OBJECTIVE:  To estimate the population attributable disease burden (PAD) of low bone mineral density (LBMD) related fractures (fragility fractures) among Chinese people over 50 years old from 1990 to 2023, using data from the Global Burden of Disease Study 2023 (GBD 2023), and to provide evidence for prevention strategies and health resource allocation. METHODS:   Based on the GBD 2023, the LBMD summary exposure values (SEV), fracture incidence, years lived with disability (YLDs), and LBMD-related falls YLDs of Chinese people over 50 years old from 1990 to 2023 were extracted. PAD was calculated with population attributable fraction (PAF), and an entropy-weight method was applied to evaluate the contribution of individual fracture sites. Temporal trends and sex differences were examined with Joinpoint regression. RESULTS:  From 1990 to 2023, the age-standardized SEV of LBMD in people over 50 years old showed an overall decline [average annual percent change (AAPC)=-0.564%]. Age-standardized fracture incidence, fracture YLDs rate, and LBMD-related falls YLDs rate all exhibited W-shaped upward trends (AAPC=1.045%, 0.296%, and 0.724%, respectively). PAF-based estimates indicated that LBMD-attributable fracture incidence likewise increased in a "W-shaped" manner (AAPC=0.558%), whereas the corresponding YLDs rate showed an overall W-shaped decline (AAPC=-0.193%). In international comparison, China and the global average displayed broadly concordant directions of change, with greater volatility in China and a progressive narrowing of the gap after 2015. Regarding sex differences, fracture YLDs rates were consistently higher in the males, whereas the other burden indicators were higher in the females; the temporal patterns were similar in both sexes. Entropy weight method identified hip fractures as contributing most to incidence (weight 0.133), and pelvic fractures as the largest contributor to YLDs rate (weight 0.115). CONCLUSION Since 1990, the LBMD attributable fracture burden in China's older population has risen, with female and hip or pelvic fractures bearing the heaviest load. Strengthened osteoporosis screening, improved insurance coverage, and targeted health education are urgently needed to curb further increases in disease burden.
Humans ; China/epidemiology* ; Middle Aged ; Female ; Male ; Bone Density ; Aged ; Incidence ; Osteoporotic Fractures/epidemiology* ; Aged, 80 and over ; Accidental Falls/statistics & numerical data* ; Cost of Illness ; Global Burden of Disease ; Osteoporosis/complications* ; Disability-Adjusted Life Years ; Fractures, Bone/epidemiology*

Objective:To analyze the types and functions of CD34 + cells in full-thickness skin defect wounds of normal mice and diabetic mice by single-cell RNA sequencing. Methods:This study was an experimental study. The CD34 + cell lineage tracing mouse was produced, and the visualization of CD34 + cells under the fluorescent condition was realized. Six male CD34 + cell lineage tracing mice aged 7-8 weeks (designated as diabetic group) were intraperitoneally injected with streptozotocin to establish a diabetic model, and full-thickness skin defect wounds were prepared on their backs when they reached 13 weeks old. Another 6 male CD34 + cell lineage tracing mice aged 13 weeks (designated as control group) were also subjected to full-thickness skin defect wounds on their backs. On post-injury day (PID) 4, wound tissue was collected from 3 mice in control group and 2 mice in diabetic group, and digested to prepare single-cell suspensions. CD34 + cells were screened using fluorescence-activated cell sorting, followed by single-cell RNA sequencing. The Seurat 4.0.2 program in the R programming language was utilized for dimensionality reduction, visualization, and cell clustering analysis of CD34 + cell types, and to screen and annotate the marker genes for each CD34 + cell subpopulation. Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analysis was performed to analyze the differentially expressed genes (DEGs) of CD34 + fibroblasts (Fbs), smooth muscle cells (SMCs), keratinocytes (KCs), and chondrocyte-like cells (CLCs) in the wound tissue of two groups of mice for exploring cellular functions. Results:On PID 4, CD34 + cells in the wound tissue of both groups of mice were consisted of 7 cell types, specifically endothelial cells, Fbs, KCs, macrophages, T cells, SMCs, and CLCs. Among these, Fbs were further classified into 5 subpopulations. Compared with those in control group, the proportions of CD34 + endothelial cells, Fbs subpopulation 1, Fbs subpopulation 4, KCs, and CLCs in the wound tissue of mice were increased in diabetic group, while the proportions