Objective To investigate the improving effect and mechanism of the traditional Chinese herbal medicine Glabridin(GLA)on cognitive impairment in Parkinson's disease(PD)mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),and its protective effect on the cerebral cortex and hippocampus through affecting the extracellular regulated protein kinases(ERK)signaling pathway involved in the regulation of neural plasticity.Methods A total of 120 C57BL//6N mice were randomly divided into control group,model group,GLA control group and MPTP+GLA low,medium and high-dose groups,with 20 mice in each group.The mouse PD model was established by intraperitoneal injection of MPTP 20 mg/kg,and the control group was injected with the same dose of normal saline.The GLA control group was given 50 mg/kg GLA by gavage;the MPTP+GLA low,medium and high dose groups were given 20,30 and 50 mg/kg GLA by gavage 1 hour after each MPTP administration,once a day for 7 consecutive days.The learning and memory abilities of the mice in each group and the pathological changes of hippocampal tissue were observed,as well as the changes in the contents of tumor necrosis factor-α(TNF-α),interleukin-18(IL-18),malondialdehyde(MDA),superoxide dismutase(SOD),tyrosine hydroxylase(TH)and protein expression levels of phosphorylated-ERK 1/2(p-ERK1/2)in the cerebral cortex.Results Compared with the control group,the levels of MDA and TNF-α,IL-18 in the cerebral cortex of the model group were significantly increased[MDA(nmol/mg):4.68±0.51 vs.2.05±0.22,TNF-α(μg/L):116.87±15.65 vs.48.52±7.83,IL-18(μg/L):57.52±6.89 vs.24.26±1.89,all P<0.05],while the activity of SOD was significantly decreased(U/mg:77.84±7.84 vs.130.89±18.56,P<0.05).Compared with the model group,the contents of TNF-α,IL-18,and MDA in each MPTP+GLA group were significantly decreased,while the activity of SOD was significantly increased(all P<0.05),and the change in the high-dose MPTP+GLA group was more obvious.The learning and memory ability of the high-dose MPTP+GLA group was significantly improved,the number of neurons in the hippocampus tissue decreased,the neurodegeneration was improved,and the glial cell proliferation was reduced.The results of immunohistochemistry showed that compared with the model group,the loss of TH positive cells in the high-dose MPTP+GLA group was significantly reduced[absorbance(A value):cerebral cortex was 39.14±3.25 vs.23.14±3.1,hippocampus was 72.14±4.25 vs.52.16±3.32,both P<0.05],and the expression of p-ERK1/2 positive cells was significantly inhibited(A value:cerebral cortex was 63.91±3.55 vs.88.35±6.41,hippocampus was 73.36±3.52 vs.93.25±6.73,both P<0.05).Western blotting showed that compared with the model group,the protein expression level of cerebral cortex and hippocampus TH in the high-dose MPTP+GLA group was significantly increased(gray value:cerebral cortex was 0.71±0.09 vs.0.53±0.06,hippocampus was 0.68±0.06 vs.0.45±0.03,both P<0.05),and the protein expression level of p-ERK1/2 was significantly inhibited(gray value:cerebral cortex was 0.76±0.10 vs.0.96±0.08,hippocampus was 0.74±0.06 vs.0.96±0.12,both P<0.05).Conclusions The traditional Chinese medicine GLA can improve the learning and memory ability of MPTP-induced PD mice,as well as prevent and treat MPTP-induced neuronal damage and glial cell proliferation.The ERK signaling pathway is associated with neural damage in PD brain tissue.GLA protects the learning and memory ability of MPTP-induced PD mice by inhibiting the ERK signaling pathway.

