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Although a significant proportion of type 2 diabetes mellitus (T2DM) cases arose from normal-weight individuals, studies on indicators of T2DM in normal-weight people are limited. Accordingly, this study aims to investigate the predictive value of obesity indices and triglyceride glucose-related parameters (TyG-related parameters) in T2DM among normal-weight Chinese elderly. A total of 24,215 normal-weight Chinese elderly (age ≥ 60 years) [body mass index–BMI (18.5–23.9 kg/m2)] were included. Obesity indices and triglyceride glucose-related parameters (TyG-related parameters) included waist circumference (WC), waist-to-height ratio (WHtR), visceral adiposity index (VAI), lipid accumulation product (LAP), and TyG-related parameters (TyG, TyG-BMI, TyG-WC, and TyG-WHtR). Multivariate logistic regression analysis was performed to examine the associations between obesity- and TyG-related indices and T2DM. The areas under the curve (AUC) of the receiver-operating characteristic (ROC) curve analyses were used to evaluate and compare the predictive value of the different indices. The prevalence of T2DM was 14.2% in normal-weight individuals. Among the indices, TyG was significantly associated with T2DM among men and women, respectively, (adjusted odds ratio–aOR per SD 3.46; 95% CI 3.23–3.71) and (aOR per SD 3.64; 95% CI 3.43–3.86). Compared with other indices, TyG had the highest AUC value for T2DM in men (AUC: 0.818, 95% CI 0.810–0.825) and women (AUC: 0.824, 95% CI 0.814–0.833). TyG is an effective marker and outperforms other indices when predicting T2DM in the normal-weight Chinese elderly population. Level V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Mucin 16 (MUC16), a cell surface-associated mucin, has been implicated to be upregulated in a large repertoire of malignances. However, its function in the pathogenesis of colorectal cancer (CRC) is unknown. Here, we explored the regulatory role of MUC16 in CRC. First, tumor and paracancerous tissues, and serum samples from 162 CRC patients, peripheral blood samples from 48 healthy volunteers and 72 benign colorectal patients were collected. The correlation between the MUC16 expression and the clinical phenotypes of the patients was analyzed. Subsequently, HCT116 and SW480 cells with deletion of MUC16 were established to detect changes in the growth and metastatic capacities of CRC cells. The genes with the highest correlation with MUC16 were predicted by bioinformatics, and their binding relationships were detected by Co-IP and double-labeled immunofluorescence, followed by functional rescue experiments. Overexpression of MUC16 in CRC patients was positively correlated with serum biomarkers and poor prognosis of patients. It was demonstrated by in vitro and in vivo experiments that knocking-down the expression of MUC16 could significantly inhibit the growth and metastasis of CRC cells. MUC16 activated janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) by interacting with JAK2. Further overexpression of JAK2 in cells with poor expression of MUC16 revealed a significant increase in the proliferative and metastatic capacities of CRC cells. MUC16 contributes to the development and progression of CRC by binding to JAK2, thereby promoting phosphorylation of JAK2 and further activating STAT3 phosphorylation.

Aims Alcohol consumption (AC) may cause workplace absence, but the findings of individual studies vary markedly. To date, no dose–response meta-analysis (DRMA) of the relationship between AC and sickness absence (SA) has been completed. This paper aims to estimate the dose–response relationship between AC and the risk of SA based on published observational studies. Methods We used DRMA and modelling to investigate the effects of varying doses of AC (including heavy episodic drinking (HED)) onSA. Results The meta-analysis included 21 studies (12 cohort studies and 9 cross-sectional). It showed that HED, risky (20–40 g of alcohol/day) and high-risk (>40 g of alcohol/day) drinkers had an elevated risk of SA when compared with light-to-moderate drinkers for both sexes. Those who abstained from alcohol had a higher risk of SA than those who drink moderately. Conclusions Our results indicate that risky, high-risk drinking and HED may increase the risk of absenteeism. The implementation of population-based strategies may be appropriate to address the burdens of alcohol-related SA. Additionally, economic evaluations of alcohol policies should incorporate their impacts on SA. However, the current literature has substantial limitations, relying on modestly designed studies from just a few settings and more studies are needed—especially those that measure abstention in more nuancedways.

Prolactin binding to the prolactin receptor exerts pleiotropic biological effects in vertebrates. The prolactin receptor (PRLR) has multiple isoforms due to alternative splicing. The biological roles and related signaling of the long isoform (PRLR-LF) have been fully elucidated. However, little is known about the short isoform (PRLR-SF), particularly in cancer development and metabolic reprogramming, a core hallmark of cancer. Here, we reveal the role and underlying mechanism of PRLR-SF in pancreatic ductal adenocarcinoma (PDAC). Methods: A human PDAC tissue array was used to investigate the clinical relevance of PRLR in PDAC. The in vivo implications of PRLR-SF in PDAC were examined in a subcutaneous xenograft model and an orthotopic xenograft model. Immunohistochemistry was performed on tumor tissue obtained from genetically engineered KPC (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) mice with spontaneous tumors. 13C-labeled metabolite measures, LC-MS, EdU incorporation assays and seahorse analyses were used to identify the effects of PRLR-SF on the pentose phosphate pathway and glycolysis. We identified the molecular mechanisms by immunofluorescence, coimmunoprecipitation, proximity ligation assays, chromatin immunoprecipitation and promoter luciferase activity. Public databases (TCGA, GEO and GTEx) were used to analyze the expression and survival correlations of the related genes. Results: We demonstrated that PRLR-SF is predominantly expressed in spontaneously forming pancreatic tumors of genetically engineered KPC mice and human PDAC cell lines. PRLR-SF inhibits the proliferation of PDAC cells (AsPC-1 and BxPC-3) in vitro and tumor growth in vivo. We showed that PRLR-SF reduces the expression of genes in the pentose phosphate pathway (PPP) and nucleotide biosynthesis by activating Hippo signaling. TEAD1, a downstream transcription factor of Hippo signaling, directly regulates the expression of G6PD and TKT, which are PPP rate-limiting enzymes. Moreover, NEK9 directly interacts with PRLR-SF and is the intermediator between PRLR and the Hippo pathway. The PRLR expression level is negatively correlated with overall survival and TNM stage in PDAC patients. Additionally, pregnancy and lactation increase the ratio of PRLR-SF:PRLR-LF in the pancreas of wild-type mice and subcutaneous PDAC xenograft tumors. Conclusion: Our characterization of the relationship between PRLR-SF signaling, the NEK9-Hippo pathway, PPP and nucleotide synthesis explains a mechanism for the correlation between PRLR-SF and metabolic reprogramming in PDAC progression. Strategies to alter this pathway might be developed for the treatment or prevention of pancreatic cancer.