of CD34 + Fbs subpopulation 2, Fbs subpopulation 3, and SMCs were decreased. The marker genes for annotating CD34 + CLCs, endothelial cells, Fbs subpopulation 1, Fbs subpopulation 2, Fbs subpopulation 3, Fbs subpopulation 4, Fbs subpopulation 5, KCs, macrophages, SMCs, and T cells were respectively metastasis-associated lung adenocarcinoma transcript 1, fatty acid binding protein 4, Gremlin 1, complement component 4B, H19 imprinted maternally expressed transcript, Dickkopf Wnt signaling pathway inhibitor 2, fibromodulin, keratin 5, CD74 molecule, regulator of G protein signaling 5, and inducible T-cell co-stimulator molecule. KEGG and GO enrichment analysis revealed that, compared with those in control group, DEGs with significant differential expression (SDE) in CD34 + Fbs from the wound tissue of mice in diabetic group on PID 4 were significantly enriched in terms related to inflammatory response, extracellular matrix (ECM) organization, regulation of cell proliferation, and aging (with Pvalues all <0.05), DEGs with SDE in CD34 + SMCs were significantly enriched in terms related to cell migration, apoptotic process, positive regulation of transcription, and phagosome (with P values all <0.05), DEGs with SDE in CD34 + KCs were significantly enriched in terms related to mitochondrial function, transcription, and neurodegenerative diseases (with P values all <0.05), and DEGs with SDE in CD34 + CLCs were significantly enriched in terms related to rhythm regulation, ECM, and viral infection (with P values all <0.05). Conclusions:CD34 + cells display high heterogeneity in the healing process of full-thickness skin defect wounds in both normal mice and diabetic mice. The significantly enriched functions of DEGs with SDE in CD34 + cell subpopulations in the wound tissue of the two mouse groups are closely related to the wound healing process.

AIM:To investigate the effects of epal-restat(Epa)on the mitochondrial oxidative stress damage of radiation pneumonitis(RP)mice and to explore its possible mechanism.METHODS:C57BL/6 mice were randomly divided into control(CON),Irradiation(IR),IR combined with Epa(10 mg/kg)and IR combined with Epa(20 mg/kg)group,16 mice in each group.Mouse models of RP were es-tablished by whole thorax irradiation at a dose of 15Gy using a 6-MV linear accelerator.Continuous intragastric administration after IR for 6 or 8 weeks.Lung histopathology was analyzed by HE staining.The expression of aldose reductase(AR)was deter-mined by immunohistochemistry.Mitochondrial morphology of lung tissues was observed by trans-mission electron microscopy.The levels of inflam-matory cytokines(IL-6,TNF-α and TGF-β1)in plas-ma were detected by ELISA.The contents of Malo-ndialdehyde(MDA)and 4-hydroxynonenal(4-HNE)in lung tissues were determined by colorimetry.Sin-gle cell suspension of lung tissues was prepared and reactive oxygen species(ROS)levels in the cells was examined using a DCFH-DA fluorescent probe.Real-time quantitative PCR was used to determine the expression of AR,IL-6,TNF-α and TGF-β1.The protein levels of AR,IL-6,TNF-α,TGF-β1,BAX,Bcl2,Cleaved Caspase-3,8-oxoguanine DNA glycosylase 1(OGG1)and silent information regulator 3(SIRT3)were detected by Western blot analysis.RESULTS:Compared with the CON group,the alveolar hyper-plasia,alveolar septum thickening and inflammato-ry cell infiltration were observed in the IR group.Moreover,the content of inflammatory factors such as IL-6,TNF-α and TGF-β1 and the expression of BAX and Cleaved Caspase-3 were significantly in-creased,and the expression of Bcl2 was obviously decreased after irradiation.Compared with the IR group,Epa robustly alleviated RP.Meanwhile,Epa down-regulated inflammatory cells infiltration and the expression of inflammatory cytokines,such as IL-6,TNF-α and TGF-β1.In addition,Epa could down-regulate the expression of BAX and Cleaved Caspase-3,and up-regulate Bcl2 in lung tissues.Compared with the CON group,the expression of AR,the levels of ROS,MDA and 4-HNE were signifi-cantly increased,the expression of OGG1 and SIRT3 were significantly decreased,and mitochon-drial damage was aggravated in the IR group.Com-pared with IR group,the expression of AR was sig-nificantly down-regulated,the levels of ROS,MDA and 4-HNE were significantly decreased,the expres-sions of OGG1 and SIRT3 were significantly in-creased,and the mitochondrial damage was signifi-cantly alleviated in IR group after 6 to 8 weeks of Epa administration.CONCLUSION:Epa has a pro-tective effect on RP,which may be related to the in-hibition of AR expression,the reduction of mito-chondrial oxidative stress injury,and the inhibition of inflammatory response and cell apoptosis.

