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Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy., IL-6 is an important cytokine in the tumour microenvironment, but its role in regulating autophagy in cancer cells is unclear. Here the authors show that IL-6 activates autophagy in colorectal cancer through the interaction between JAK2 and autophagy regulator, BECN1, which leads to chemotherapeutic resistance.

This study proposed the combination of PR26S and PP1 as a good choice for RT-qPCR normalization in pecan under abiotic stress, developing kernels, grafting, and various tissues. Reference gene selection is an essential pre-requisite to generate reliable results in real-time quantitative polymerase chain reaction (RT-qPCR) analysis. However, studies regarding systematic validation of suitable reference genes in pecan are still lacking. In this study, 17 candidate reference genes were selected and evaluated for their expression stabilities in pecan under various experimental conditions, including various tissues, developing kernels, grafting, and two plant tissues (leaves and roots) subjected to three abiotic stresses (salt, drought, and Zn deficiency). The stability of the candidate genes was assessed by geNorm, NormFinder, and BestKeeper, and their outputs were integrated to obtain a final comprehensive rank of stability based on the geometric mean. The results indicated that samples under different experimental conditions possessed their own best reference genes, and using two reference genes for RT-qPCR normalization was recommended for the tested experiments. Overall, the combination of 26S protease regulatory subunit 7A (PR26S) and serine/threonine-protein phosphatase-1 (PP1) was recognized as a good choice for RT-qPCR normalization in pecan across all the treatments. More importantly, the widely used alpha-tubulin (α-TUB), ubiquitin (UBQ), and actin (ACT) genes were not the best suitable reference genes in most of our experiments. Our results will be helpful for future gene-expression studies in pecan.

As a "genomic guardian", p53 mainly functions as a transcription factor that regulates downstream targets responsible for cell fate control, and the activity of p53 is tightly regulated by a complex network that include an abundance of post-translational modifications. Notably, acetylation of p53 at many positions has been demonstrated to play a major role in accurate p53 regulation and cell fate determination. However, no evidence has been provided to compare the effect of acetylation at different sites on p53 regulation. Here, we constructed six acetylation-defective p53 mutants that lysine was substituted by arginine at residues 120, 164, 305, 320, 370/372/373 or 381/382/386, respectively, and determined their effects on p53 activity systematically. Our results showed that all six mutants exhibited diminished transactivation ability and selective regulation of target genes expression through distinct mechanisms. Specifically, lysine 370/372/373 and 381/382/386 mutations decreased p53 stability, and lysine 305 mutation reduced p53 phosphorylation level at serine 15, while lysine 120 and 164 mutations decreased p53 acetylation level at lysine 382. Collectively, these data indicate that acetylation of p53 at different sites has diverse regulatory effects on p53 transcriptional activity through different mechanisms.

Objective: Interpersonal theories of suicide suggest that the Interpersonal Needs Questionnaire (INQ) can be used to measure suicidal ideation, but few studies have focused on migrant people, a group with a high prevalence of suicidal ideation. The aim of this study was to validate the psychometric properties of the INQ-15 and its prediction of suicidal ideation among migrant industrial workers in China. Method: A stratified multi-stage sample of 2023 industrial workers was recruited from 16 factories in Shenzhen, China. There were 1805 nonlocal workers, which we defined as migrant workers with a mean age of 32.50 ± 8.43 years old who were 67.3% male. The structure of the Chinese version of the INQ-15 and its correlation and predictive utility for suicidal ideation were examined through factor analysis, the Item Response Theory, the M2 test, logistic regression, and receiver operating characteristic (ROC) analysis. Results: Different from studies among various samples in which a two-factor solution is identified, results within this sample indicated three factors: perceived burdensomeness, thwarted belongingness, and social isolation. The model fit statistics of three-factor INQ were 0.075 for RMSEA, 0.945 for CFI, 0.932 for TLI, and 0.067 for SRMR. The model standard estimated factor loadings ranged from 0.366 to 0.869. The summed scores of INQ and perceived burdensomeness predicted suicidal ideation after controlling for sociodemographic characteristics such as age, gender, and income with AUC of 0.733 (95% CI: 0.712/0.754) and 0.786 (95% CI: 0.766/0.804). In the meantime, the comparison of the predictive ability between INQ total scores and PB scores was significant with p &lt, 0.05. Conclusion: The INQ has good psychometric properties and can be used to assess how migrant workers living in the Shenzhen perceive meeting interpersonal psychological needs and shows good predictive ability of suicidal ideation. Perceived burdensomeness appears to play a role in suicide and may be a point of intervention, yet the notable deviation from previous findings and the relative weakness of two of the other factors warrant further study.