BACKGROUND:Ankylosing spondylitis is a chronic inflammatory disease with chronic rheumatic immunity.Soft tissue ossification and fusion and spinal stiffness can cause biomechanical changes. OBJECTIVE:To reconstruct the lumbar-sacral intervertebral disc in ankylosing spondylitis patients with lumbar kyphosis by finite element analysis,and to study the range of motion of each segment of T11-S1 and the biomechanical characteristics of annulus fibrosus and nucleus pulposus. METHODS:The imaging data were obtained from an ankylosing spondylitis patient with lumbar kyphosis.The original CT image data of continuously scanned spine were imported into Mimics 21.0 in DICOM format,and T11-S1 was reconstructed respectively.The established model was imported into 3-Matic software in the format of"Stl"to reconstruct the intervertebral disc,and the fibrous intervertebral disc model was obtained.The improved model was further imported into Hypermesh software,and the vertebra,nucleus pulposus,annulus fibrosus and ligament were mesh-divided.After the material properties were given,the model was imported into ABAQUS software to observe the range of motion of each vertebral body in seven different working conditions of T11-S1,and analyze the biomechanical characteristics of each segment of annulus fibrosus and nucleus pulposus. RESULTS AND CONCLUSION:(1)The range of motion of L1 vertebrae was higher than that of other vertebrae under six different working conditions:extension,forward flexion,rotation(left and right),and lateral flexion(left and right).The maximum range of motion was 2.18° during L1 vertebral flexion,and the minimum range of motion was 0.12° during L5 vertebral extension.(2)The annular fiber flexion at L2-L3 segments was greater than the extension(P<0.05),and the annular fiber flexion at L3-L4 and L4-L5 segments was less than the extension(P<0.05).The left rotation of L1-L2 annular fibers was greater than the right rotation(P<0.05).The left flexion of the annulus was greater than the right flexion in L1-L2,L2-L3,L3-L4,L4-L5 and L5-S1 segments(P<0.05).(3)The nucleus pulposus stresses of T11-L12,L1-L2,L2-L3,L3-L4 and L4-L5 segments in forward flexion were greater than in extension(P<0.05).The left rotation of T12-L1 and L3-L4 segments was smaller than the right rotation(P<0.05),and that of T11-T12,L1-L2,and L2-L3 segments was larger than the right rotation(P<0.05).The left flexion was larger than the right flexion in the T11-S1 segment.(4)It is concluded that in ankylosing spondylitis patients with lumbar kyphosis,the minimum range of motion of the vertebral body is located at the L5 vertebral body in extension.To prevent fractures,it is recommended to avoid exercise in the extension position.During the onset of lumbar kyphosis in patients with ankylosing spondylitis,the maximum stress of the annulus fibrosus and nucleus pulposus is located in the L1-L2 segment,which is fixed and will not alter with the change of body position.The late surgical treatment and correction of deformity should focus on releasing the pressure of the annulus fibrosus and nucleus pulposus in this segment to avoid the rupture of the annulus fibrosus and the injury of the nucleus pulposus.

ObjectiveTo investigate the effect of Yishen Tongluo prescription （YSTLP） on apoptosis of renal tubular epithelial cells and explore the mechanism based on endoplasmic reticulum stress pathway of protein kinase R-like endoplasmic reticulum kinase （PERK）/activating transcription factor 4 （ATF4）/transcription factor C/EBP homologous protein （CHOP）. MethodThe db/db mice were randomly divided into model group， valsartan group （10 mg·kg^-1）， and low， middle， high-dose YSTLP groups （1， 2.5， 5 g·kg^-1）. Samples were collected after eight weeks of drug intervention. In addition， db/m mice in the same litter served as the control group. Human renal tubular epithelial cells （HK-2） were cultured in vitro and divided into the control group， advanced glycated end-product （AGE） group， and AGE + low， middle， and high-dose YSTLP groups （100， 200， 400 mg·L^-1）. TdT-mediated dUTP nick end labeling （TUNEL） staining was used to detect the apoptosis rate of HK-2 cells. Methylthiazolyldiphenyl-tetrazolium bromide （MTT） assay