In order to understand the prevalence and antimicrobial resistance of Enterococcus faeca-lis(E.faecalis)and Enterococcus faecium(E.faecium)isolated from human,pig and environ-ment in a Xinjiang pig farm,and to investigate the prevalence and potential harm of antimicrobial resistance genes,858 fecal samples from pig farm workers,anal swabs from pig and environment were collected for isolation,identification,antimicrobial susceptibility test and drug resistance gene detection.The results showed that 429 strains of E.faecalis and 222 strains of E.faecium were i-solated.The distribution of Enterococcus species varied among different sources.The isolation rate of E.faecalis was higher in pig anal swabs(73.1％,309/423)and human fecal samples(68.4％,26/38).E.faecium(42.3％,168/397)was mainly isolated from environmental samples.The drug resistance of E.faecalis and E.faecium isolated from pigs was similar to that of E.faecium isola-ted from environment.The drug resistance rates of E.faecalis and E.faecium isolated from pigs were more serious than those from humans to tetracycline,doxycycline,florfenicol and erythromy-cin,and they were more sensitive to ciprofloxacin and levofloxacin.More than 30.0％of E.faecalis and E.faecium isolated from pigs and environment were intermediate to linezolid.E.faecalis from three sources and E.faecium from environmental sources were mainly resistant to five drugs,while E.faecium from pigs was mainly resistant to six drugs.The detection rates of tet(M)and tet(L)genes in E.faecalis and E.faecium isolates from human,animal and environmental sources were more than 70.0％,which was consistent with the results of drug sensitivity.In addition,the cfr,optrA and poxtA genes that mediate oxazolidinone resistance were detected to varying extent.The cfr gene was only detected in four E.faecalis isolates from swine,one E.faecalis isolate from environment and two E.faecium isolates from environment.The positive rate of optrA gene in E.faecium isolated from pigs and environment was higher than that from humans,and the posi-tive rate was more than 60.0％.The positive rate of poxtA gene in E.faecium isolated from pigs and humans was more than 45.0％.The similar drug resistance situation suggests that there is the phenomenon of mutual contamination of drug-resistant bacteria in human-animal-environment.Therefore,we should consider from the perspective of one health,formulate comprehensive disin-fection and control programs,block the transmission route of drug-resistant strains and drug re-sistance genes between human-animal-environment,standardize the use of antibiotics,and reduce the enrichment of antibiotics in human-animal-environment,so as to reduce the risk of drug-resist-ant bacteria.