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils., Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease characterized by an immunosuppressive microenvironment. Here the authors show that a subset of P2RX1-negative neutrophils with immunosuppressive properties accumulate in PDAC metastatic liver tissues and promote tumor growth.

BACKGROUND: Most previous studies of the family doctor contract services (FDCS) evaluated its quality by using residents’ signing rates, awareness, and satisfaction. We hypothesize that renewal willingness could be another important indicator to examine the quality of FDCS. OBJECTIVE: To measure residents’ willingness to maintain contracts with family doctors and examine the influencing factors. DESIGN: Cross-sectional study. PARTICIPANTS: 11,250 residents in 31 provincial administrative regions across China. MAIN METHODS: A multistage stratified random sampling method was used to recruit participants. Univariate analysis, mixed-effect regression model analysis, and stepwise multivariate logistic regression analysis were performed to determine the influencing factors of residents’ willingness to maintain contracts with family doctors. KEY RESULTS: About 71.3% participants who contracted with and received healthcare services from family doctors were willing to maintain contracts with family doctors in China. Residents registering as local households (OR = 1.192, 95% CI = 1.039–1.368), enrolled in medical insurance (OR = 1.299, 95% CI = 1.011–1.668), reporting better health (OR = 1.246, 95% CI = 1.100–1.413), with shorter walking time to the nearest healthcare center (compared with > 30 min walking time

The phosphoarginine-arginine kinase shuttle system plays a critical role in maintaining insect cellular energy homeostasis. Insect molting and metamorphosis are coordinated by fluctuations of the ecdysteroid and juvenile hormone. However, the hormonal regulation of insect arginine kinases remain largely elusive. In this report, we comparatively characterized two arginine kinase genes, TcAK1 and TcAK2, in Tribolium castaneum. Functional analysis using RNAi showed that TcAK1 and TcAK2 play similar roles in adult fertility and stress response. TcAK1 was detected in cytoplasm including mitochondria, whereas TcAK2 was detected in cytoplasm excluding mitochondria. Interestingly, TcAK1 expression was negatively regulated by 20-hydroxyecdysone and positively by juvenile hormone, whereas TcAK2 was regulated by the opposite pattern. RNAi, dual-luciferase reporter assays and electrophoretic mobility shift assay further revealed that the opposite hormonal regulation of TcAK1 and TcAK2 was mediated by transcription factor Broad-Complex. Finally, relatively stable AK activities were observed during larval-pupal metamorphosis, which was generally consistent with the constant ATP levels. These results provide new insights into the mechanisms underlying the ATP homeostasis in insects by revealing opposite hormonal regulation of two phylogenetically distant arginine kinase genes., Zhang et al. characterize the functions of two distinct arginine kinase genes in flour beetles. Using RNA interference and electophoretic mobility shift assays, they identify Broad-Complex transcription factor as the mediator of opposing hormonal regulation in these genes.

Background The AMP-activated protein kinase (AMPK) is an intracellular fuel sensor for lipid and glucose metabolism. In addition to the short-term regulation of metabolic enzymes by phosphorylation, AMPK may also exert long-term effects on the transcription of downstream genes through the regulation of transcription factors and coactivators. In this study, RNA interference (RNAi) was conducted to investigate the effects of knockdown of TcAMPKα on lipid and carbohydrate metabolism in the red flour beetle, Tribolium castaneum, and the transcriptome profiles of dsTcAMPKα-injected and dsEGFP-injected beetles under normal conditions were compared by RNA-sequencing. Results RNAi-mediated suppression of TcAMPKα increased whole-body triglyceride (TG) level and the ratio between glucose and trehalose, as was confirmed by in vivo treatment with the AMPK-activating compound, 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR). A total of 1184 differentially expressed genes (DEGs) were identified between dsTcAMPKα-injected and dsEGFP-injected beetles. These include genes involved in lipid and carbohydrate metabolism as well as insulin/insulin-like growth factor signaling (IIS). Real-time quantitative polymerase chain reaction analysis confirmed the differential expression of selected genes. Interestingly, metabolism-related transcription factors such as sterol regulatory element-binding protein 1 (SREBP1) and carbohydrate response element-binding protein (ChREBP) were also significantly upregulated in dsTcAMPKα-injected beetles. Conclusions AMPK plays a critical role in the regulation of beetle metabolism. The findings of DEGs involved in lipid and carbohydrate metabolism provide valuable insight into the role of AMPK signaling in the transcriptional regulation of insect metabolism.

Cervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP‐insensitive CC cell lines with CDDP‐sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.

Osteoporosis is characterized by the reduction of bone mineral density and deterioration of bone quality which leads to high risk of fractures. Some microRNAs (miRNAs) have been confirmed as potential modulators of osteoblast differentiation to maintain bone mass maintenance. We aimed to clarify whether miR-122 could regulate osteoblast differentiation in ovariectomized rats with osteoporosis. miR-122 was upregulated and Purkinje cell protein 4 (PCP4) was downregulated in ovariectomized rats. PCP4 was identified as a target of miR-122 by dual-luciferase reporter gene assay. We transfected isolated osteoblasts from ovariectomized rats with miR-122 mimic or inhibitor or PCP4 overexpression vectors. Proliferation and differentiation of osteoblasts were repressed by the overexpression of miR-122 but enhanced by overexpression of PCP4. miR-122 could induce the activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway, while PCP4 blocked this pathway. Rescue experiments further demonstrated that the inhibiting effects of miR-122 on osteoblast differentiation could be compensated by activation of the PCP4 or inhibition of JNK signaling pathway. Collectively, our data imply that miR-122 inhibits osteoblast proliferation and differentiation in rats with osteoporosis, highlighting a novel therapeutic target for osteoporotic patients.

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion–triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. Significance: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.

BackgroundAdolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait.ObjectiveWe aimed to explore the oligogenic nature of this disease and identify novel AIS genes.MethodsWe analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients.ResultsMultiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in theFLNBgene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided inFLNB. In functional studies, we found that the AIS-associatedFLNBvariants altered the protein’s conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis.ConclusionOur data indicate that AIS is an oligogenic disease and identifyFLNBas a susceptibility gene for AIS.

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

Background: This study aims to examine the prevalence and predictors associated with self-medication, and related consequences in Wuhan, China. Methods: Two-hundred-sixty residents were interviewed from randomly selected four districts of Wuhan, China. A modified version of Anderson’s health behavioral model was used in the survey to collect information of self-medication behavior. Multivariable logistic regression analyses were used to measure correlates of the prevalence of self-medication. Results: Nearly half of the respondents would select self-medication, and 39.1% would see a doctor if they felt sick. The most common self-medicated illnesses were cold and cough, cardiovascular disease and gastrointestinal disease. The main reasons for self-medication were that the illness was not severe (enough) to see the doctor (45%); the patient did not think that the trouble of seeing a doctor was worth the effort (23%); the patient had no time to see the doctor (12%), and the patient did not want to pay high medical costs (15%). Logistic regression results suggested that respondents tended to select self-medication if the illness was minor or short-term (less than seven days). Conclusions: Our findings suggest that more strict regulation on over-the-counter medicines may be required to reduce health risks related to self-medication. Targeted health education on the risks of self-medication should be considered.

The regulatory function of histone acetylation in the expression of genes encoding heat shock proteins (Hsps) has been documented in Drosophila melanogaster; however, knowledge of the role of acetylation in modulating Hsps in other insect pests is limited. In this study, two full-length cDNAs encoding inducible Hsp70 (designated TcHsp70) and heat shock cognate 70 (TcHsc70) were isolated and characterized in the red flour beetle, Tribolium castaneum. TcHsp70 and TcHsc70 cDNAs were 2256 and 2132 bp and encoded 1941- and 1893-bp open reading frames, respectively. The deduced TcHsp70 and TcHsc70 proteins contained 646 and 630 amino acids, respectively, and contained sequences typical of the Hsp70 family, including the EEVD motif for cytoplasmic localization. Expression patterns after heat shock indicated that TcHsp70 was strongly heat-inducible, whereas the expression level of TcHsc70 remained unchanged under heat shock. RNA interference-mediated knock-down of three genes encoding class I histone deacetylases differentially influenced both basal and heat shock inducible expression of TcHsp70 and TcHsc70, suggesting the involvement of histone acetylation in epigenetic regulation of Hsp70 transcription in T. castaneum.

Background High occupational burnout among general practitioners (GPs) is an important challenge to China’s efforts to strengthen its primary healthcare delivery; however, data to help understand this issue are unavailable. This study aimed to investigate the prevalence of burnout and associated factors among GPs. Methods A cross-sectional design was used to collect data from December 12, 2014, to March 10, 2015, with a self-administered structured questionnaire from 1015 GPs (response rate, 85.6%) in Hubei Province, Central China. Burnout was measured using a 22-item Maslach Burnout Inventory-Human Services Survey (MBI-HSS). MBI-HSS scores and frequency were analyzed by the three dimensions of emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA). Factors associated with burnout among GPs were estimated using a multiple linear regression model. Results Of the respondents, 2.46% had a high level of burnout in all three dimensions, 24.83% reported high levels of EE, 6.21% scored high on DP, and 33.99% were at high risk of PA. GPs who were unmarried, had lower levels of job satisfaction, and had been exposed to workplace violence experienced higher levels of burnout. Intriguingly, no statistically significant associations were found between burnout and the duration of GP practice, age, sex, income, practice setting, and professional level. Conclusion This is the first study of occupational burnout in Chinese general practice. Burnout is prevalent among GPs in Hubei, China. Interventions aimed at increasing job satisfaction, improving doctor-patient relationships and providing safer workplace environments may be promising strategies to reduce burnout among GPs in Hubei, China.

