Objective:To investigate the effect and mechanism of treadmill training on Purkinje cells in the cerebellum of the rats with spinal cord injury(SCI). Method:Total of 108 female SD rats were randomly divided into 3 groups:the sham-operated group,the SCI group,and the SCI+treadmill training(TT)group.The rats in the SCI exercise group started treadmill train-ing after surgery,and BBB scores were used to assess the hindlimb motor function of rats with spinal cord in-jury.The cerebellum tissues were collected on the 3,7 and 14 day after surgery respectively,and the number and morphological changes of Purkinje cells in the cerebellum were detected by HE staining and Nissler stain-ing.The expression of caspase-9 and mGluR1 in Purkinje cells was detected by immunohistochemistry;the ex-pression of caspase-3 and mGluR1 was detected by immunofluorescence;the expression of apoptosis-related proteins Bax,Bcl-2,Cyt-C,caspase-9 and caspase-3 in cerebellar tissue was detected by Western Blot. Result:Compared with the sham-operated group,the BBB scores in SCI and SCI+TT groups were significant-ly decreased(P＜0.05).The number of Purkinje cells in cerebellum was reduced,and the size was reduced and lost the normal morphology.The expression levels of apoptosis-related proteins Bax,Cyt-C,activated caspase-9,and activated caspase-3 proteins in cerebellum were significantly increased(P＜0.05),and Bcl-2 expression was significantly decreased;caspase-9 and caspase-3 expression was increased and mGluR1 expression was decreased in Purkinje cells(P＜0.05).Compared with the SCI group,there was no significant difference in the BBB scores of the SCI+TT group(P＞0.05);the number and normal morphology of Purkinje cells in cerebellum increased;the expression levels of apoptosis-related proteins Bax,Cyt-C,activated caspase-9 and activated caspase-3 de-creased(P＜0.05),and the expression of Bcl-2 increased;the expression levels of caspase-9 and caspase-3 in Pur-kinje cells were decreased,and the expression level of mGluR1 was significantly increased(P＜0.05). Conclusion:Treadmill training can reduce the apoptosis of Purkinje cells in the cerebellum of the rats with spi-nal cord injury through the mitochondrial apoptosis pathway.

Objective To analyze the correlation between the prevalence of chronic non-communicable diseases (NCDs) and fall incidence among the elderly in urban and rural areas in Chongqing, and to provide evidence for targeted intervention. Methods In 2019, a questionnaire survey was conducted among the elderly aged 65 and over in four districts and counties using multistage stratified cluster random sampling. The difference of NCDs prevalence and fall incidence was compared by Chi-square test. The correlation between NCDs and fall incidence was analyzed by multivariate logistic regression. Results A total of 806 and 801 elderly people aged 65 and above in urban and rural areas，respectively, were investigated The fall incidence among the elderly in rural areas (12.98%) was higher than that in urban areas (7.94%) (χ2=10.916, P=0.001). The multivariable logistic regression analysis showed that the prevalence of heart disease (OR=2.988, 95%CI:1.544-5.785), osteoporosis (OR=2.696, 95%CI:1.527-4.760) and vestibular dysfunction or deafness (OR=3.180, 95%CI:1.142-8.861) was associated with fall incidence among urban elderly people. Factors including need for care (OR=2.315，95%CI：1.130-4.744), diabetes (OR=3.067，95%CI:1.634-5.756), osteoporosis (OR=1.972, 95%CI:1.210-3.214), and arthritis (OR=2.975, 95%CI:1.901-4.657) were associated with fall incidence among rural elderly people. Conclusion The fall incidence among the elderly in rural areas is higher than that in urban areas in Chongqing. The prevalence of NCD is high among the elderly. Timely treatment of NCDs should be provided to reduce fall incidence among the elderly.

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.
Animals ; Mice ; Methylation ; Chromatin ; Histones/metabolism* ; RNA, Messenger/genetics* ; Methyltransferases/metabolism* ; RNA/metabolism*

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Objective To investigate the current situation of animal injury among children in Chongqing, and to provide a scientific basis for relevant departments to formulate and implement strategies and measures to prevent and control animal injury to children. Methods According to the method of multi-stage stratified cluster sampling, 14,056 children in grades 4-12 in four districts of Chongqing were selected as the investigation subjects, and the occurrence of animal injuries in the past 6 months was investigated. Results The incidence of animal injury among school children in Chongqing was 0.35% and the incidence of person-time was 0.36%. The incidence rate in males (0.48%) was higher than that in females (0.31%). The incidence rate in urban children (0.43%) was higher than that in rural children (0.30%). The incidence of animal injury was the lowest in nuclear families (0.25%), and the highest in single-parent families (0.82%). There were statistically significant differences in the incidence of animal injuries in children among different fathers' occupational types, family types and parents' parenting styles (P<0.05).  The main place of child animal injury was home (57.14%). Recreational activities were the main cause of animal injury (51.02%). The main injuries were lower limbs (42.86%), upper limbs (24.49%) and head (10.20%). Conclusion The prevention and control of children's animal injury in Chongqing should focus on boys and families. It is suggested to take targeted and comprehensive interventions to prevent animal injuries in children.

