Yeast-based evolutionary modeling of androgen receptor mutations and natural selection.

Cancer progression is associated with the evolutionary accumulation of genetic mutations that are biologically significant. Mutations of the androgen receptor (AR) are associated with the development of prostate cancer (PCa) by responding to non-androgenic hormones, and the lack of annotations in their responsiveness to hormone ligands remains a daunting challenge. Here, we have used a yeast reporter system to quickly evaluate the responsiveness of all fifty clinical AR mutations to a variety of steroidal ligands including dihydrotestosterone (DHT), 17ß-estradiol (E2), progesterone (PROG), and cyproterone acetate (CPA). Based on an AR-driven reporter that synthesizes histidine, a basic amino acid required for yeast survival and propagation, the yeast reporter system enabling clonal selection was further empowered by combining with a random DNA mutagenesis library to simulate the natural evolution of AR gene under the selective pressures of steroidal ligands. In a time-frame of 1-2 weeks, 19 AR mutants were identified, in which 11 AR mutants were validated for activation by tested steroidal compounds. The high efficiency of our artificial evolution strategy was further evidenced by a sequential selection that enabled the discovery of multipoint AR mutations and evolution directions under the pressure of steroidal ligands. In summary, our designer yeast is a portable reporter module that can be readily adapted to streamline high-throughput AR-compound screening, used as a PCa clinical reference, and combined with additional bioassay systems to further extend its potential.

Common risk factors for dental caries and impaired glucose regulation in Guangxi, China.

OBJECTIVES: To assess the prevalence of caries and impaired glucose regulation (IGR) and try to investigate their common risk factors among adult residents in Guangxi province. METHODS: A cross-sectional study was conducted on a sample of 2993 adults from five different areas of Guangxi province. The sociodemographic data, history of personal habits such as diet and physical activities, physical measurements, oral examination results and biochemical laboratory test data were collected to establish a database and prepare a sound research model. Chi-square test and multiple logistic regression were used to analyse the risk factors for dental caries and IGR. RESULTS: The prevalence rate for caries was 85.9%, and the mean DMFT score was 7.35. In multiple logistic regression, after adjustment, education level, occupation, daily consumption of vegetables, weekly consumption of carbonated beverages and weekly exercise were associated with caries (odds ratio [OR]: 2.10, OR: 1.80, OR: 1.40, OR: 2.45, OR: 2.38). The prevalence of IGR was 33.5%, and after adjustment, results showed that occupation, body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, high-density lipoprotein-C levels and low-density lipoprotein-C levels were significantly associated with IGR (OR: 0.80, OR: 1.70, OR: 1.56, OR: 1.88, OR: 1.60, OR: 1.43, OR: 1.48). The strength of association between caries/IGR and risk factors was a weak association or moderate association. CONCLUSIONS: We have not found common risk factors between dental caries and IGR. Therefore, further studies are needed to explore these common risk factors to prevent caries and IGR.

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer.

BACKGROUND: The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region. METHODS: RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites. RESULTS: In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site. CONCLUSION: Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions.

BACKGROUND: Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance. METHODS: Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms. RESULTS: Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites. CONCLUSION: Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution.

Primary treatment and recent survival trends in patients with primary diffuse large B-cell lymphoma of central nervous system, 1995-2016: A population-based SEER analysis.

