ObjectivesTo analyze the spatial and temporal clustering characteristics and related influencing factors of late diagnosis of HIV/AIDS in Lanzhou， to identify its high-risk areas and time trends in Lanzhou， and to provide a theoretical basis for developing targeted HIV/AIDS prevention and control strategies in Lanzhou. MethodsThe subjects of this study were adult HIV/AIDS cases reported in Lanzhou City between 2011 and 2018. Data used in the study were sourced from the Lanzhou Center for Disease Control and Prevention and the Lanzhou Statistical Yearbook. To analyze the spatial distribution characteristics and influencing factors of the relative risk （RR） of late HIV/AIDS diagnosis， Bayes spatial-temporal model was used. ResultsA total of 1984 new HIV/AIDS cases were reported in Lanzhou from 2011 to 2018， with an mean age of 37.51 years and predominantly male （91.8%）. The number of late diagnosis cases was 982， with an mean age of 39.67 years and a predominance of males （91.8%）. Late diagnosis was more common in older individuals and women with HIV/AIDS. Chengguan District （51.1%）， Anning District （50.3%） and Yuzhong County （51.9%） had an above-average proportion of late diagnosis of HIV/AIDS. The proportion of late diagnosis cases in Lanzhou showed a fluctuating upward trend from 2011 to 2018. The results of Bayes spatial-temporal model showed that the risk of late HIV/AIDS diagnosis in Lanzhou had fluctuated from 2011 to 2015， and then increased rapidly after 2015 ［RR （95% credibility interval， 95%CI） increased from 1.01 （0.84， 1.23） to 1.11 （0.77， 1.97）］； the trends of risk of late diagnosis in Honggu district and three counties were similar to the overall trend in Lanzhou city， while the risk of late diagnosis in Chengguan District and Qilihe District showed a decreasing trend. The regions with the RR for late diagnosis greater than 1 included Yongdeng County （RR=1.07， 95% CI： 0.55， 1.96）， Xigu District （RR=1.04， 95% CI： 0.67， 1.49）， Chengguan District （RR=2.41， 95% CI： 0.85， 6.16）， and Qilihe District （RR=2.03， 95% CI： 1.10， 3.27）. Besides， the heatmap analysis showed that Chengguan District and Qilihe District were the hot spots. The influencing factors analysis showed that the higher GDP per capita （RR=0.65， 95% CI： 0.35， 0.90） and the larger proportion of males with HIV/AIDS cases （RR=0.53， 95% CI： 0.19， 0.92） could lead to the lower the relative risk of late HIV/AIDS diagnosis. However， the higher the population density （RR=1.35， 95% CI： 1.01， 1.81） caused the higher the risk of late diagnosis. ConclusionOur study shows the risk of late diagnosis of HIV/AIDS in Lanzhou was on the rise， and there are significant regional differences. GDP per capita， the proportion of males in HIV/AIDS cases and population density are influencing factors in the late diagnosis of HIV/AIDS. Therefore， for regions with a high risk of late diagnosis or related risk factors， targeted HIV screening and prevention services should be given priority in order to reduce the proportion and risk of late diagnosis of HIV/AIDS.

【Objective】 To statistically analyze the relationship between homologous recombination repair deficiency (HRD) score and clinicopathological characteristics, genomic mutations in patients with high-risk and metastatic hormone-sensitive prostate cancer (mHSPC) and the prognostic predictive value in mHSPC. 【Methods】 A total of 127 patients diagnosed with high-risk prostate cancer and mHSPC, treated at the Department of Urology of Chinese PLA General Hospital during Dec.2021 and Nov.2023 were enrolled.Homologous recombination repair (HRR) gene sequencing was performed, and the genomic scar score (GSS) algorithm were conducted to calculate the HRD score.The relationship between HRD scores and clinicopathological features, genomic alterations, and prognosis were analyzed. 【Results】 The median HRD score was 1.6(0.8, 5.2), 30(23.6%) patients’ HRD scores ≥10, and 11(8.7%) patients’ HRD scores ≥20.Clinicopathological features, including ISUP classification ≥4 (P=0.044) and metastatic status (P=0.008) were associated with high HRD score.Patients with mutations in the BRCA, TP53 and MYC systems had significantly higher HRD score than those with wild-type genes (P<0.05).In mHSPC, the risk of biochemical recurrence was 12.836 times higher in patients with HRD score ≥20 than in those with <20 [OR:12.836 (1.332-124.623), P=0.028]. 【Conclusion】 Baseline HRD score was lower in patients with high-risk prostate cancer and mHSPC.Patients with high HRD score may have higher histological grading (ISUP≥4) and later clinical stage.Further investigation is needed to determine the threshold of HRD scores as biochemical markers suggestive of a poor prognosis.