BACKGROUND:Tauroursodeoxycholic acid is a hydrophilic bile acid derivative that has neuroprotective effects in a variety of neurological disease models.However,there are few reports on the effects of tauroursodeoxycholic acid on spinal cord injury. OBJECTIVE:To investigate the effect of tauroursodeoxycholic acid on apoptosis of spinal cord neurons under hypoglycemic and hypoxic conditions,as well as the effect on recovery of motor function in mice after spinal cord injury. METHODS:(1)In vitro experiment:Primary spinal cord neurons were isolated from C57 BL/6 mouse embryos at 13.5 days of gestation.After 72 hours of culture,the cells were divided into three groups.In the normal group,cells were cultured in Neurobasal complete medium that was incubated in a CO2 incubator(5%CO2 + 95%air)for 24 hours.In the oxyglucose-deprived group,sugar-free Neurobasal medium was added and incubated in a triple-gas incubator(94%N2+5%CO2+1%O2)for 12 hours,and then the medium was replaced with Neurobasal complete medium and incubated in a CO2 incubator for 12 hours.In the experimental group,the treatment procedure was approximately the same as that in the oxyglucose-deprived group,except that taurodeoxycholic acid was added along with the sugar-free Neurobasal medium.TUNEL staining was used to detect apoptosis,cell counting kit-8 assay was applied to detect cell activity,and immunofluorescence staining was performed to detect cellular β-microtubule protein expression.(2)Animal experiment:Sixty C57 BL/6 mice were randomly divided into sham-operated group,spinal cord injury group and experimental group,with 20 mice in each group.Animal models of T9-T10 spinal cord injury were established using Allen's percussion method in the spinal cord injury group and the experimental group.Starting from the 1st day after modeling,taurodeoxycholic acid solution was given by gavage in the experimental group and normal saline was given by gavage in the sham-operated and spinal cord injury groups once a day for 14 consecutive days.Spinal cord tissue repair was assessed using behavioral and histological methods. RESULTS AND CONCLUSION:In vitro experiment:TUNEL staining,cell counting kit-8 and immunofluorescence staining showed that compared with the normal group,the number of apoptotic cells was higher(P＜0.01),while cell activity and β-microtubule protein expression were lower in the oxyglucose-deprived group(P＜0.01);compared with the oxyglucose-deprived group,the number of apoptotic cells was lower(P＜0.01),while cell activity and β-microtubule protein expression were higher in the experimental group(P＜0.01).Animal experiment:The Basso-Beattie-Bresnahan scores in the open field test and hind limb footprint experiments showed that the mice in the experimental group had better recovery of walking and motor functions than those in the spinal cord injury group.Hematoxylin-eosin staining showed that significant deformities and cavities were observed at the site of spinal cord injury and the number of nerve cells was significantly reduced in the spinal cord injury group.Compared with the spinal cord injury group,the experimental group showed a significant reduction in the area of spinal cord injury,less spinal cord deformity,fewer cavities,and an increase in the number of nerve cells.Immunofluorescence staining showed that the number of neuronal nucleus-labeled neuronal cells in the spinal cord injury group was less than that in the sham-operated group(P＜0.01),and the number of neuronal nucleus-labeled neuronal cells in the experimental group was higher than that in the spinal cord injury group(P＜0.01).To conclude,tauroursodeoxycholic acid could effectively reduce glucose/oxygen deprivation-induced apoptosis of spinal cord neurons and axonal loss,and promote the recovery of motor function in mice with spinal cord injury.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (American Psychiatric Association, 2013) defines autism spectrum disorder (ASD) as a complex neurodevelopmental disorder that begins in early childhood and is accompanied by social communication deficits and repetitive stereotyped behaviors. According to the monitoring data released in 2021 in the United States, the prevalence of ASD in children was as high as 2.27%; that is, one in 44 children had autism (Maenneret al., 2021). China publicly reported this figure to be around 0.7% (Zhou et al., 2020). The current view is that children with ASD are generally impaired in their adaptation ability (McDonaldet al., 2016; Hodgeet al., 2021; Opertoet al., 2021). Adaptive behaviors comprise the conceptual, social, and practical skills that enable individuals to adapt to the environment, which play an important role in daily life (McDonald et al., 2019). "Adaptive behavior" was first described by Doll (1936). Subsequently, abnormalities in adaptive behavior were included in the criteria for intellectual disability for the first time (Heber, 1961). The American Association on Mental Retardation (AAMR) has refined and specified this term several times. Researchers hold different opinions on the structure of social adaptive capability. Greenspan and Granfield (1992) divided social adaptive capability into social understanding and social interaction. However, an increasing number of scholars considered that the concept of adaptive behaviors in children was constructed via multiple dimensions. The most representative one among them was the Vineland Adaptive Behavior Scales (VABS) proposed by Sparrow et al. (1984). This scale illustrates that adaptive behavior includes communication, daily living skills, socialization, and motor skills. Harrison and Oakland (2003) developed an Adaptive Behavior Assessment System (ABAS), by applying the theory of adaptive behavior proposed by AAMR and the American Association on Intellectual and Developmental Disabilities (AAIDD). This system shows that adaptive behavior has three adaptive composites, namely, conceptual composite (including communication, learning function, and self-management), social composite (including leisure and social skills), and practical composite (including community application, home living, health and safety, and self-care). As there are different requirements for the social adaptive capability of children from different cultural backgrounds and various regions, Chinese scholars have translated the Normal Development of Social Skills from Infant to Junior High School Children (S-M) scale compiled by Japanese scholars into Chinese, which is now widely used in China (Zhang et al., 1995). The impairment of adaptive function in children with ASD includes multiple dimensions, such as socialization, communication, and daily living skills (Kanne et al., 2011), and the degree of impairment can predict the prognosis and outcome in real life, including education acquisition and independent living ability (Farley et al., 2009). Therefore, adaptive behavioral capacity is considered to be a key intervention point that directly affects the individual and social outcomes of autistic children (Veenstra-VanderWeele et al., 2017; Bölte et al., 2019).