This retrospective cohort study aimed to evaluate primary treatment and recent survival trends in patients with primary diffuse large B-cell lymphoma of central nervous system (CNS) from 1995 to 2016. Using the SEER data, patients diagnosed with non-HIV-associated primary central nervous system lymphoma (PCNSL)-diffuse large B-cell lymphoma (DLBCL) aged ⩾18 years between 1995 and 2016 were identified. The year of diagnosis was divided into the time period-1 (1995-2002), the time period-2 (2003-2012), and the time period-3 (2013-2016). Chi-square tests, the Kaplan-Meier method, log-rank test, and Cox regression model were used in the analysis. Overall, 3760 patients were included. Both the use of radiotherapy alone and the application of combined chemoradiotherapy decreased significantly, following the wider use of chemotherapy alone during 1995-2016. There was a significant improvement in PCNSL cause-specific survival (CSS) (period-1: 13 months vs. period-2: 19 months vs. period-3: 41 months, p < 0.001). Survival of patients aged above 70 years did not change from the time period-1 to the time period-2 (p = 0.101). However, there was an increase in CSS from the time period-2 to the time period-3 in the elderly patients (period-2: 5 months vs. period-3: 9 months, p < 0.001). On multivariable analyses, diagnosed in the time period-3 was significantly and independently associated with better CSS (hazard ratio 0.577, 95% confidence interval 0.506-0.659, p < 0.001). Our analysis shows the use of radiotherapy in the treatment of PCNSL has waned over the study span. There was a significant improvement in CSS during 1995-2016, which reflected developments in treatment over time. The elderly patient population also gained a significant CSS benefit in the most recent period.

Rh(III)-Catalyzed C-H Functionalization/Annulation of 1-Arylindazolones: Divergent Synthesis of Fused Indazolones and Allyl Indazolones.

Rh(III)-catalyzed C-H/N-H annulation and C-H allylation of phenylindazolones have been realized by employing 5-methylene-1,3-dioxan-2-one and 4-vinyl-1,3-dioxolan-2-one as scalable cross-coupling partners, delivering functionalized indazolone fused heterocycles and branched and linear allyl indazolones respectively in moderate to high yield. These divergent synthesis protocols showcase mild conditions, broad substrate scope, and high functional-group compatibility. In addition, scale-up synthesis and preliminary mechanistic exploratory were also accomplished.

Synthesis of Indole-Substituted Trifluoromethyl Sulfonium Ylides by Cp*Rh(III)-Catalyzed Diazo-carbenoid Addition to Trifluoromethylthioether.

The indole-substituted trifluoromethyl sulfonium ylide has been developed via Cp*Rh(III)-catalyzed diazo-carbenoid addition to trifluoromethylthioether and is the first example of an Rh(III)-catalyzed diazo-carbenoid addition reaction with trifluoromethylthioether. Several kinds of indole-substituted trifluoromethyl sulfonium ylide were constructed under mild reaction conditions. The reported method exhibited high functional group compatibility and broad substrate scope. In addition, the protocol was found to be complementary to the method disclosed by a Rh(II) catalyst.

Associations of PART1 and DEFB1 polymorphisms with Dental Caries in twelve-year-old children in Southern China: a cross-sectional study.

OBJECTIVE: The aim of this study was to assess associations of PART1 rs27565 and DEFB1 rs11362 polymorphisms with the prevalence of dental caries in twelve-year-old children in Nandan County, Guangxi, China. METHODS: A total of 1,061 children were included in this cross-sectional study and divided into two groups based on the Decayed, Missing and Filled teeth (DMFT) index: caries-free children (DMFT score = 0) and children with caries (DMFT score ≥ 1). Demographic characteristics, oral hygiene behaviour and dietary habits were collected through household records and questionnaires. Genomic DNA was extracted from buccal cells, and PART1 rs27565 and DEFB1 rs11362 polymorphisms were genotyped using a custom-designed 48-Plex single nucleotide polymorphism-scan kit. RESULTS: Carriers of the PART1 rs27565 C allele (odds ratio [OR] = 1.338, 95% confidence interval (CI) = 1.015-1.764, P value = 0.039) and carriers of the DEFB1 rs11362 T allele (OR = 1.364, 95% CI = 1.056-1.762, P value = 0.017) had a higher risk of caries. Carriers of the PART1 rs27565 TC or CC genotype who ate sugary food more than once a week had a 1.6-fold higher risk of caries than TT carriers who ate sugary food at most once a week (OR = 1.579, 95% CI = 1.032-2.414, P value = 0.035). Carriers of the DEFB1 rs11362 CT or TT genotype who ate sugary food more than once a week had a 2.1-fold higher risk of caries than CC carriers who ate sugary food at most once a week (OR = 2.057, 95% CI = 1.438-2.940, P value < 0.001). CONCLUSION: PART1 rs27565 and DEFB1 rs11362 polymorphisms were associated with caries in 12-year-old children in Nandan County, Guangxi, China. Carriers of the PART1 rs27565 TC or CC genotype and the DEFB1 rs11362 CT or TT genotype who ate sugary food more than once a week had a high probability of having caries.