Objective To establish the sheep model of lumbar spine osteoporosis in vitro,and to search the texture parameters with identification significance and establish its regression formula relation with DXA measured bone mineral density,bone ash density and bone ash degree.Methods The L1-L3 trigeminy verte-bral body in 120 sheep conducted the immersion and decalcification by EDTA-Na2 solution (0.4916 mmol/L) immersion method,the muscles and attachment bone were removed.Then they were randomly divided into 4 groups (group A,B,C and D),30 cases in each group.They were immersed in 10％ formaldehyde solution for anticorrosion.The group A,B,C and D were immersed in the prepared EDTA-Na2 solution for decalcification 0,4,9,15 d to prepare the in vitro osteoporosis models.Thin-slice CT scan and DXA bone density measure-ment on the above-mentioned lumbar vertebrae were performed,and the volume and dry weight of each verte-bral body were measured,and then calcined at a constant temperature of 1100 ℃ in a muffle furnace for 6 h to measure the weight of ashes.The bone ash weight,bone ash density and bone ash degree were measured.The MaZda texture analysis software was used to conduct the texture analysis on the cancellous substance of the vertebral body in the above CT images,and the texture features were screened by the Fisher coefficient,classi-fication error probability combined with average correlation coefficient,interactive information and the three combined method.The 4 groups of bone mineral density conducted the classification analysis by the original data analysis (ODA),principal component analysis (PCA),linear discriminant analysis (LDA) and nonlinear discriminant analysis (NDA).The correlation analysis between the texture parameters screened by the above method with the bone density,bone grey degree and bone ash density for searching the texture parameters with strongest correlation.The texture parameters with strongest correlation served as the independent varia-bles,the bone density,bone grey degree and bone ash density as the dependent variables,and the unitary and binary linear regression analyses were performed for obtaining the regression equation.Results With the pro-longation of decalcification time,the CT images showed that the bone cortex gradually thinned,the cancellous bone density was decreased,and the trabecular bone became sparse.The identification ability of FPM com-bined with NDA was strongest,and the false judgment rate was only 2.5％.Among them,the contrast in the gray symbiosis matrix had strongly negative correlation with the bone gray degree (r=-0.938).The entropy in the gray co-occurrence matrix had strongly negative correlation with the bone ash density and bone mineral density (r=-0.927,-0.896).The unitary linear regression equation was expressed as bone grey degree=0.692-0.002×Contrast,bone ash density=0.802-0.121×Entropy,bone density=1.301-0.200×Entro-py.Conclusion The significant correlation exists between some texture parameters and bone mineral density related parameters in thin slice CT images of sheep lumbar spine,which could establish a regression formula relationship.