Humans ; Autism Spectrum Disorder/psychology* ; Male ; Adaptation, Psychological ; Child, Preschool ; Female ; Child ; Retrospective Studies ; China/epidemiology*

Objective To investigate the effects and mechanism of Interleukin-33 (IL-33) mediated proliferation and differentiation of pulmonary myofibroblasts (MFbs) in pulmonary fibrosis (PF). Methods C57BL/6 mice were randomly divided into four groups: a control group, a bleomycin (BLM) group, a BLM combined with IL-33 group and a BLM combined with anti-IL-33 antibody group, 12 mice in each group. The PF model was induced by intratracheal injection of BLM (5000 U/kg). The degrees of fibrosis were examined using HE and Masson staining. ELISA was used to measure the plasma levels of IL-33. Immunohistochemical staining was used to measure the expression of alpha smooth muscle actin (α-SMA) in lung tissue. Primary pulmonary fibroblasts were isolated and cultured from lung tissues of mice. The cells were divided into four groups: a control group, an IL-33 group, an IL-33 combined with dimethyl sulfoxide (DMSO) group and an IL-33 combined with pyrrolidine dithiocarbamate (PDTC) group. The cells were treated with DMSO or PDTC for 1 hour and then with IL-33 for 48 hours. Cell proliferation was measured by 5-ethynyl-2'-deoxyuridine (EdU) assay and cell cycle was measured by flow cytometry. Transwell^TM assay was used to analyze cell migration. Real-time quantitative PCR was used to measure the expression of collagen type I (Col1), Col3 and α-SMA mRNA. The protein levels of IL-33, Col1, Col3, α-SMA, eukaryotic initiation factor 3a (eIF3a), phosphorylated IκBα (p-IκBα) (total lysate), p-NF-κB p65(total lysate) and NF-κB p65 (nucleus) were measured by Western blot analysis. Results In vivo, compared with the control group, the expressions of IL-33, p-IκBα (total lysate), p-NF-κB p65 (total lysate), NF-κB p65(nucleus), eIF3a, α-SMA, Col1 and Col3 in the BLM group significantly increased. Compared with the BLM group, the expressions of p-IκBα (total lysate), p-NF-κB p65 (total lysate), NF-κB p65 (nucleus), eIF3a, α-SMA, Col1 and Col3 in the IL-33 group increased further and the PF was further aggravated. But the effect of anti-IL-33 antibody was just opposite to that of IL-33. In vitro, IL-33 markedly induced the proliferation and migration of pulmonary fibroblasts, and significantly up-regulated the expression of p-IκBα (total lysate), p-NF-κB p65(total lysate), NF-κB p65 (nucleus), eIF3a, α-SMA, Col1 and Col3. But all these effects of IL-33 were reversed by pyrrolidine dithiocarbamate. Conclusion The results suggest that IL-33 may promote the expression of eIF3a by activating NF-κB signaling pathway, thus inducing the proliferation and differentiation of MFbs and promoting the occurrence and development of PF.