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Objective: In this study, we used artificial intelligence (AI) technology to explore for automated medical record quality control methods, standardize the process for medical record documentation, and deal with the drawbacks of manually implemented quality control. Methods: In this study, we constructed a medical record quality control system based on AI. We first designed and built, for the system, a quality control rule base based on authoritative standards and expert opinions. Then, medical records data were automatically collected through a data acquisition engine and were converted into structured data through a post-structured engine. Finally, the medical record quality control engine was combined with the rule base to analyze the data, identify quality problems, and realize automated intelligent quality control. This system was applied to the quality control of medical records and five quality control points were selected, including similarities in the history of the present illness, defects in the description of chief complaints, incomplete initial diagnosis, missing in formation in the history of menstruation, marriage, and childbirth, and mismatch between the chief complaints and the history of the present illness. We randomly selected 2 918 medical records of patients discharged in January 2022 to conduct AI quality control. Then we organized medical record quality control experts to conduct an accuracy review, made a comparison with previous manual quality control records, and analyzed the results. The number of quality problems that were verified in the accuracy review was taken as the gold standard and receiver operating characteristic (ROC) curves were drawn for the 5 quality control points. Results: According to the accuracy review performed by medical record quality control experts, the accuracy of AI quality control reached 89.57%. For the sampled medical records, the results of AI quality control were compared with those of previous manually performed quality control and only one problem detected by manual quality control of the sampled medical records was not detected by the AI quality control system. The number of medical record quality problems correctly detected by AI quality control was about 2.97 times that of manual quality control. Analysis of the ROC curves showed that the AUC of the five quality control points of the AI quality control system were statistically significant (P<0.05) and all the AUC values approximated or exceeded 0.9. In contrast, results obtained through manually performed quality control found significant AUC (0.797) for only one quality control point-similarities in the history of present illness (P<0.05). Comparison of the AUC values of the two quality control methods showed that AI quality control system had an advantage over manually performed quality control for the five quality control points. Conclusion: Through the application of medical record quality control system based on AI, efficient full quality control of medical record documentation can be achieved and the detection rate of quality problems can be effectively improved. In addition, the system helps save manpower and improve the quality of medical record documentation.

Rhodium(III)-catalyzed regioselective C(sp2)-H activation of indoles at the C4-position with iodonium ylides.

Herein, we report a Rh(III)-catalyzed C4-selective activation of indoles by using iodonium ylides as carbene precursors. This protocol proceeded under redox neutral reaction conditions and provided important coupling products with good tolerance of functional groups and high yields. In addition, one-pot synthesis and scale-up and mechanistic studies were also conducted.

A hybrid adaptive approach for instance transfer learning with dynamic and imbalanced data.

Machine learning has demonstrated success in clinical risk prediction modeling with complex electronic health record data. However, the evolving nature of clinical practices can dynamically change the underlying data distribution over time, leading to model performance drift. Adopting an outdated model is potentially risky and may result in unintentional losses. In this paper, we propose a novel Hybrid Adaptive Boosting approach (HA-Boost) for transfer learning. HA-Boost is characterized by the domain similarity-based and class imbalance-based adaptation mechanisms, which simultaneously address two critical limitations of the classical TrAdaBoost algorithm. We validated HA-Boost in predicting hospital-acquired acute kidney injury using real-world longitudinal electronic health records data. The experiment results demonstrate that HA-Boost stably outperforms the competing baselines in terms of both AUROC and AUPRC across a 7-year time span. This study has confirmed the effectiveness of transfer learning as a superior model updating approach in dynamic environment.

Mild Synthesis of 3,4-Dihydroisoquinolin-1(2H)-ones via Rh(III)-Catalyzed Tandem C-H-Allylation/N-Alkylation Annulation with 2-Methylidenetrimethylene Carbonate.

