AIM:To evaluate the safety and toler-ability of single dose oral BTK inhibitor YZJ-3058 tablets under fasting conditions in healthy adults,as well as the pharmacokinetic and pharmacologi-cal characteristics of YZJ-3058 and its metabolites.METHODS:A total of 22 healthy subjects were en-rolled in this experiment and administered a single dose orally.They were divided into three groups:50 mg,100 mg,and 200 mg.Among them,2 sub-jects were enrolled in the 50 mg dose group,and 10 subjects were enrolled in the 100 mg and 200 mg dose groups,respectively.RESULTS:In healthy subjects,YZJ-3058 tablets were administered orally on an empty stomach at doses of 50,100,and 200 mg,with a median Tmax of 1.25 to 2.00 hours and an average Cmax of 62.85,89.44,and 99.20 ng/mL,re-spectively.The average AUC0-t was 183.87,297.72,and 453.98 h·ng-1·mL,respectively.The average AUC0-∞ was 189.30,321.33,and 551.44 h·ng-1·mL,and the median t1/2 was 1.16,5.06,and 7.97 hours,respectively.After a single oral administration of 50,100,and 200 mg YZJ-3058 tablets,the highest target occupancy rate was achieved at 4 hours.The average BTK occupancy rates at 24 hours after ad-ministration were 88.95％,96.73％,and 99.24％,re-spectively.The average BTK occupancy rates at 48 hours after administration were 75.65％,89.80％,and 96.68％,respectively.No serious adverse events or adverse events leading to withdrawal oc-curred,and all subjects had good tolerability.CON-CLUSION:YZJ-3058 tablets have good safety and tolerability for single oral administration on an empty stomach in healthy subjects within the dose range of 50-200 mg.Cmax and AUC increase with dose,with fast absorption and saturation.The ter-minal elimination rate gradually slows down with dose increase,and it has a significant and sus-tained occupying effect on BTK targets.

BACKGROUND: Diabetic foot is a complex condition with high incidence, recurrence, mortality, and disability rates. Current treatments for diabetic foot ulcers are often insufficient. This study was conducted to identify potential therapeutic targets for diabetic foot. METHODS: Datasets related to diabetic foot and diabetic skin were retrieved from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using R software. Enrichment analysis was conducted to screen for critical gene functions and pathways. A protein interaction network was constructed to identify node genes corresponding to key proteins. The DEGs and node genes were overlapped to pinpoint target genes. Plasma and chronic ulcer samples from diabetic and non-diabetic individuals were collected. Western blotting, immunohistochemistry, and enzyme-linked immunosorbent assays were performed to verify the S100 calcium binding protein A9 (S100A9), inflammatory cytokine, and related pathway protein levels. Hematoxylin and eosin staining was used to measure epidermal layer thickness. RESULTS: In total, 283 common DEGs and 42 node genes in diabetic foot ulcers were identified. Forty-three genes were differentially expressed in the skin of diabetic and non-diabetic individuals. The overlapping of the most significant DEGs and node genes led to the identification of S100A9 as a target gene. The S100A9 level was significantly higher in diabetic than in non-diabetic plasma (178.40 ± 44.65 ng/mL vs. 40.84 ± 18.86 ng/mL) and in chronic ulcers, and the wound healing time correlated positively with the plasma S100A9 level. The levels of inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1, and IL-6) and related pathway proteins (phospho-extracellular signal regulated kinase [ERK], phospho-p38, phospho-p65, and p-protein kinase B [Akt]) were also elevated. The epidermal layer was notably thinner in chronic diabetic ulcers than in non-diabetic skin (24.17 ± 25.60 μm vs. 412.00 ± 181.60 μm). CONCLUSIONS S100A9 was significantly upregulated in diabetic foot and was associated with prolonged wound healing. S100A9 may impair diabetic wound healing by disrupting local inflammatory responses and skin re-epithelialization.
Calgranulin B/therapeutic use* ; Diabetic Foot/metabolism* ; Humans ; Datasets as Topic ; Computational Biology ; Mice, Inbred C57BL ; Animals ; Mice ; Protein Interaction Maps ; Immunohistochemistry