In recent years, with the in-depth study of PD-1 and PD-L1 and the development of immunotherapy, the first problem is how to screen the beneficiaries. Recent clinical studies have shown that the expression level of PD-L1 in circulating tumor cells (CTC) can be used as a potential biomarker to play a guiding role in immunotherapy of malignant tumors. This article reviews the latest clinical research progress on the expression of PD-L1 in circulating tumor cells in various solid tumors.

In recent years, immunotherapy with immune checkpoint as the target has made revolutionary breakthroughs in the treatment of a variety of advanced solid tumors. Notwithstanding the impressive long-term therapeutic benefits, their efficacy is limited to a small subset of cancer patients. Some patients experienced drug resistance and immune-related adverse events (irAEs). Immune checkpoint inhibitors (ICIs) primarily include antibodies targeting CTLA-4 and antibodies targeting PD-1 and its ligands. Thus, it is of utmost importance to screen potential biomarkers in populations that may benefit from immunotherapy, to maximize therapeutic benefits. This review summarizes the mechanism of ICIs and its related efficacy biomarker, to better guide the application of immunotherapy in clinical practice.

Objective: To analyze the trend change of the drowning mortality among children and adolescents in Chongqing, 2012-2021, and to provide suggestion for drowning prevention and control. Methods: Drowning death cases (ICD-10:W65.0-W74.9) among children and adolescents in Chongqing from 2012 to 2021 were derived from Chongqing death registration system. The difference of the drowning mortality between male and female, urban and rural area were compared by Chi square test. The trend change of the drowning mortality between 2012 and 2021 was analyzed by annual percent change( APC ). Results: The mortality and ASMR of drowning among children and adolescents decreased from 9.57/10 5, 9.42/10 5 in 2012 to 2.80/10 5, 2.83/10 5 in 2021 significantly( t=10.93, 10.52, P <0.01). And its APC were -13.15% and 13.06% respectively. The drowning mortality in male was higher than that in female( P <0.05). The drowning mortality in rural area was higher than that in urban area( P <0.05). The mortality of drowning among children aged between 0 and 4 years old, 5 and 9 years old, 10 and 14 years old decreased by 15.30 %,17.80% and 11.40%( APC =-15.30%, -17.80%, -11.40%, t=11.11, 9.22, 5.62, P <0.05). The proportion of drowning in natural water field among children and adolescents accounted for about 80%. Conclusion The mortality of drowning among children and adolescents in Chongqing decreases rapidly. Vulnerable population of drowning includes boys, rural children and adolescents, and children age of 0-14 years old. Comprehensive prevention for drowning should be carried out continuously.

Objective To understand the prevalence of osteoporosis and its influence factors in residents of Chongqing, and to provide the reference for osteoporosis prevention and treatment. Methods The data were from ^“An epidemiological survey of osteoporosis in Chongqing in 2018^”, and the multi-stage stratified cluster random sampling method was used to select 1885 subjects (≥20 years old) from 32 villages/neighborhood committee in 4 areas (countries) of Chongqing. The investigation was performed by questionnaire (sociodemographic factors, lifestyle factors, history of orthopedics) and the bone mineral density was measured by QDR 4 500A dual energy X-ray absorptiometry. The chi-square test and multi factor multi-variant logistic regression analysis were utilized to analyze the data, the used software was SPSS 25.0. Results The morbidities of osteoporosis and osteopenia in residents (>20 years old) of Chongqing in China were 12.99% and 48.70%, respectively. The osteoporosis morbidity (19.08%) in females was significantly higher than that (4.42%) in males, and increased with age. The multi-variant logistic regression indicated that women (OR=6.10, 95% CI:4.08-9.14), the past medical history of fracture (OR=1.79, 95%CI:1.18-2.73) and age (OR=16.80, 95% CI:9.19-30.77) were risk factors for osteoporosis; milk intake (OR=0.65, 95%CI:0.47-0.89), overweight (OR=0.51, 95%CI:0.36-0.93)and obesity (OR=0.30, 95%CI:0.19-0.47), as compared with ≤primary school group, junior high school group (OR=0.57, 95%CI:0.39-0.82);≥high school group (0.40, 95%CI:0.26-0.61) were considered to be protective factors for osteoporosis. Conclusion The prevalence of osteoporosis among residents with age above 50 years old of Chongqing was very high. Health education and behavior intervention should be focused on the elderly or female residents to promote the formulation of healthy lifestyle.

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.