A tandem rhodium(III)-catalyzed system was established to access 3,4-dihydroisoquinolin-1(2H)-one by coupling of N-methoxy-3-methylbenzamide with 2-methylidenetrimethylene carbonate. This one-pot synthesis protocol processed smoothly under mild reaction conditions. Moreover, a total of 28 examples, broad substrate scope, and high functional-group compatibility were observed. Preliminary mechanism studies were also conducted and demonstrated that the rhodium(III) catalyst played a vital role in the C-H-allylation and N-alkylation cyclization process.

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells.

Silkworm cocoon was recorded to cure carbuncle in the Compendium of Materia Medica. Previous studies have demonstrated that the supplemental silk protein sericin exhibits anticancer activity. In the present study, we investigated the effects of silk fibroin peptide (SFP) extracted from silkworm cocoons against human lung cancer cells in vitro and in vivo and its possible anticancer mechanisms. SFP that we prepared had high content of glycine (~ 30%) and showed a molecular weight of ~ 10 kDa. Intragastric administration of SFP (30 g/kg/d) for 14 days did not affect the weights, vital signs, routine blood indices, and blood biochemical parameters in mice. MTT assay showed that SFP dose-dependently inhibited the growth of human lung cancer A549 and H460 cells in vitro with IC50 values of 9.921 and 9.083 mg/mL, respectively. SFP also dose-dependently suppressed the clonogenic activity of the two cell lines. In lung cancer H460 xenograft mice, intraperitoneal injection of SFP (200 or 500 mg/kg/d) for 40 days significantly suppressed the tumor growth, but did not induce significant changes in the body weight. We further examined the effects of SFP on cell cycle and apoptosis in H460 cells using flow cytometry, which revealed that SFP-induced cell cycle arrest at the S phase, and then promoted cell apoptosis. We demonstrated that SFP (20-50 mg/mL) dose-dependently downregulates Bcl-2 protein expression and upregulates Bax protein in H460 cells during cell apoptosis. The results suggest that SFP should be studied further as a novel therapeutic agent for the treatment of lung cancer.

Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer.

P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.

Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation.

The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein-related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R(2) = 0.6213, P < 5 × 10(-11)) and KLK2 (R(2) = 0.5893, P < 5 × 10(-10)) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen-induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression.

Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPß-regulated atrogin1 expression in cancer cachexia.

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPß), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPß-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPß, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPß binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia.

Androgen ablation elicits PP1-dependence for AR stabilization and transactivation in prostate cancer.

BACKGROUND: Previous reports have documented protein phosphatase 1 (PP1) as an essential androgen receptor (AR) activator. However, more systemic studies are needed to further define PP1 effects on AR, particularly in the settings of prostate cancer cells and under conditions mimicking androgen ablation. METHODS: PP1 effects on AR protein expression, degradation, ubiquitination, and stabilization were examined in non-prostate cancer cells, followed by validation on exogenous settings in androgen-sensitive (LNCaP and VCaP) and castration-resistant (C4-2) prostate cancer cells. Effects of PP1 on AR protein expression, on AR-mediated transcription of exogenous reporter and endogenous gene, and on LNCaP and C4-2 cell proliferation were monitored under androgen-containing versus androgen-depleted conditions to assess the effects of PP1 on AR responsiveness to androgen. RESULTS: In this report, we determined that PP1 functions to stabilize AR proteins that exclusively undergo the proteasome-dependent degradation, and the stimulatory effects of PP1 were predominantly mediated by the AR ligand-binding domain (LBD). Consistently, PP1 enhances AR protein stability by disrupting the LBD-mediated and K48-linked ubiquitination cascade. We further validated the above findings in the prostate cancer cells by showing that PP1 inhibition can increase ubiquitin- and proteasome-dependent degradation of endogenous AR under androgen deprivation. Significantly, we found that PP1 could markedly activate AR transcriptional activities under conditions mimicking androgen ablation and that androgen sensitivity was substantially evoked by PP1 inhibition in the prostate cancer cell lines. CONCLUSIONS: As summarized in a simplified model, our studies defined an essential PP1-mediated pathway for AR protein stabilization that can compensate the loss of androgen and established a mechanistic link between PP1 and androgen responsiveness. The amplified PP1-dependence for AR activation under the androgen ablated conditions provides a rationale to therapeutically target the PP1-AR module in the castration-resistant prostate cancer (CRPC). Our findings also suggested an alternative AR-targeting compounds screening strategy that aims to circumvent PP1-AR interaction.

