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Ferroptosis, a defensive strategy commonly employed by the host cells to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of cancer. However, the role of ferroptosis in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers remains elusive. While a growing number of non-histone proteins have been identified as acetylation targets, the functions of these modifications have yet to be revealed. Here, we show KSHV reprogramming of host acetylation proteomics following cellular transformation of rat primary mesenchymal precursor. Among them, SERPINE1 mRNA binding protein 1 (SERBP1) deacetylation is increased and required for KSHV-induced cellular transformation. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. Consequently, a SIRT3-specific inhibitor, 3-TYP, suppresses KSHV-induced cellular transformation by inducing ferroptosis. Our findings unveil novel roles of vIL-6 and SERBP1 deacetylation in regulating ferroptosis and KSHV-induced cellular transformation, and establish the vIL-6-SIRT3-SERBP1-ferroptosis pathways as a potential new therapeutic target for KSHV-associated cancers. Author summary: Ferroptosis has been implicated in viral infections and the development of cancers, however, its role in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers is still unknown. Although abnormal protein lysine acetylation modification has been strongly implicated in tumorigenesis, the exact role of this modification in KSHV-induced cell transformation remains elusive. Our study uncovers the reduction of acetylation of SERPINE1 mRNA binding protein 1 (SERBP1), which is required for KSHV-induced cellular transformation. KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. A SIRT3-specific inhibitor, 3-TYP, induces ferroptosis and inhibits survival of KSHV-transformed cells. These findings define a novel mechanism contributing to KSHV-induced cellular transformation and provide a rationale for therapeutically targeting lysine acetylation and the associated enzyme for infectious diseases. [ABSTRACT FROM AUTHOR]

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), 17β-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. Author summary: Androgens are a group of steroid-type sex hormones that regulate secondary sexual characteristics through interacting with the androgen receptor. Androgen-activated androgen receptor has been linked to prostate cancer progression, thus steroid drugs structurally similar to but different from androgens are clinically used to block androgen activation and to treat prostate cancers. However, mutations of the androgen receptor occur in clinics. As a result of some of these mutants, the steroidal hormone drugs become inactive and even by themselves can activate the androgen receptor exacerbating the disease conditions. Due to lack of an efficient screening method, how other clinical mutants respond to various steroidal hormone drugs remain unknown. Here, we developed a yeast-based system that allows high throughput study of the interaction between each hormone drug and androgen receptor mutant by eye-ball observation of yeast colony formation. Using this method, we thoroughly investigated all 50 clinically relevant mutants of the androgen receptor and how they individually respond to each of a variety of hormone drugs. Furthermore, the capacity of this system allowed us to perform random mutagenesis and quickly accumulate high volume of data regarding a large number of mutants, informative in guiding future precision medicine to treat prostate cancer. [ABSTRACT FROM AUTHOR]

Ex-ante online risk assessment for building emergency evacuation is essential to protect human life and property. Current risk assessment methods are limited by the tradeoff between accuracy and efficiency. In this paper, we propose an online method that overcomes this tradeoff based on multimedia data (e.g. videos data from surveillance cameras) and deep learning. The method consists of two parts. The first estimates the evacuee position as input for training the assessment model to then perform risk assessment in real scenarios. The second considers a social force model based on the evacuation simulation for the output of training model. We verify the proposed method in simulation and real scenarios. Model sensitivity analyses and large-scale tests demonstrate the usability and superiority of the proposed method. By the method, the computation time of risk assessment could be decreased from 10 minutes (by traditional simulation method) to 2.18 s. [ABSTRACT FROM AUTHOR]

Objectives: China has high burden on both of tuberculosis (TB) and tobacco use. This study aims to explore the potential link between smoking and TB infection using baseline survey data of a large-scale population-based prospective study in rural China Methods: Between July 1 and Sept 30, 2013, based on the baseline survey of a population-based, prospective study in rural China, the relationship between smoking and TB infection, assessed by interferon-gamma release assays (IGRA), was investigated among the total study population and only among those smokers, respectively. Results: A total of 21,008 eligible rural registered residents (≥ 5 years old) from 4 rural sites were included in the analysis. Ever-smokers were more likely to be QuantiFERON-TB Gold In-Tube (QFT) positive than never smokers with an adjusted odds ratio (OR) of 1.34 (95% confidence interval (CI): 1.21–1.49). Among ever smokers, a significant linear dose–response relation was observed between duration of smoking (by years) and QFT positivity (p < 0.001). Stratified analysis suggested that such an association was not influenced by gender and age. Evidence for interaction of smoking status with age was found. Conclusions: Our results provide further evidence to support smoking might increase host susceptibility to TB infection. Populations under high risk of infection, such as elderly smokers, should be prior to TB infection controlling under a premise of community level intervention. [ABSTRACT FROM AUTHOR]

Background: Anal human papillomavirus (HPV) infection and its related diseases are relatively common in men who have sex with men (MSM), especially in those HIV positive. In China, molecular epidemiology of anal HPV infection among HIV-positive MSM has been sparsely studied. Methods: A cross-sectional study was conducted among HIV-positive MSM in Xi’an, China between April and July 2014. Anal swabs were collected for HPV genotyping. Results: A total of 195 HIV-positive MSM were included in this study. HPV genotyping showed that 99.0% (191/193) of participants were positive for at least one of the targeted 37 HPV genotypes. 183 (94.8%) of them were infected with multiple high-risk types and 154 (79.8%) of them with low-risk HPV types. HPV 18 was the most frequently identified high-risk type, followed by HPV 16 and HPV 51. As for low-risk types, HPV11, HPV 6 and HPV 81 were most commonly observe. High-risk HPV infection was found to be associated with the status of antiretroviral therapy (ART), the distribution of low-risk types was observed to be varied by CD4+ T cell level. Conclusion: Almost all HIV-positive MSM were anal HPV infected in our study. It is highly recommended to consider regular active screening and preventive intervention of HPV infection among this high risk population. [ABSTRACT FROM AUTHOR]