Background COVID-19 vaccines will become available in China soon. Understanding communities’ responses to the forthcoming COVID-19 vaccines is important. We applied the theory of planned behavior as the theoretical framework. Objective This study investigates the prevalence of and factors associated with behavioral intention to receive self-financed or free COVID-19 vaccinations among Chinese factory workers who resumed work during the pandemic. We examined the effects of factors including sociodemographics, perceptions related to COVID-19 vaccination, exposure to information about COVID-19 vaccination through social media, and COVID-19 preventive measures implemented by individuals and factories. Methods Participants were full-time employees 18 years or older who worked in factories in Shenzhen. Factory workers in Shenzhen are required to receive a physical examination annually. Eligible workers attending six physical examination sites were invited to complete a survey on September 1-7, 2020. Out of 2653 eligible factory workers, 2053 (77.4%) completed the online survey. Multivariate two-level logistic regression models and ordinal logistic regression models were fitted. Results The prevalence of behavioral intention to receive a COVID-19 vaccination was 66.6% (n=1368, conditional on 80% vaccine efficacy and market rate) and 80.6% (n=1655, conditional on 80% vaccine efficacy and free vaccines). After adjusting for significant background characteristics, positive attitudes toward COVID-19 vaccination (adjusted odds ratio [AOR] 1.20, 95% CI 1.15-1.25 and AOR 1.24, 95% CI 1.19-1.30), perceived support from significant others for getting a COVID-19 vaccination (AOR 1.43, 95% CI 1.32-1.55 and AOR 1.37, 95% CI 1.25-1.50), and perceived behavioral control to get a COVID-19 vaccination (AOR 1.51, 95% CI 1.32-1.73 and AOR 1.28, 95% CI 1.09-1.51) were positively associated with both dependent variables (conditional on 80% vaccine efficacy and market rate or free vaccines, respectively). Regarding social media influence, higher frequency of exposure to positive information related to COVID-19 vaccination was associated with a higher intention to receive a COVID-19 vaccination at market rate (AOR 1.53, 95% CI 1.39-1.70) or a free vaccination (AOR 1.52, 95% CI 1.35-1.71). Higher self-reported compliance with wearing a face mask in the workplace (AOR 1.27, 95% CI 1.02-1.58 and AOR 1.67, 95% CI 1.24-2.27) and other public spaces (AOR 1.80, 95% CI 1.42-2.29 and AOR 1.34, 95% CI 1.01-1.77), hand hygiene (AOR 1.21, 95% CI 1.00-1.47 and AOR 1.52, 95% CI 1.19-1.93), and avoiding social gatherings (AOR 1.22, 95% CI 1.01-1.47 and AOR 1.55, 95% CI 1.23-1.95) and crowded places (AOR 1.24, 95% CI 1.02-1.51 and AOR 1.73, 95% CI 1.37-2.18) were also positively associated with both dependent variables. The number of COVID-19 preventive measures implemented by the factory was positively associated with the intention to receive a COVID-19 vaccination under both scenarios (AOR 1.08, 95% CI 1.04-1.12 and AOR 1.06, 95% CI 1.01-1.11). Conclusions Factory workers in China reported a high behavioral intention to receive a COVID-19 vaccination. The theory of planned behavior is a useful framework to guide the development of future campaigns promoting COVID-19 vaccination.

Aims Type 2 diabetes is considered to be one of the essential risks of adverse outcomes in coronavirus disease 2019 (COVID-19).1 Metformin and insulin were suggested to affect the outcomes. However, divergent views are still expressed. We aim to gain further insight into metformin and insulin in both pre-admission and in-hospital usage in COVID-19 patients with pre-existed type 2 diabetes. Main methods This is a multicentral retrospective study of the hospital confirmed COVID-19 patients between January 19 to April 09, 2020, who admitted to 3 main hospitals in Xiangyang city, China. The effect of type 2 diabetes, metformin, and insulin on COVID-19 were analyzed, respectively. Clinical characteristics, blood laboratory indices, clinical observational indices, and outcomes of these cases were collected. Key findings A total of 407 confirmed COVID-19 patients (including 50 pre-existed type 2 diabetes) were eligible in our study. COVID-19 patients with type 2 diabetes had more adverse outcomes than non-diabetes (OR2: mortality: 1.46 [95% CI3 1.11, 1.93]; P, Graphical abstract Unlabelled Image