was conducted to detect the viability of HK-2 cells. Calcium fluorescence probe staining and luciferase reporter gene method were adopted to detect the luciferase activity of folded protein response element （UPRE） and endoplasmic reticulum stress. Immunohistochemical （IHC） analysis was carried out to measure the protein expressions of phosphorylated PKR （p-PERK）， CHOP， and ATF4. Real-time polymerase chain reaction （Real-time PCR） was used to measure the mRNA expression levels of CHOP and X-box binding protein 1 （XBP1） in mouse kidney and HK-2 cells. Western blot was used to detect the protein expression level of p-PERK， PERK， CHOP， ATF4， B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）， and cleaved Caspase-3 in mouse kidney and HK-2 cells. ResultIn the cellular assay， HK-2 cell viability was significantly reduced， and the apoptosis rate was elevated in the AGE group compared with the control group （P<0.01）. The mRNA and protein expression levels of apoptosis-related factor Bcl-2 were significantly reduced （P<0.01）， and those of Bax were significantly increased （P<0.01）. The protein expression level of cleaved Caspase-3 was significantly increased （P<0.01）. Compared with the AGE group， YSTLP administration treatment resulted in elevated cell viability and reduced apoptosis rate （P<0.01）. The mRNA and protein expression levels of Bcl-2 were significantly elevated in a time- and dose-dependent manner （P<0.01）， and those of Bax were significantly reduced in a time- and dose-dependent manner. The protein expression level of cleaved Caspase-3 was significantly reduced in a time- and dose-dependent manner （P<0.01）. The intracellular Ca²⁺ imbalance and UPRE luciferase fluorescence intensity were increased in the AGE group compared with the control group （P<0.01）. The mRNA levels of endoplasmic reticulum stress-related factors CHOP and XBP1 were significantly increased （P<0.01）， and the protein expression levels of p-PERK， CHOP， and ATF4 were significantly increased （P<0.05）. Compared with the AGE group， YSTLP effectively improved intracellular Ca²⁺ imbalance in HK-2 cells and decreased UPRE luciferase fluorescence intensity in a dose-dependent manner （P<0.01）. It reduced the mRNA levels of endoplasmic reticulum stress-related factors CHOP and XBP1 （P<0.01） and the protein expression levels of intracellular p-PERK， CHOP， and ATF4 in a dose- and time-dependent manner （P<0.01）. In animal experiments， the protein expression level of Bcl-2 was significantly reduced（P<0.01）， and that of cleaved Caspase-3 and Bax was significantly increased in the model group compared with the control group （P<0.05）. The protein expression level of Bcl-2 was dose-dependently elevated， and that of cleaved Caspase-3 and Bax was dose-dependently decreased in the YSTLP groups compared with the model group （P<0.01）. Compared with the control group， the mRNA expression levels of CHOP and XBP1 were significantly elevated in the model group （P<0.05， P<0.01）， and the protein expression levels of p-PERK， CHOP， and ATF4 were significantly increased （P<0.05）. Compared with the model group， YSTLP significantly decreased the mRNA expression levels of CHOP and XBP1 （P<0.01） and the protein expression levels of p-PERK， CHOP， and ATF4 （P<0.01）. ConclusionYSTLP can effectively inhibit endoplasmic reticulum stress and improve apoptosis of renal tubular epithelial cells， and its mechanism may be related to the regulation of the PERK/AFT4/CHOP pathway.

Abstract Tobacco use is not only harmful to adolescents physical and mental health, but is also closely related to future adults smoking prevalence, and interventions can delay the age at which adolescents take their first puff as much as possible. The article summarizes and analyzes the effectiveness of tobacco control interventions based on schools, communities or families, and a combination of multiple venues. It compares the characteristics of offline, online, and a combination of offline and online tobacco control interventions for adolescents,so as to provide references for the design and implementation of adolescent tobacco control interventions, and the effective, sustainable, and replicable adolescent tobacco control intervention models.