Asthma is essentially a chronic inflammatory disease of the airways,and the proposed"gut-lung axis"provides a new idea for exploring its pathogenesis and therapeutic targets.A number of studies have confirmed that gut microbiota dysbiosis may affect the immune-inflammatory response through metabolites,which were involved in the disease process of asthma.Fecal microbiota transplantation(FMT)is a method that can efficiently reconstruct the gut microbiota of patients.It has been used to treat gastrointestinal diseases,central nervous system diseases,inflammatory diseases,and so on.Standardized operational protocols have been established.The use of probiotics or prebiotics in treating and preventing asthma and applying FMT in mice models of asthma have pointed the way for new prevention and treatment strategies.This article reviews the relationship between gut microbiota and asthma,and the feasibility of FMT in treating and preventing asthma.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To assess functional abnormalities in frontoparietal attention network of patients with traumatic brain injury(TBI),and to analyze neural mechanism of its attention disorders based on independent component analysis(ICA).Methods Totally 84 TBI patients were prospectively enrolled and divided into mild(n=33),moderate(n=27)and severe TBI groups(n=24)according to symptoms,non-contrast enhanced MRI findings,Glasgow coma scale(GCS)and Mayo craniocerebral trauma grading criteria.ICA was used to extract and analyze the optimal independent components(IC)of the dorsal attention network(DAN)and ventral attention network(VAN).Multiple linear regression analyses were performed to explore the correlations of functional connectivity(FC)of brain regions being significantly different among groups within attention network and the scores of trail making test A/B(TMT-A/B).Results Compared with control group and mild TBI group,spatial distribution of DAN(especially bilateral frontal eye field[FEF])in moderate and severe TBI groups were significantly smaller,the clusters tended to be discrete,and the intensity were significantly weakened.The right temporal parietal junction(TPJ)and right ventral frontal cortex(VFC)of VAN in control group,mild and moderate TBI groups were significantly affected,and VFC connection strength was the highest in severe TBI group.FC intensity in right VFC of TBI patients was positively correlated with TMT-A score(r=0.654,P＜0.001),which in left FEF was negatively correlated with TMT-B score(r=—0.383,P＜0.001).Conclusion FC of frontoparietal attention network was abnormal in TBI patients,which might be neural mechanism for its attention behavior disorders.

Objective:To develop a Knowledge-Attitude-Practice (KAP) Scale for Dietary Management During Hemodialysis and to test its reliability and validity.Methods:Based on the KAP theoretical framework, an initial version of the scale was developed through a literature review and expert consultations. A convenience sampling method was used to recruit hemodialysis patients from four hospitals in Suzhou in March 2024. Questionnaire item analysis and reliability and validity tests were conducted.Results:A total of 460 questionnaires were distributed and 438 valid responses were collected, with an effective response rate of 95.22%. The final scale included three dimensions (knowledge, attitude, and practice) with 34 items. Content validity at the scale level was 0.910, and the item level ranged from 0.800 to 1.000. Exploratory factor analysis extracted three common factors, with a cumulative variance contribution rate of 74.520%. Confirmatory factor analysis showed a good model fit. The total Cronbach's α coefficient of the scale was 0.971, and the Cronbach's αcoefficients for the three dimensions were 0.963, 0.933, and 0.934, respectively. The test-retest reliability coefficient was 0.839.Conclusions:The Knowledge-Attitude-Practice Scale for Dietary Management During Hemodialysis demonstrates good reliability and validity, making it a valuable tool for assessing the KAP level of dietary management in hemodialysis patients.

AIM:To evaluate the safety and toler-ability of single dose oral BTK inhibitor YZJ-3058 tablets under fasting conditions in healthy adults,as well as the pharmacokinetic and pharmacologi-cal characteristics of YZJ-3058 and its metabolites.METHODS:A total of 22 healthy subjects were en-rolled in this experiment and administered a single dose orally.They were divided into three groups:50 mg,100 mg,and 200 mg.Among them,2 sub-jects were enrolled in the 50 mg dose group,and 10 subjects were enrolled in the 100 mg and 200 mg dose groups,respectively.RESULTS:In healthy subjects,YZJ-3058 tablets were administered orally on an empty stomach at doses of 50,100,and 200 mg,with a median Tmax of 1.25 to 2.00 hours and an average Cmax of 62.85,89.44,and 99.20 ng/mL,re-spectively.The average AUC0-t was 183.87,297.72,and 453.98 h·ng-1·mL,respectively.The average AUC0-∞ was 189.30,321.33,and 551.44 h·ng-1·mL,and the median t1/2 was 1.16,5.06,and 7.97 hours,respectively.After a single oral administration of 50,100,and 200 mg YZJ-3058 tablets,the highest target occupancy rate was achieved at 4 hours.The average BTK occupancy rates at 24 hours after ad-ministration were 88.95％,96.73％,and 99.24％,re-spectively.The average BTK occupancy rates at 48 hours after administration were 75.65％,89.80％,and 96.68％,respectively.No serious adverse events or adverse events leading to withdrawal oc-curred,and all subjects had good tolerability.CON-CLUSION:YZJ-3058 tablets have good safety and tolerability for single oral administration on an empty stomach in healthy subjects within the dose range of 50-200 mg.Cmax and AUC increase with dose,with fast absorption and saturation.The ter-minal elimination rate gradually slows down with dose increase,and it has a significant and sus-tained occupying effect on BTK targets.