Background Factory workers in low- and middle-income countries (LMICs) are vulnerable to HIV transmission. Interventions are needed to prevent HIV in this population. We systematically reviewed published literature on the efficacy of various HIV interventions in reducing stigma, risk behaviors and HIV transmission among factory workers. Methods A systematic review was performed using predefined inclusion and exclusion criteria. Four databases (PubMed, PsycINFO, Scopus and EMBASE) were searched for relevant publications between January 1, 1990 and December 31, 2018. Two independent reviewers assessed the methodological quality of studies. Results Thirteen articles were included, with 2 randomized controlled trials and 11 cohort studies. Five interventions and their combinations were summarized. Educational intervention increased condom use and reduced the use of recreational drugs and alcohol before sex. Community intervention that proactively provide HIV counselling and testing (HCT) services could increase the detection rate of HIV and other sexually transmitted diseases (STDs). Lottery intervention increased HCT uptake and decreased HIV public stigma. Education combined with community intervention reduced the proportion of workers with casual sex and enhanced HIV knowledge. Peer education combined with community intervention increased the proportion of workers who were willing to take their partners to HCT. Policy intervention combined with peer education enhanced HIV knowledge, perceived condom accessibility and condom use with regular partners. Conclusions Various interventions improved HIV knowledge, decreased HIV stigma and reduced HIV-related risk behaviors among factory workers in LMICs. The combination of multiple interventions tended to achieve better efficacy than a single intervention. Persistent combination interventions are essential to address HIV in this population.

The aim of this study was to investigate the correlation between the low-density lipoprotein cholesterol (LDL-C) in serum and the onset of transient ischemic attack caused by cerebral small vascular disease (CSVD). Between September 2012 and September 2015, 249 patients who were diagnosed as CSVD were randomly enrolled in this study. According to MRI results, patients were divided into the patient and control groups. In the patient group, the patients were further subdivided into the white matter lesion (WML) group (n=86) and lacunar infarction (LI) group (n=53). Head MRI and/or CT were conducted on all the patients. This included T1 and T2 phases, diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR). Additionally, mini-mental status examination (MMSE) test and Montreal cognitive assessment (MoCA) test were carried out on all the patients. As a result, the age, total cholesterol (TC) level and low-density lipoprotein (LDL) levels in the patient group were higher than those in the control group (p

Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD.

// Ting Liu 1, * , Rong Li 2, 1, * , Hui Zhao 1 , Juan Deng 1 , Ying Long 1 , Meng-ting Shuai 1 , Qian Li 1 , Huan Gu 1 , Ya-qi Chen 1 , Ai-min Leng 1 1 Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, China 2 Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China * These authors contributed equally to this work Correspondence to: Ai-min Leng, email: aimin.leng@aliyun.com Keywords: esophageal squamous cell carcinoma, eIF4E, cisplatin, chemosensitivity, PI3K/AKT pathway Received: January 09, 2016 Accepted: August 22, 2016 Published: August 30, 2016 ABSTRACT Patients with esophageal squamous cell cancer are often diagnosed with advanced diseases that respond poorly to chemotherapy. Overexpression of eIF4E leads to enhance the translation of key malignancy-related proteins and enabling tumor growth and chemoresistance in a variety of human malignancies, but whether it has a role in ESCC remains obscure. We hypothesized that eIF4E promoted ESCC tumorigenesis and facilitated the development of acquired resistance to the cisplatin-based chemotherapy. In this study, we showed that eIF4E expression was increased significantly in clinical ESCC tissues and and ESCC cell lines and its expression level was correlated with lymph node metastasis, TNM stage, as well as overall and disease-free survival of ESCC. We also showed here that knockdown of eIF4E in EC9706 would dramatically reduced cell proliferation, colony formation, migration and invasion, apoptosis in vitro as well as in vivo , and vice versa. Moreover, “weak mRNAs” were demonstrated to be regulated by eIF4E in ESCC, which might interpret the above function. Overexpression of eIF4E decreased the efficacy of cisplatin-induced cell growth inhibition in ESCC cell line and xenograft model ( P < 0.05). eIF4E knockdown by shRNA increased cisplatin-induced cytotoxicity in ESCC cell lines, and enhanced chemosensitivity to cisplatin in xenograft tumor models. Furthermore, we found that the PI3K/AKT pathway and Bcl-2/Bax ratio might be responsible for the eIF4E-induced cisplatin resistance in ESCC. Our data collectively show association of eIF4E expression with chemotherapeutic response in ESCC, and suggest that therapeutically targeting eIF4E may be a viable means of improving chemotherapy response in ESCC.

We propose a new algorithm, called line integral alternating minimization (LIAM), for dual-energy X-ray CT image reconstruction. Instead of obtaining component images by minimizing the discrepancy between the data and the mean estimates, LIAM allows for a tunable discrepancy between the basis material projections and the basis sinograms. A parameter is introduced that controls the size of this discrepancy, and with this parameter the new algorithm can continuously go from a two-step approach to the joint estimation approach. LIAM alternates between iteratively updating the line integrals of the component images and reconstruction of the component images using an image iterative deblurring algorithm. An edge-preserving penalty function can be incorporated in the iterative deblurring step to decrease the roughness in component images. Images from both simulated and experimentally acquired sinograms from a clinical scanner were reconstructed by LIAM while varying the regularization parameters to identify good choices. The results from the dual-energy alternating minimization algorithm applied to the same data were used for comparison. Using a small fraction of the computation time of dual-energy alternating minimization, LIAM achieves better accuracy of the component images in the presence of Poisson noise for simulated data reconstruction and achieves the same level of accuracy for real data reconstruction.