Diamide insecticides target insect ryanodine receptors (RYRs) and cause dysregulation of calcium signaling in insect muscles and neurons, generating worldwide sales over 2 billion US dollars annually. Several resistance mutations have been reported to reduce the efficacy of the diamides, but the exact binding sites and mechanism of resistance mutations were not clear. Recently, we solved the cryo-electron microscopy (cryo-EM) structure of RYR in complex with the anthranilic diamide chlorantraniliprole (CHL). CHL binds to the pseudo–voltage-sensor domain (pVSD) of RYR, a site in proximity to the previously identified resistance mutations. Mutagenesis studies in silico, in mutant cell lines, and in transgenic Drosophila strains revealed the key residues involved in diamide coordination and the molecular mechanism under species-selectivity and resistance mutations. We also proposed that CHL may alleviate the loss-of-function effects of some central core disease (CCD) mutations by increasing the opening probability (Po) of RYR1. In addition, we solved the crystal structures of several RYR domains from the diamondback moth and the bee, revealing insect-specific structural features which could be potentially targeted by novel insecticides. Interestingly, we found that the phosphorylation of insect RYR is temperature dependent, facilitated by the low thermal stability and dynamic structure of the insect RYR. Our structures provide a foundation for developing novel pesticides to overcome the resistance crisis.

Over the past decade, several drugs have been approved for the treatment of relapsed or refractory multiple myeloma (RRMM). This retrospective study, using the French National Healthcare database (SNDS), describes the treatment patterns and outcomes of patients with RRMM treated in real-world clinical practice in France. Patients were adults, with a diagnosis of multiple myeloma, who initiated second-line (2L) treatment approved for use in France between 2014 and 2018; this included bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide, or pomalidomide. Data were analyzed overall, by first-line (1L) autologous stem cell transplant (ASCT) status and by lenalidomide treatment status at 2L. In total, 12987 patients with RRMM were included in the study (mean age 69.5 years); 27% received an ASCT at 1L, and 30% received a lenalidomide-sparing regimen at 2L. Overall, and among the ASCT and non-ASCT subgroups, most patients received a bortezomib-based regimen at 1L, whereas lenalidomide-based regimens were most common at 2L. Among patients who received a lenalidomide-sparing regimen at 2L, this was most often a proteasome inhibitor-based regimen. Mortality rate was 26.1/100 person-years, and median (95% confidence interval) survival from 2L initiation was 32.4 (31.2–33.6) months. Survival differed by various factors, shorter survival was reported in the non-ASCT group, those receiving a lenalidomide-sparing regimen at 2L, older patients (≥ 70 years), and those with multiple comorbidities. This analysis provides insight into the real-world use of approved novel MM treatments and highlights an ongoing unmet need to improve outcomes, particularly for selected patient groups. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04522-y.

The classical neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), synthesized from tryptophan, can be produced both centrally and peripherally. Through binding to functionally distinct receptors, serotonin is profoundly implicated in a number of fundamental physiological processes and pathogenic conditions. Recently, serotonin has been found covalently incorporated into proteins, a newly identified post-translational modification termed serotonylation. Transglutaminases (TGMs), especially TGM2, are responsible for catalyzing the transamidation reaction by transferring serotonin to the glutamine residues of target proteins. Small GTPases, extracellular matrix protein fibronectin, cytoskeletal proteins and histones are the most reported substrates for serotonylation, and their functions are triggered by this post-translational modification. This Review highlights the roles of serotonylation in physiology and diseases and provides perspectives for pharmacological interventions to ameliorate serotonylation for disease treatment.

AIM Vascular calcification (VC) is a common complication in chronic kidney disease (CKD) and has been shown to be associated with increased cardiovascular events and mortality. This study was to explore the role of Wnt-signaling pathway in CKD VC, and the association between VC and blood pressure variability (BPV) which is a risk factor of cardiovascular events. METHODS Adult male Sprague-Dawley rats were divided into adenine-induced CKD group (n = 5), 5/6 nephrectomy CKD group (n = 5), sham group (n = 5) and control group (n = 5). Low-calcium-high-phosphate diets were introduced to induce vascular calcification. Both daytime (hour-to-hour during the day) and mid-term (day-to-day for 9 days) blood pressure (BP) were collected and analyzed for BPV metrics. At sacrifice, kidney, heart and aorta samples were taken for histological analyses. Calcium deposition in aorta was identified with Alizarin Red stain and graded. Immunohistochemistry stain and western blot were performed for Wnt3a, Wnt5a, β-catenin, sclerostin, osteopontin, and α-SMA. RESULTS Compared with control rats, CKD rats suffered from markedly severer VC (Grade 2.6 ± 0.2 and 1.8 ± 0.8 vs 0.0 ± 0.0 and 0.2 ± 0.4, P = .0010). VC was positively correlated with vascular Wnt3a and β-catenin expression (P = .0032 and .0000), but not significantly associated with Wnta5a or sclerostin. Besides, CKD rats showed increased BPV (P

Aberrant expression of the tripartite motif containing 59 (TRIM59) has been reported to participate in the development and progression of various human cancers. However, its expression pattern and cellular roles in pancreatic cancer (PC) remains unclear. In our study, we found that TRIM59 expression was significantly increased in PC tissues and was positively correlated with several malignant behaviors and poor overall survival of PC patients based on bioinformatics analysis and immunohistochemistry staining. Functionally, small interfering RNA-mediated TRIM59 depletion inhibited cell proliferation and migration in vitro, while TRIM59 overexpression promoted cell proliferation and migration in vitro and drove tumor growth and liver metastasis in vivo. Mechanically, TRIM59 was found to enhance glycolysis through activating the PI3K/AKT/mTOR pathway, ultimately contributing to PC progression. Taken together, our results demonstrate that TRIM59 may be a potential predictor for PC and promotes PC progression via the PI3K/AKT/mTOR-glycolysis signaling pathway, which establishes the rationale for targeting the TRIM59-related pathways to treat PC.

