALT,AST,LDH,AKP,and ALB,inhibiting the expression of multiple subtypes of enzymes in the key enzyme CYP450 of liver drug metabolism,and then reducing the me-tabolism of toxic substances.