Mounting evidence has demonstrated that angiogenesis plays an important role in tumour progression. However, the key regulators in tumour angiogenesis remain unclear. Recently, emerging reports have indicated that SIRT2 plays critical roles in proliferation, metastasis and tumourigenesis in diverse tumours. However, the function of SIRT2 in tumour angiogenesis and the mechanism underlying the regulation of angiogenesis by SIRT2 are still unknown. Here, we found that SIRT2 was upregulated in colorectal cancer tissues compared to that in normal samples and that the elevated SIRT2 was associated with poor prognosis in patients with colorectal cancer. In addition, a series of in vitro and in vivo experiments were performed to demonstrate the role of SIRT2 in tumour angiogenesis. We showed that silencing SIRT2 significantly suppressed tumour angiogenesis. Mechanistically, the knockdown of SIRT2 inhibited STAT3 phosphorylation, causing decreased secretion of VEGFA. Notably, we found that SIRT2 directly interacted with STAT3 and affected the phosphorylation of STAT3 and the translocation of phosphorylated STAT3 to the nucleus. Importantly, a series of rescue experiments suggested that the function of SIRT2 in tumour angiogenesis depends on the STAT3/VEGFA signalling pathway. Our findings provide insight into the important role of SIRT2 in colon tumour angiogenesis and suggest that SIRT2/STAT3/VEGFA might be a novel prognostic biomarker and a potential therapeutic target for patients with colorectal cancer.

Summary RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

Since its establishment in 2009, single-cell RNA sequencing (RNA-seq) has been a major driver behind progress in biomedical research. In developmental biology and stem cell studies, the ability to profile single cells confers particular benefits. Although most studies still focus on individual tissues or organs, the recent development of ultra-high-throughput single-cell RNA-seq has demonstrated potential power in characterizing more complex systems or even the entire body. However, although multiple ultra-high-throughput single-cell RNA-seq systems have attracted attention, no systematic comparison of these systems has been performed. Here, with the same cell line and bioinformatics pipeline, we developed directly comparable datasets for each of three widely used droplet-based ultra-high-throughput single-cell RNA-seq systems, inDrop, Drop-seq, and 10X Genomics Chromium. Although each system is capable of profiling single-cell transcriptomes, their detailed comparison revealed the distinguishing features and suitable applications for each system.

Sirtuin type 1 (SIRT1) belongs to the family of NAD+dependent histone deacetylases and plays a critical role in cellular metabolism and response to oxidative stress. Traditional Chinese medicines (TCMs), as an important part of natural products, have been reported to exert protective effect against oxidative stress in mitochondria. In this study, we screened SIRT1 activators from TCMs and investigated their activities against mitochondrial damage. 19 activators were found in total byin vitroSIRT1 activity assay. Among those active compounds, four compounds, ginsenoside Rb2, ginsenoside F1, ginsenoside Rc, and schisandrin A, were further studied to validate the SIRT1-activation effects by liquid chromatography-mass spectrometry and confirm their activities against oxidative damage in H9c2 cardiomyocytes exposed to tert-butyl hydroperoxide (t-BHP). The results showed that those compounds enhanced the deacetylated activity of SIRT1, increased ATP content, and inhibited intracellular ROS formation as well as regulating the activity of Mn-SOD. These SIRT1 activators also showed moderate protective effects on mitochondrial function in t-BHP cells by recovering oxygen consumption and increasing mitochondrial DNA content. Our results suggested that those compounds from TCMs attenuated oxidative stress-induced mitochondrial damage in cardiomyocytes through activation of SIRT1.

To develop a potent and safe gene therapy for esophageal cancer.An expression vector carrying fusion suicide gene (yCDglyTK) and shRNA against vascular endothelial growth factor (VEGF) was constructed and delivered into EC9706 esophageal cancer cells by calcium phosphate nanoparticles (CPNP). To achieve tumor selectivity, expression of the fusion suicide gene was driven by a tumor-specific human telomerase reverse transcriptase (hTERT) promoter. The biologic properties and therapeutic efficiency of the vector, in the presence of prodrug 5-fluorocytosine (5-FC), were evaluated in vitro and in vivo.Both in vitro and in vivo testing showed that the expression vector was efficiently introduced by CPNP into tumor cells, leading to cellular expression of yCDglyTK and decreased VEGF level. With exposure to 5-FC, it exhibited strong anti-tumor effects against esophageal cancer. Combination of VEGF shRNA with the fusion suicide gene demonstrated strong anti-tumor activity.The shVEGF-hTERT-yCDglyTK/5-FC system provided a novel approach for esophageal cancer-targeted gene therapy.