Animals ; Mice ; Bleomycin/metabolism* ; Cell Differentiation ; Cell Proliferation ; Dimethyl Sulfoxide/pharmacology* ; Fibroblasts ; Interleukin-33/pharmacology* ; Mice, Inbred C57BL ; Myofibroblasts/metabolism* ; NF-kappa B/metabolism* ; NF-KappaB Inhibitor alpha/metabolism* ; Pulmonary Fibrosis ; Signal Transduction

Objective: To investigte the efficacy of docetaxel combined with androgen deprivation therapy for the treatment of metastatic hormone-sensitive prostate cancer based on Chinese population. Methods: A total of 497 patients were enrolled from January 2004 to July 2018 in the Changhai Hospital. 459 patients received androgen deprivation therapy alone and 38 patients received androgen deprivation therapy combined with docetaxel. The mean age was (72.1±8.7)years. The median PSA level was 100.0 ng/ml, ranging 42.3-999.0 ng/ml. Patients of clinical T₂, T₃, T₄ stage were 213(42.9%), 160(32.2%), 124(24.9%), respectively. Patients of clinical N₀, N₁, N_x stage were 319(64.2%), 144(29.0%), 34(6.8%), respectively. Patients of clinical M₀, M_1a, M_1b, M_1c, M_x stage were 100(20.1%), 51(10.3%), 332(66.8%), 9(1.8%), 5(1.0%), respectively. Gleason scores of biopsy showed that 146(29.4%) patients was ≤7, 103(20.7%) was 8 and 248(49.9%)was ≥9. Propensity score matching was used to match the baseline between groups. Caliper value was set at 0.02. SPSS 22 software was used to achieve a 1∶1 match between the two groups. There were no statistical difference in the age(P=0.102), PSA(P=0.713), T stage(P=0.113), N stage(P=0.226), M stage(P=0.514), Gleason score(P=0.612), tumor loading(P=0.812)between the two groups. The castration resistance-free rate and cancer specific survival rate of the two groups were compared by log-rank and breslow-wilcoxon test. Furthermore, forest plots were used to display the analysis results of different subgroups such as age, PSA, clinical stage, Gleason score, tumor load, whether patients had received palliative resection, and the differences in castration resistance-free rate were compared between the subgroups with high tumor load. Results: The median follow-up time was 22.6 months in the androgen deprivation therapy group and 13.7 months in the combined therapy group. The number of patients with castration resistance in the two groups was 23 and 17, respectively. There were 3 and 6 deaths, respectively. There was no statistically significant difference in the overall progression time to castration resistance between the two groups (10.3 m vs. 16.5 m, P>0.05), and no statistically significant difference in the prostate cancer specific survival rate (21.9 m vs.14.8 m, P>0.05). When subgroup analysis was performed, it was found that patients in the high-metastasis-volume subgroup who received the combination therapy had a significantly longer castration resistance free lifetime (10.6 m vs. 7.2 m, P=0.044), but there was no significant difference in the low- metastasis-volume subgroup(10.5 m vs.12.6 m, P>0.05). Conclusion Docetaxel combined with androgen deprivation therapy can improve the castration resistance free rate in patients with high metastasis volume, but not in low metastasis volume group.

Aim To investigate the effect of 2-deoxy-D-glucose(2-DG)on the sensitivity of leukemia multi-drug resistant K562/ADMcells to adriamycin by inhib-iting glycolytic pathway as well as its molecular mecha-nisms.Methods The leukemia drug-resistant K562/ADM cells and parental K562 cells were used as the target cell models.The cell proliferating activity was assessed with an MTT colorimetric assay,and the gly-colysis including glucose consumption,lactate export, and hexokinase activity was determined by glucose, lactic acid and hexokinase (HK)testing kits.The ex-pression and phosphorylation of mammalian target of rapamycin(mTOR)and glucose transporter-4 (GLUT-4)expression were analyzed by western blot.Results K562/ADM drug-resistant cells possessed higher HK activity,GLUT-4 expression level and aerobic glycolic ability than K562 sensitive cells. 2-DG treatment markedly inhibited HK activity,glucose consumption, and lactate export both in K562 cells and K562/ADM cells,and suppressed the proliferation of the two cells in a time-and concentration-dependent manner.Low concentration of 2-DG or adriamycin could increase the expression and phosphorylation of mTOR.However, the co-administration of 2-DG and adriamycin markedly counteracted adriamycin-mediated enhancement of mTOR expression and phosphorylation and down-regu-lated GLUT-4 expression in K562/ADM cells,and 2-DG dramatically improved the sensitivity of K562/ADM cells to cytotoxicity.Conclusion 2-DG inhibits the proliferation of drug-resistant K562/ADM cells and en-hances the sensitivity to adriamycin by blocking aerobic glycolysis pathway through inhibiting hexokinase activi-ty,counteracting adriamycin-stimulated increased ex-pression and phosphorylation of mTOR and downregu-lating GLUT-4 expression.