Objective:To develop a Knowledge-Attitude-Practice (KAP) Scale for Dietary Management During Hemodialysis and to test its reliability and validity.Methods:Based on the KAP theoretical framework, an initial version of the scale was developed through a literature review and expert consultations. A convenience sampling method was used to recruit hemodialysis patients from four hospitals in Suzhou in March 2024. Questionnaire item analysis and reliability and validity tests were conducted.Results:A total of 460 questionnaires were distributed and 438 valid responses were collected, with an effective response rate of 95.22%. The final scale included three dimensions (knowledge, attitude, and practice) with 34 items. Content validity at the scale level was 0.910, and the item level ranged from 0.800 to 1.000. Exploratory factor analysis extracted three common factors, with a cumulative variance contribution rate of 74.520%. Confirmatory factor analysis showed a good model fit. The total Cronbach's α coefficient of the scale was 0.971, and the Cronbach's αcoefficients for the three dimensions were 0.963, 0.933, and 0.934, respectively. The test-retest reliability coefficient was 0.839.Conclusions:The Knowledge-Attitude-Practice Scale for Dietary Management During Hemodialysis demonstrates good reliability and validity, making it a valuable tool for assessing the KAP level of dietary management in hemodialysis patients.

Objective To assess functional abnormalities in frontoparietal attention network of patients with traumatic brain injury(TBI),and to analyze neural mechanism of its attention disorders based on independent component analysis(ICA).Methods Totally 84 TBI patients were prospectively enrolled and divided into mild(n=33),moderate(n=27)and severe TBI groups(n=24)according to symptoms,non-contrast enhanced MRI findings,Glasgow coma scale(GCS)and Mayo craniocerebral trauma grading criteria.ICA was used to extract and analyze the optimal independent components(IC)of the dorsal attention network(DAN)and ventral attention network(VAN).Multiple linear regression analyses were performed to explore the correlations of functional connectivity(FC)of brain regions being significantly different among groups within attention network and the scores of trail making test A/B(TMT-A/B).Results Compared with control group and mild TBI group,spatial distribution of DAN(especially bilateral frontal eye field[FEF])in moderate and severe TBI groups were significantly smaller,the clusters tended to be discrete,and the intensity were significantly weakened.The right temporal parietal junction(TPJ)and right ventral frontal cortex(VFC)of VAN in control group,mild and moderate TBI groups were significantly affected,and VFC connection strength was the highest in severe TBI group.FC intensity in right VFC of TBI patients was positively correlated with TMT-A score(r=0.654,P＜0.001),which in left FEF was negatively correlated with TMT-B score(r=—0.383,P＜0.001).Conclusion FC of frontoparietal attention network was abnormal in TBI patients,which might be neural mechanism for its attention behavior disorders.

AIM:To investigate the mechanism by which L-Se-methylselenocysteine(L-SeMSC)inhibits foam cell formation in THP-1-derived macrophages from human monocytic leukemia cells.METHODS:THP-1-derived macrophages were first induced using phorbol 12-myristate 13-acetate(PMA),followed by the use of oxidized low-density lipoprotein(ox-LDL)to establish a foam cell model.The effects of various concentrations of L-SeMSC on THP-1 cell via-bility and apoptosis were assessed using the CCK-8 assay and flow cytometry.Lipid droplet accumulation was visualized through oil red O staining.Additionally,the mRNA levels of interleukin-1β(IL-1β),intercellular adhesion molecule 1(ICAM-1),fatty acid translocase(FAT/CD36),solute carrier family 27 member 4(SLC27A4),and superoxide dis-mutase 1(SOD1)were measured using qRT-PCR.The levels of inflammatory proteins,including IL-6,IL-1β,tumor ne-crosis factor-α(TNF-α),matrix metalloproteinase 9(MMP9),and nuclear factor-κB(NF-κB)signaling-related proteins in activated B cells were assessed via Western blot.RESULTS:Treatment with L-SeMSC at concentrations ranging from 25 to 200 μmol/L enhanced cell viability,with no significant impact on apoptosis observed across the different concentra-tions.The accumulation of lipid droplets was notably reduced in the L-SeMSC group compared to the ox-LDL group.The mRNA levels of lipid transport-related genes(CD36 and SLC27A4)and inflammation-related genes(IL-1β and ICAM-1)were significantly decreased,while SOD1 mRNA levels increased significantly.Furthermore,the expression levels of in-flammatory proteins IL-1β,IL-6,TNF-α,MMP9,and phosphorylated p65(p-p65)were markedly reduced.CONCLU-SION:L-SeMSC may exert anti-atherosclerotic effects by decreasing inflammatory factor levels,inhibiting foam cell for-mation,and reducing lipid droplet accumulation in macrophages.The associated anti-inflammatory mechanism appears to primarily involve the modulation of key proteins in the NF-κB signaling pathway.