Background Although long-term alcohol and tobacco use have widely been recognised as important risk factors for cancer, the impacts of alcohol and tobacco health policies on cancer mortality have not been examined in previous studies. This study aims to estimate the association of key alcohol and tobacco policy or events in Australia with changes in overall and five specific types of cancer mortality between the 1950s and 2013. Methods Annual population-based time-series data between 1911 and 2013 on per capita alcohol and tobacco consumption and head and neck (lip, oral cavity, pharynx, larynx and oesophagus), lung, breast, colorectum and anus, liver and total cancer mortality data from the 1950s to 2013 were collected from the Australian Bureau of Statistics and Cancer Council Victoria, the WHO Cancer Mortality Database and the Australian Institute of Health and Welfare. The policies with significant relations to changes in alcohol and tobacco consumption were identified in an initial model. Intervention dummies with estimated lags were then developed based on these key alcohol and tobacco policies and events and inserted into time-series models to estimate the relation of the particular policy changes with cancer mortality. Results Liquor licence liberalisation in the 1960s was significantly associated with increases in the level of population drinking and thereafter of male cancer mortality. The introduction of random breath testing programs in Australia after 1976 was associated with a reduction in population drinking and thereafter in cancer mortality for both men and women. Meanwhile, the release of UK and US public health reports on tobacco in 1962 and 1964 and the ban on cigarette ads on TV and radio in 1976 were found to have been associated with a reduction in Australian tobacco consumption and thereafter a reduction in mortality from all cancer types except liver cancer. Policy changes on alcohol and tobacco during the 1960s–1980s were associated with greater changes for men than for women, particularly for head and neck, lung and colorectum cancer sites. Conclusion This study provides evidence that some changes to public health policies in Australia in the twentieth century were related to the changes in the population consumption of alcohol and tobacco, and in subsequent mortality from various cancers over the following 20 years.

Background Community exercise might be beneficial to stroke recovery. However, the results remained controversial. We conducted a systematic review and meta-analysis to explore the effect of community exercise on stroke patients. Methods PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of community exercise vs. usual care on stroke were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcome were 6-Minute walk test and walking speed. Metaanalysis was performed using random-effect model. Results Four RCTs involving 497 patients were included in the metaanalysis. Overall, compared with control intervention, community exercise intervention was found to significantly improve 6-Minute walk distance (Std. mean difference=0.48; 95% CI=0.22 to 0.74; P=0.0003), and walking speed (Std. mean difference=0.40; 95% CI=0.10 to 0.70; P=0.009) in stroke patients, but resulted in no influence on Berg Balance Scale (Std. mean difference=0.39; 95% CI=−0.29 to 1.07; P=0.26), muscle strength (Std. mean difference=0.05; 95% CI=-0.34 to 0.43; P=0.82) and mental quality of life (Std. mean difference=0.04; 95% CI=−0.25 to 0.34; P=0.77). Conclusions Compared to control intervention, community exercise was found to significantly increase 6-Minute walk test, walking speed and Berg Balance Scale, but showed no influence on Berg Balance Scale, muscle strength and mental quality of life.

The AMP-activated protein kinase (AMPK) has important roles in the regulation of energy metabolism, and AMPK activity and its regulation have been the focus of relevant investigations. However, functional characterization of AMPK is still limited in insects. In this study, the full-length cDNA coding AMPKα (TcAMPKα) was isolated from the red flour beetle, Tribolium castaneum. The TcAMPKα gene contains an ORF of 1581 bp encoding a protein of 526 amino acid residues, which shared conserved domain structure with Drosophila melanogaster and mammalian orthologs. Exposure of female adults to oxidative, heat, and cold stresses caused an increase in TcAMPKα mRNA expression levels and phosphorylation of Thr-173 in the activation loop. The RNAi-mediated knockdown of TcAMPKα resulted in the increased sensitivity of T. castaneum to oxidative, heat, and cold stresses. These results suggest that stress signals regulate TcAMPKα activity, and TcAMPKα plays an important role in enabling protective mechanisms and processes that confer resistance to environmental stress. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12192-019-01030-x) contains supplementary material, which is available to authorized users.

The interactions between charge carriers and electrode structures represent one of the most important considerations in the search for new energy storage devices. Currently, ionic bonding dominates the battery chemistry. Here we report the reversible insertion of a large molecular dication, methyl viologen, into the crystal structure of an aromatic solid electrode, 3,4,9,10-perylenetetracarboxylic dianhydride. This is the largest insertion charge carrier when non-solvated ever reported for batteries; surprisingly, the kinetic properties of the (de)insertion of methyl viologen are excellent with 60% of capacity retained when the current rate is increased from 100 mA g−1 to 2000 mA g−1. Characterization reveals that the insertion of methyl viologen causes phase transformation of the organic host, and embodies guest-host chemical bonding. First-principles density functional theory calculations suggest strong guest-host interaction beyond the pure ionic bonding, where a large extent of covalency may exist. This study extends the boundary of battery chemistry to large molecular ions as charge carriers and also highlights the electrochemical assembly of a supramolecular system., Rechargeable batteries are governed by reversible intercalation reactions. Here the authors expand the intercalation chemistry to include methyl viologen as a large dicationic charge carrier in aqueous batteries. The bonding between guest and aromatic host is not pure ionic but shows strong covalent character.