Objective:To observe the development process of the neuronal synapse in cerebral cortex and basal ganglionic eminence(GE)regions of the mice,and to clarify the differences in the development of excitatory and inhibitory synapses in different brain regions in vivo and in vitro.Methods:The female C57BL/6 mice were euthanized by cervical dislocation from the 13.5th day to the 15.5th day during the pregnancy,and the embryos were collected under the sterile conditions.The cortex and GE regions of brain tissue of the embryonic mice were gradually isolated under microscope.The primary neurons from the embryonic mice were cultured in vitro,and the cell samples were collected on the 3rd,7th,14th,and 21th days,respectively,and regarded as culture 3 d,7 d,14 d,and 21 d groups.The expression levels of postsynaptic density 95(PSD95)and Gephyrin mRNA in the primary neurons from the cortex and GE regions of the mice in various groups were detected by real-time fluorescence quantitative PCR(RT-qPCR)method.Immunofluorescence method was used to detect the expression levels of vesicular glutamate transporter 1(vGLUT1),PSD95,vesicular GABA transporter(vGAT),and Gephyrin proteins in the neurons from the cortex and GE regions of the mice in various groups.Immunofluorescence method was also used to detect the expression levels of vGLUT1 and vGAT proteins in the neurons from the cortical and GE regions in brain tissue of the embryonic mice.Results:Compared with culture 3 d group,the expression levels of PSD95 and Gephyrin mRNA in cortex and GE regions of the mice in culture 14 d and 21 d groups were significantly increased(P<0.01).Compared with cortex area,the expression level of Gephyrin mRNA in the neurons from GE region of the mice in culture 14 d group was significantly decreased(P<0.01).The microscope observation results showed that the excitatory and inhibitory synapses in the neurons from cortex and GE regions of the mice in culture 14 d group showed preliminary development,with positive expression of relevant proteins;among them,the excitatory synaptic proteins showed more distinct positive expression in the cortex neurons,and the presynaptic vGLUT1 and postsynaptic PSD95 molecules exhibited co-localization in the cell bodies and protrusions of the cortical neurons;the inhibitory presynaptic vGAT protein and postsynaptic Gephyrin protein in the neurons from GE region also exhibited co-localization in the cell bodies and protrusions,and there were more distinct expressions of the presynaptic molecule proteins than postsynaptic molecule proteins.Compared with cortex region,the levels of vGLUT1 and PSD95 proteins in the neurons from GE region of the mice in culture 14 d group were significantly decreased(P<0.01),while the levels of vGAT and gephyrin proteins were significantly increased(P<0.01).In culture 21 d group,the positive expressions of synaptic protein in the neurons from cortex and GE regions were increased,and the excitatory and inhibitory synapses further matured and enhanced.In the neurons from cortex and GE regions,rich patterns of corresponding pre-and postsynaptic expression were formed in the cell bodies and protrusions,and synapse structures showed gradual,positive development,with more apparent expression of presynaptic molecules compared wih postsynaptic proteins.Compared with cortex region,the levels of vGLUT1 and PSD95 proteins in the neurons from GE region of the mice in culture 21 d group were significantly decreased(P<0.01),and the levels of vGAT and Gephyrin proteins were significantly increased(P<0.01).Compared with cortex region,the expression level of vGLUT1 protein in the neurons from GE region in brain tissue of the embryonic mice was significantly decreased(P<0.01),while the expression level of vGAT protein was significantly increased(P<0.05).Conclusion:There are distinct differences in synaptic development between the neurons from cortex and GE regions,the excitatory synapses develope earlier in the cortical region and the inhibitory synapses develope earlier in the GE region.The region-specific development of synapses suggests that different types of neural diseases with different cell types might originate from different developmental processes.

Objective To analyze the differential expressed genes(DEGs)in the lung tissues of rat model of high altitude pulmonary edema(HAPE)by using microarray analysis in order to provide new clues for molecular mechanism of HAPE.Methods Healthy male SD rats(8 weeks old,weighing 200±20 g)were randomized into normoxia control(NC)group,lipopolysaccharide(LPS)group,hypoxia group and hypoxia+low-dose LPS(HL)group.The rats of the LPS group and HL group were injected with 0.1 mL 0.05％LPS per 100 g body weight,and those of the NC group and the hypoxia group were administered with an equivalent volume of normal saline.The rats of the hypoxia group and the HL group were housed in a hypobaric chamber simulating an altitude of 5 000 m,and those of the NC group and the LPS group were raised simultaneously outside of the chamber.The wet/dry mass ratio(WDR)of lung tissue and total protein content in bronchoalveolar lavage fluid(BALF)were measured,and the histopathological changes of lung tissue was observed using HE staining.The total RNA was extracted from the lung tissues,and the mRNA expression profile was obtained with Affymetrix microarray followed by Gene Ontology(GO)analysis and Kyoto encyclopedia of genes and genomes(KEGG)pathway analysis with Metascape(http://metascape.org).Results The rats of the HL group showed significant congestion,edema,and widened alveolar septa.Compared with the NC group,the HL group had significantly increased lung WDR(P＜0.01)and total protein content in BALF(P＜0.05).Gene expression analysis revealed that there were 79 genes up-regulated and 59 genes down-regulated in the hypoxia group,473 genes up-regulated and 695 genes down-regulated in the LPS group,and especially,669 genes up-regulated and 1 253 genes down-regulated in the HL group.GO and KEGG pathway analyses revealed that the upregulated genes in the HL group were mainly enriched in biological processes,such as cytokine mediated signaling pathways,response to IL-1,regulation of inflammatory response,as well as signaling pathways,including cytokine-cytokine receptor interactions,TNF,NF-κB,IL-17,complement and coagulation cascades,etc.The down-regulated genes were mainly enriched in biological processes,such as extracellular matrix organization,regulation of endothelial cell migration,cell substrate adhesion,as well as signaling pathways,such as focal adhesion,Wnt,cGMP-PKG,PI3K-Akt,Rap1,etc.The mRNA expression of NF-κB,TNF-α,IL-1βand IL-6 was significantly up-regulated in the lung tissue of the HL group(P＜0.01).Conclusion Hypoxia+low-dose LPS is an effective procedure to establish a reliable model for HAPE in rats.Hypoxia can significantly aggravate LPS-induced inflammation and immune response,enhance the expression of inflammatory mediators,and thus promote the pathogenesis of HAPE.