Socioeconomic Status and Tooth Loss Impact on Oral Health-Related Quality of Life in Chinese Elderly.

OBJECTIVE: We studied the association between the socioeconomic status (SES), tooth loss, and oral health-related quality of life (OHRQoL) in an adult cohort in western China. As socioeconomic inequalities in oral health are often neglected in oral health promotion. we aimed to verify the impact of SES on tooth loss and OHRQoL. METHODS: In all, 348 participants aged 60 years and older were selected for this study. Relationships amongst SES, tooth loss, and OHRQoL were identified by using a structural equation model (SEM). RESULTS: In the final sample, 312 people were included, and the response rate was 89.7%. The bias-corrected 95% confidence intervals of the total, direct, and indirect effects were (-0.267 to 0.475), (-0.489 to 0.185), and (0.088 to 0.450), respectively. The comparative fit index of SEM was 0.943. The model showed that their SES directly affected tooth loss in the elderly population. This indirectly affects their oral health-related quality of life. The numbers of natural teeth and occlusal units (with standardised path coefficients of 0.79 and 0.74, respectively) were found to be the most significant factors relating to tooth loss. CONCLUSION: SES affected the oral health-related quality of life in elderly people through tooth loss in a Chinese study population. Our data suggest that improvements in the social and economic environments are a primary measure that should be implmented to prevent tooth loss and improve the OHRQoL.

Prevalence and contributing factors of malocclusion in Zhuang children aged 7-8 years in southern China.

Introduction: Malocclusion, a common oral health problem in children, is associated with several contributing factors. This study aimed to investigate the prevalence of mixed dentition stage malocclusion and its contributing factors in Chinese Zhuang children aged 7-8 years. Methods: Overall, 2,281 Zhuang children, about 7-8 years old, were randomly selected using a stratified whole-cluster sampling method from schools in counties in Northwestern Guangxi, China. The children were examined on-site for malocclusion and caries by trained dentists, and basic data on the children were collected using questionnaires, including age, sex, parental education, parental accompaniment, and children's knowledge of malocclusion and treatment needs. Data were analyzed using the chi-square test and logistic regression analysis. Results: The total prevalence of malocclusion in Zhuang children aged 7-8 years was 58.5%, with the highest prevalence of anterior crossbite tendency, and the prevalence of anterior crossbite and anterior edge-to-edge occlusion was 15.1% and 7.7%, respectively. This was followed by an anterior increased overjet of 13.3% and an inter-incisor spacing of 10.3%. The lowest prevalence was 2.7% for anterior open bite. Sex, parental accompaniment, parental education, and decayed, missing, and filled teeth of the first primary molar were factors that contributed to malocclusion in Zhuang children. Conclusion: Malocclusion is a common oral problem among Zhuang children. Therefore, more attention must be paid to the intervention and prevention of malocclusion. The impact factors should be controlled as early as possible.

A carboxy-terminal ubiquitylation site regulates androgen receptor activity.

Degradation of unliganded androgen receptor (AR) in prostate cancer cells can be prevented by proteasome inhibition, but this is associated with only modest increases in polyubiquitylated AR. An inhibitor (VLX1570) of the deubiquitylases associated with the proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiquitylases. We then identified a series of AR ubiquitylation sites, including a not previously identified site at K911, as well as methylation sites and previously identified phosphorylation sites. Mutagenesis of K911 increases AR stability, chromatin binding, and transcriptional activity. We further found that K313, a previously reported ubiquitylation site, could also be methylated and acetylated. Mutagenesis of K313, in combination with K318, increases AR transcriptional activity, indicating that distinct posttranslational modifications at K313 differentially regulate AR activity. Together these studies expand the spectrum of AR posttranslational modifications, and indicate that the K911 site may regulate AR turnover on chromatin.