We compared the depression levels of juvenile and adolescent patients with idiopathic scoliosis who had undergone bracing and identified the factors that influenced the extent of depression in these patients.Our study included 112 patients with adolescent idiopathic scoliosis (AIS) and 96 patients with juvenile idiopathic scoliosis (JIS). The demographic characteristics and Zung Self-Rating Depression Scale, Strengths and Difficulties Questionnaire, and Center for Epidemiological Studies Depression Scale for Children scores were evaluated to select the relative factors of depression in patients and parents. Cognitive evaluations, using the Wechsler Intelligence Scale for Children-Revised scale, and an independent evaluation using the Functional Independence Measure for Children scale, were conducted.The mean Center for Epidemiological Studies Depression Scale for Children score in the AIS group (38.3 ± 3.0) was greater than that in the JIS group (23.8 ± 4.6), a statistically significant difference (P0.05). Age at initial bracing, bracing duration, parental depression, Cobb angle at initial bracing, cognitive function, independence, peer problems, prosocial behaviors, emotional symptoms, and total difficulties were significant factors in our regression model for JIS. The AIS patients showed similar results, except for the age at initial bracing, cognitive function, and independence.Patients with AIS and JIS who had undergone bracing showed differences in the extent of depression, and female adolescents were more vulnerable to depressive psychological status. Higher levels of cognitive function and independence and older age at bracing, longer bracing duration, larger Cobb angle, negative parental attitudes, and undesirable Strengths and Difficulties Questionnaire scores contributed to greater depression.

To determine the relationship between the bone formation-related functions of GPR126 and the structural asymmetry of spine in adolescent idiopathic scoliosis (AIS). Vertebral body samples were obtained from 51 AIS patients during spinal surgery between October 2014 and November 2017, and the expression pattern of GPR126 in the convex/concave sides of AIS spine was identified by RT-qPCR. Next, we explored the bone formation-related functions of GPR126 by knocking down and overexpressing GPR126 in human mesenchymal stem cells (hMSC) and further performing osteogenic differentiation. We also applied overexpression of N-terminal fragments derived from GPR126 (GPR126-NTFs) and osteogenic differentiation experiments to determine the functional part of GPR126 in skeletal development. We provided evidence that GPR126 showed a marked convex/concave asymmetric expression in the spine of AIS. Further RNA detection found that exon6-included transcripts of GPR126 (GPR126-exon6in) were significantly higher expressed in the convex side of AIS patients. Knocking down of GPR126 accelerated ossification of hMSCs during osteogenic differentiation, and overexpression of GPR126-exon6in delayed this process. Overexpression of GPR126-NTFs revealed that NTF is a functional fragment and exon6-included NTF (NTF-exon6in) delayed ossification of hMSCs. Our findings indicated that GPR126-NTFs play a role in skeletal development, and the inclusion/exclusion of exon6 may regulate the bone formation-related functions of GPR126. The convex/concave asymmetric expression of GPR126-exon6in may be an important factor in abnormal bone formation of AIS. These slides can be retrieved under Electronic Supplementary Material.

Reversible acetylation of core histones plays an important role in the epigenetic regulation of gene transcription, and is controlled by the action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). While HDACs have been well studied in Drosophila melanogaster, information from insect pests is still limited. In the current study, we cloned and characterized three class I enzymes, TcHDAC1, TcHDAC 3 and TcHDAC 8, in the red flour beetle, Tribolium castaneum. Expression profiling showed that T. castaneum HDAC genes are expressed in all developmental stages and tissues examined. A dramatic increase of mRNA expression level was observed from prepupae to 1-day-old pupae for all three T. castaneum HDAC genes. Both TcHDAC1 and TcHDAC3 exhibited the highest mRNA expression levels in thorax, whereas TcHDAC8 was highly expressed in fat body. Furthermore, T. castaneum HDAC genes were found to respond to heat, cold and oxidative stresses. While the heat-stress treatment decreased the mRNA expression levels of T. castaneum HDAC genes, their transcripts were induced by paraquat treatment. These results suggest a possible role for class I HDAC genes in the epigenetic regulation of T. castaneum development and stress responses.

Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.MethodsThe Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.ResultsGABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.ConclusionsOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

Background Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. Methods Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1−/− mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. Results Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-β signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC−/− mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. Interpretation We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-β signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-β signaling and avoid the side effects caused by directly targeting TGF-β. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. Fund This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Background Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC. Methods LOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting. Results LOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis. Conclusions Taken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0948-8) contains supplementary material, which is available to authorized users.

Background Accumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. Methods Primary HSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. Loss-of-function experiments were applied to determine the cellular functions of KDM4D in HSCs. Transcriptome analysis was applied to explore the downstream targets of KDM4D. Real-time qPCR, western blotting, immunohistochemical staining, and chromatin immunoprecipitation were performed to uncover the underlying mechanism concerning KDM4D during liver fibrogenesis. Findings KDM4D was identified as a remarkable up-regulated histone H3 demethylase during HSC activation. The overexpression profile of KDM4D was confirmed in three fibrosis animal models and human fibrotic liver tissues. In vitro Kdm4d knockdown impaired the collagen gel contraction and migration capacity of primary HSCs. In established CCl4-induced mice model, Kdm4d knockdown inhibited fibrosis progression, and promoted fibrosis reversal, with enhanced thinning and splitting of fibrotic septa, as well as a dramatic decrease in collagen area. Whole gene transcriptome analysis showed the regulatory role of KDM4D in Toll-Like Receptor (TLR) signaling pathway. Mechanistically, KDM4D catalyzed histone 3 on lysine 9 (H3K9) di-, and tri-demethylation, which promoted TLR4 expression, and subsequently prompted liver fibrogenesis by activating NF-κB signaling pathways. Interpretation KDM4D facilitates TLR4 transcription through demethylation of H3K9, thus activating TLR4/NF-κB signaling pathways in HSCs, contributing to HSC activation and collagen crosslinking, further, hepatic fibrosis progression. Fund Shanghai New Hundred Talents Program, Shanghai Municipal Commission of Health and Family Planning, Key Developing Disciplines Program, Shanghai Key disciplines program of Health and Family Planning and Shanghai Sailing Program.