Objective:To investigate diagnostic and prognostic value of actin-binding protein ANLN in clear cell renal cell carcinoma(ccRCC)and its relationship with tumor microenvironment.Methods:Gene expression data and clinical data for ccRCC were downloaded from The Cancer Genome Atlas(TCGA).Relationship between ANLN expression and clinicopathological features was assessed by Wilcoxon rank sum test and Logistic regression.Receiver operating characteristic(ROC)curve was used to assess diagnostic value of ANLN expression in ccRCC.Kaplan-Meier and Cox regression analysis were used to investigate effect of ANLN expression on overall survival.Gene set enrichment analysis(GSEA)was used to identify signaling pathways associated with ANLN in ccRCC.Relationship between ANLN expression and immune infiltration was analyzed by ESTIMATE algorithm,tumor immune estima-tion resource(TIMER)and CIBERSORT algorithms.Relationship between ANLN and drug sensitivity was calculated using CellMiner database.Results:ANLN expression was significantly upregulated in ccRCC tissues.ANLN expression in ccRCC was correlated with clinicopathological features.ROC analysis showed that ANLN had a high diagnostic value in ccRCC.High ANLN expression was signifi-cantly associated with poor prognosis.Multivariate Cox regression analysis showed that high ANLN expression was an independent risk factor for overall survival in ccRCC patients.GSEA showed that ANLN was associated with multiple signaling pathways.In terms of immunity,ANLN was closely associated with tumor microenvironment,immune infiltration and immune checkpoint molecules in ccRCC.ANLN expression was negatively correlated with sensitivity of most antitumor drugs.Conclusion:ANLN is a potential diagnos-tic and prognostic biomarker and immunotherapeutic target for ccRCC.

Objective:To investigate the correlation between Piwi-interacting RNA (piRNA) and diabetic nephropathy (DN).Methods:The differential expression profiles of piRNAs in renal tissues of patients with DN (experimental group) and renal tissues adjacent to tumors of patients with renal tumors (control group) were detected by high-throughput sequencing. The biological function of differentially expressed piRNAs was described by gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis. Real-time fluorescence quantitative PCR was used to detect the serum expression level of target piRNAs in patients with DN. Spearman correlation analysis was used to analyze the correlation between serum target piRNAs and clinical indexes of patients with DN.Results:The results of high throughput sequencing showed that there were 127 differentially expressed piRNAs between DN group and control group, with screening condition of |log 2(fold changes)|≥2 and P<0.05. Among them, there were 99 up-regulated piRNAs and 28 down-regulated piRNAs. The top 5 up-regulated piRNAs were piRNA-hsa-161686, piRNA-hsa-349255, piRNA-hsa-355720, piRNA-hsa-151229 and piRNA-hsa-154959, respectively. The top 5 down-regulated piRNAs were piRNA-hsa-1929960, piRNA-hsa-174194, piRNA-hsa- 148658, piRNA-hsa-172594 and piRNA-hsa-172421, respectively. The PCR verification results of 3 up-regulated genes and 3 down-regulated genes with low P values and high expression levels showed that serum expression level of piRNA-hsa-77976 was significantly down-regulated in patients with DN ( P=0.028), which was consistent with that of sequencing, while the expression levels of other genes were inconsistent with the sequencing results or had no statistical significance. Bioinformatics analysis results predicted that significantly differentially expressed piRNAs might participate in the regulation of DN through Rap1, Ras, PI3K-Akt and axon guiding pathways. The results of correlation analysis showed that the expression level of piRNA-hsa-77976 was negatively correlated with blood urea nitrogen ( r=-0.584, P=0.028), serum creatinine ( r=-0.637, P=0.014), cystatin C ( r=-0.738, P=0.003) and β2 microglobulin ( r=-0.822, P<0.001), and positively correlated with estimated glomerular filtration rate ( r=0.661, P=0.010). Conclusion:The differential expression of piRNA is closely related to DN, and may be used as a new biomarker for the diagnosis and prognosis of DN.

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
Mice ; Animals ; Epilepsy, Temporal Lobe/pathology* ; Parvalbumins/metabolism* ; Parkinson Disease/pathology* ; Neurons/metabolism* ; Interneurons/physiology* ; Disease Models, Animal ; Brain/pathology*