OBJECTIVE To explore the distribution of airborne pollen in Cangzhou,to analyze the correlation between pollen characteristics,meteorological factors and the rate of allergic rhinitis visits,and to provide a reference basis for the precise prevention and treatment of allergic rhinitis in Cangzhou.METHODS The gravity deposition method was applied to collect daily airborne pollen from the monitoring sites in Cangzhou from March to October 2022 and record the pollen species and quantities.We also collected information on allergic rhinitis patients who visited the ENT Department of Cangzhou Central Hospital during the same period and meteorological data(daily maximum temperature,minimum temperature,maximum relative humidity,maximum precipitation,and maximum wind speed at ground level)during the same period,and analyzed the relationship between the number of AR patients'visits,the amount of pollen,and the meteorological factors.RESULTS 1.A total of 229 pollen exposures were collected from March to October 2022,totaling 19 368 pollen grains,of which 18 750 grains of pollen could be identified in 19 families and 618 grains were difficult to identify the families.2.There were two peaks of pollen during the period,in April and September respectively.Spring pollen to tree-based category,to the pine family,willow willow family,Xylariaceae(ash)most often;summer pollen volume has declined,but still tree-based category;fall pollen to herbaceous category,to the Asteraceae Artemisia,mulberry,Gramineae most often.3.The pollen concentration in Cangzhou City was negatively correlated with maximum humidity,maximum precipitation,maximum temperature,and minimum temperature.Maximum wind speed at ground level was positively correlated with pollen concentration.4.Pollen concentration was positively correlated with the number of visits.The correlation analysis between daily medical visits from June to October and air pollen concentration showed a significant positive correlation,while the results from March to May showed no significant correlation.CONCLUSION The peak of airborne pollen dispersal in April and September in Cangzhou.Spring and summer pollen is dominated by tree species,and the dominant pollen is Pinaceae,Willow genus of Populus,and Xylariaceae(ash genus);fall pollen is dominated by herbaceous species,and the dominant pollen is Artemisia,Asteraceae,Mulberry,and Gramineae.Meteorological factors are important factors affecting pollen concentration.Within a certain range,the lower the maximum humidity,the lowest maximum precipitation,the lower the highest or the lowest temperature,the higher the pollen concentration,and the pollen concentration is more affected by the lowest temperature.There is a correlation between pollen concentration and the number of AR patients'visits from June to October,which can be used as an environmental early warning indicator of the prevalence of AR.

Objective To establish and validate a prediction model for gastric cancer lymph node metastasis based on four machine learning (ML) algorithms. Methods A retrospective analysis was conducted on clinical data of 531 patients who underwent radical gastrectomy. The patients were randomly divided into training set (399 patients) and test set (132 patients) in a ratio of 3 to 1. Univariate analysis was used to screen for variables associated with gastric cancer lymph node metastasis, and Logistic regression, random forest, K-nearest neighbor algorithm, and support vector machine algorithm models were established to rank the importance of variables. All ML algorithm models were validated in the test set, and receiver operating characteristic (ROC) curves were plotted. The optimal ML algorithm model was determined based on the area under the curve (AUC), sensitivity, specificity, and accuracy. A nomogram model was constructed based on the variable importance ranking of the optimal ML algorithm model. The discrimination, calibration, and clinical applicability of the nomogram model were evaluated using ROC curves, calibration curves, and decision curves. Results The results of the comparison of the four ML algorithm models showed that the random forest model was the optimal algorithm model. The accuracy, sensitivity, and specificity of the random forest model in the training set were 72.7%, 69.9%, and 75.0%, respectively, with an AUC of 0.803. The accuracy, sensitivity, and specificity of the random forest model in the test set were 64.4%, 66.7%, and 62.5%, respectively, with an AUC of 0.751. A nomogram model was constructed based on the variables of the random forest algorithm model. The ROC curve showed that the AUCs of the nomogram model in the training set and test set were 0.721 and 0.776, respectively. Calibration curves and decision curves showed that the nomogram model had good calibration and clinical applicability in both the training set and test set. Conclusion The random forest model is the optimal algorithm model among the four ML algorithm models. The nomogram model based on the random forest model can accurately predict the risk of gastric cancer lymph node metastasis, thereby better guiding clinical diagnosis and treatment decisions.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective:To understand the research hotspots and development trends of oncology nurses at home and abroad from 2011 to 2020, so as to provide reference for related research.Methods:The articles related to oncology nurses at home and abroad from 2011 to 2020 were retrieved through China National Knowledge Infrastructure database, Web of Science database and PUBMED database, and the included literatures′ published journals, institutions and keywords were analyzed by using the online analysis of Statistical Analysis Toolkit for Informetrics3.2 and the software CiteSpace5.7.R1.Results:A total of 588 domestic and 738 foreign articles were included. Keywords analysis showed that domestic oncology nurse related research hotspots were occupational evaluation, hospice care, psychology and occupational protection. Oncology nurse at home and abroad research hotspots had both similarities and differences, different in fertility preservation, communication and so on.Conclusions:The domestic core journal forums of oncology nurse research are still too scattered, and there is a certain gap in the number of articles published between our country and other countries. China still needs to increase the research efforts in this field.