This study was aimed to determine the diagnostic performance of perfusion-related parameters derived from intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) by comparing them with quantitative parameters from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on differentiation grades of rectal cancer. We retrospectively analyzed 98 patients with rectal cancer. Perfusion-related IVIM parameters ( D ∗ , f , and f · D ∗ ) and quantitative DCE parameters ( K trans , K ep , V e , and V p ) were obtained by plotting the volume-of-interest on in-house software. Furthermore, we compared the difference and diagnostic performance of all well-moderately and poorly differentiated rectal cancer parameters. Finally, we analyzed the correlation between those DCE and IVIM parameters and pathological differentiation grade. The values of f , K trans , and K ep significantly differentiated poor and well-moderate rectal cancers. K trans achieved the highest area under the curve (AUC) value compared to perfusion-related IVIM and DCE parameters. Furthermore, K trans showed a better correlation with pathological differentiation grade than f . The diagnostic efficiency of DCE-MRI was greater than perfusion-related IVIM parameters. The f value derived from perfusion-related IVIM offered a diagnostic performance similar to DCE-MRI for patients with renal insufficiency.

Background Reprogrammed glucose metabolism, also known as the Warburg effect, which is essential for tumor progression, is regarded as a hallmark of cancer. MAP17, a small 17-kDa non-glycosylated membrane protein, is frequently dysregulated in human cancers. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. Methods Immunohistochemistry was used to analyze the expression pattern of MAP17 in HCC. Loss-of-function and gain-of-function studies were performed to investigate the oncogenic roles of MAP17 in vitro and in vivo. RNA sequencing, co-immunoprecipitation, immunofluorescence and western blotting were used to study the molecular mechanism of MAP17 affecting the tumor growth and glycolytic phenotype of HCC. Results An integrative analysis showed that MAP17, a small 17-kDa non-glycosylated membrane protein, is significantly related to the glycolytic phenotype of hepatocellular carcinoma (HCC). Firstly, we found that MAP17 expression is hypoxia-dependent and predicts a poor prognosis in HCC. Genetic silencing of MAP17 reduced the rate of glucose uptake, lactate release, extracellular acidification rate, and expression of glycolytic genes. Ectopic expression of wild type MAP17 but not its PDZ binding domain mutant MAP17-PDZm increased tumor glycolysis. Further research showed that MAP17 knockdown markedly retarded in vivo tumor growth in HCC. Importantly, attenuation of tumor glycolysis by galactose largely hijacked the growth-promoting role of MAP17 in HCC cells. RNA sequencing analysis revealed that MAP17 knockdown leads to transcriptional changes in the ROS metabolic process, cell surface receptor signaling, cell communication, mitotic cell cycle progression, and regulation of cell differentiation. Mechanistically, MAP17 exerted an increased tumoral phenotype associated with an increase in reactive oxygen species (ROS), which activates downstream effectors AKT and HIF1α to enhance the Warburg effect. In HCC clinical samples, there is a close correlation between MAP17 expression and HIF1α or phosphorated level of AKT. Conclusions Our results show that MAP17 is a novel glycolytic regulator, and targeting MAP17/ROS pathway may be an alternative approach for the prevention and treatment of HCC.

Extracellular matrix (ECM) plays an important role in the progression of cancer. Collagen is the most abundant component in ECM, and it is involved in the biological formation of cancer. Although type XI collagen is a minor fibrillar collagen, collagen XI alpha 1 chain (COL11A1) has been found to be upregulated in a variety of cancers including ovarian cancer, breast cancer, thyroid cancer, pancreatic cancer, non-small-cell lung cancer, and transitional cell carcinoma of the bladder. High levels of COL11A1 usually predict poor prognosis, while COL11A1 is related to angiogenesis, invasion, and drug resistance of cancer. However, little is known about the specific mechanism by which COL11A1 regulates tumor progression. Here, we have organized and summarized the recent developments regarding elucidation of the relationship between COL11A1 and various cancers, as well as the interaction between COL11A1 and intracellular signaling pathways. In addition, we have selected therapeutic agents targeting COL11A1. All these indicate the possibility of using COL11A1 as a target for cancer treatment.