Objective: To evaluate the prognostic value of kinetic changes in minimal residual disease (MRD) status, as well as its relationship with risk stratification, therapeutic response and treatment in patients with newly-diagnosed multiple myeloma (MM) . Methods: A total of 135 patients with newly-diagnosed MM were screened, and 105 patients who achieved VGPR or more as the best responses were included into this study. The MRD status was determined by multiparameter flow cytometry (MFC) at multiple intervals after two cycles of treatment until clinical relapse, death, or last follow-up. The statistical methods included Kaplan-Meier analysis, Cox regression, etc. Results: ①In all 135 patients, 57.8% (78/135) patients achieved MRD negativity (MRD^-) after treatment. In 105 patients who achieved VGPR and thus included in this study, the MRD^- rate was 72.4% (76/105) , with a median interval of 3 months from starting treatment to achievement of MRD^- status. ②The 2-year PFS rate of patients with MRD^- status was significantly higher than that of MRD⁺ status (62.2% vs 41.3%, P=0.001) , while MRD persistence (MRD⁺) was an independent factor for poor prognosis (multivariate analysis for PFS: P=0.044, HR=3.039, 95%CI 1.029-8.974) . ③Loss of MRD^- status (i.e., MRD reappearance) showed inferior outcomes compared with MRD sustained negative ones, the PFS was 18 months versus not reach (P<0.001) and the OS was not reach for both (P=0.002) . ④The 2-year PFS and OS rates of patients with duration of MRD^-status≥12 months were significantly higher than those of the control group (PFS: 77.7% vs 36.7%, P<0.001; OS: 96.4% vs 57.9%, P<0.001 respectively) . Duration of MRD^- status was associated with a marked reduction in risk of relapse or death (univariate analysis for PFS: P<0.001, HR=0.865, 95%CI 0.815-0.918; for OS: P=0.001, HR=0.850, 95%CI 0.741-0.915 respectively) . ⑤Moreover, even in patients carrying high-risk cytogenetic abnormalities (CA) or ineligible for ASCT, MRD negativity remained its prognostic value to predict PFS (high-risk CA medianPFS: not reach vs 19 months, P=0.006; ineligible for ASCT medianPFS: not reach vs 25 months, P=0.052 respectively) . ⑥Last, treatment with the bortezomib-based regimens contributed to prolonged MRD^- duration (median MRD^- duratio: 25 months vs 10 months, P=0.034) . Conclusion Our findings supported MRD⁺ status as an independent poor prognostic factor in MM patients, which implicated that duration of MRD^- status also played a significant role in evaluation of prognosis, while loss of MRD^-status might serve as an early biomarker for relapse. Therefore, monitoring of MRD kinetics might more precisely predict prognosis, as well as guide treatment decision, especially for when to start retreatment in relapsed patients.

Objective To analyze the effect of haploidentical hematopoietic stem cell transplantation (HID-HSCT) on high-risk acute lymphoblastic leukemia (ALL),and to explore the influence of minimal residual disease (MRD) before transplant on the outcomes.Methods A retrospective analysis was performed on 39 high risk ALL patients receiving HID-HSCT in our hospital from Jan.2013 to Jan.2018.The clinical features,stem cell engraftment,complications,survival and recurrence were compared between patients with pretransplant MRD + and MRD-.Results All the 39 patients presented with successful engraftment.The overall survival (OS) was 54.67％;the disease free survival (DFS) was 40.96％;the incidence rate of acute graft versus host disease (aGVHD) was 53.8％,including 23.1％ Ⅱ-Ⅳ degree aGVHD and 2.6％ Ⅲ-Ⅳ degree aGVHD.There was no significant difference in stem cell engraftment,GVHD,cytomegalovirus infection and hemorrhagic cystitis between MRD + and MRD-patients.DFS and OS in MRD + patients were significantly lower than those in MRD-patients;the cumulative RR rate increased significantly,and there was no significant difference in cumulative TRM.Conclusion HID-HSCT was an effective method to treat high-risk ALL,but MRD + patients had high recurrence rate and poor prognosis.Strategy adjustment should be considered to reduce tumor residual and the transplantation strategy should be optimized for these kinds of high risk patients,so as to improve long-term outcomes.