Background Short interspersed nuclear elements (SINEs) belong to non-long terminal repeat (non-LTR) retrotransposons, which can mobilize dependent on the help of counterpart long interspersed nuclear elements (LINEs). Although 234 SINEs have been identified so far, only 23 are from insect species (SINEbase: http://sines.eimb.ru/). Results Here, five SINEs were identified from the genome of Plutella xylostella, among which PxSE1, PxSE2 and PxSE3 were tRNA-derived SINEs, PxSE4 and PxSE5 were 5S RNA-derived SINEs. A total of 18 related SINEs were further identified in 13 lepidopteran insects and a baculovirus. The 3′-tail of PxSE5 shares highly identity with that of LINE retrotransposon, PxLINE1. The analysis of relative age distribution profiles revealed that PxSE1 is a relatively young retrotransposon in the genome of P. xylostella and was generated by recent explosive amplification. Integration pattern analysis showed that SINEs in P. xylostella prefer to insert into or accumulate in introns and regions 5 kb downstream of genes. In particular, the PxSE1-like element, SlNPVSE1, in Spodoptera litura nucleopolyhedrovirus II genome is highly identical to SfSE1 in Spodoptera frugiperda, SlittSE1 in Spodoptera littoralis, and SlituSE1 in Spodoptera litura, suggesting the occurrence of horizontal transfer. Conclusions Lepidopteran insect genomes harbor a diversity of SINEs. The retrotransposition activity and copy number of these SINEs varies considerably between host lineages and SINE lineages. Host-parasite interactions facilitate the horizontal transfer of SINE between baculovirus and its lepidopteran hosts.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective treatment strategies. There is an urgent need for the development of new strategies for PDAC therapy. The genetic and phenotypic heterogeneity of PDAC cancer cell populations poses further challenges in the clinical management of PDAC. In this study, we performed single-cell RNA sequencing to characterize PDAC tumors from KPC mice. Functional studies and clinical analysis showed that PDAC cluster 2 cells with highly Hsp90 expression is much more aggressive than the other clusters. Genetic and pharmacologic inhibition of Hsp90 impaired tumor cell growth both in vitro and in vivo. Further mechanistic study revealed that HSP90 inhibition disrupted the interaction between HSP90 and OPA1, leading to a reduction in mitochondrial cristae amount and mitochondrial energy production. Collectively, our study reveals that HSP90 might be a potential therapeutic target for PDAC.

Karyopherin-β proteins are critically involved in cancer progression and have been reported as potential biomarkers and therapeutic targets for tumor treatment. However, TNPO1, as an important karyopherin-β family member, underlying functional roles in cancers remain largely unclear. In this study, under integrated gene-expression profiling screen of karyopherin-β in gynecologic cancer, we identify TNPO1 as a pivotal contributor to the gynecologic cancer progression. Remarkably, ARID1A-deficient gynecologic cancer cells are specifically vulnerable to the genetic perturbations of TNPO1 in vitro and in vivo. Mechanistically, TNPO1 is selectively responsible for nuclear import of ARID1B, which is a synthetic lethal target in ARID1A-inactivating mutation cancers. Furthermore, TNPO1 or ARID1B knockdown changes chromatin accessibility that results in loss of H3K4me1 and H3K27ac marker, diminishing activated transcription factor of the AP-1 family, and inactivating the PI3K/AKT signaling pathway by reducing growth pathway genes expression including PIK3CA and FGFR2. Together, this work indicates that the oncogenic function of TNPO1 and maybe represent a novel therapeutic strategy to treat ARID1A-deficient gynecologic cancer.

Endometrial cancer (EC) is becoming one of the most common gynecologic malignancies. Lipid metabolism is a hallmark feature of cancers. The molecular mechanisms underlying lipid metabolism in EC remain unclear. In this study, we revealed that many lipid metabolism-related genes were aberrantly expressed in endometrial cancer tissues, especially ACLY. Upregulated ACLY promoted EC cell proliferation and colony formation, and attenuated apoptosis. Mechanistically, cotreatment with obesity-related factors (estradiol, insulin and leptin) promoted nuclear translocation of ACLY through Akt-mediated phosphorylation of ACLY at Ser455. Nuclear-localized ACLY increased histone acetylation levels, thus resulting in upregulation of pyrimidine metabolism genes, such as DHODH. Moreover, STAT3 altered the ACLY expression at the transcriptional level via directly binding to its promoter region. In conclusion, our findings clarify the roles and mechanisms of ACLY in endometrial cancer and ACLY could link obesity risk factors to the regulation of histone acetylation. We believe that novel therapeutic strategies for EC can be designed by targeting the ACLY axis.

Background Although many studies have analyzed mental health problems in college students in China, the associations of mental health with individual and family circumstances, academic performance, and social support were rarely discussed. Objectives The study aimed to determine the mental health status and its associated factors among college students in China. Methods An online survey was conducted on 300 students selected through a cluster sampling strategy in a university in Hubei, China, tapping into sociodemographic characteristics of the participants, their mental health status measured by the modified Symptom Checklist-90 (SCL-90), and social support measured by the Social Support Rating Scale. Multivariate linear regression models were established to identify predictors of the SCL-90 scores. Results Mental health disorders were found in 8% of the respondents, with obsessive compulsive, interpersonal sensitivity and depression as the top three reported problems. Compared with the national population norms of university students in 2014, our study participants had higher scores in SCL-90. There were statistically significant difference in the Global Severity index (GSI) and all nine subscales scores (pp Conclusions College students in Hubei, China may experience a range of different mental health problems, which are associated with their individual, study, and social circumstances.

Background The complex interrelationships between professional identity, job satisfaction, burnout, and turnover intention among general practitioners (GPs) are insufficiently understood in China. This study aimed to investigate the interrelationships between professional identity, job satisfaction, burnout, and turnover intention in China, and to examine whether job satisfaction and burnout played mediating roles between professional identity and turnover intention. Methods A cross-sectional survey was conducted between October, 2017 and February, 2018 in China. The participants were selected using a multistage stratified random sampling method. Data were collected with a self-administered questionnaire from 3236 GPs (response rate, 99.8%) working in community health institutions in China. Professional identity was measured by the 13 items scale, and job satisfaction scale with an 11-item designed by Shi et al. was employed. Burnout was measured using a 22-item Maslach Burnout Inventory-Human Services Survey, and turnover intention was measured with a 6 items scale. Descriptive statistics were calculated and groups’ differences were estimated Student’s t-test and analyses of variance. Pearson’s correlation analysis was used to assess the degree of correlation among different dimensions of professional identity, job satisfaction, burnout, and turnover intention. Structural equation modeling analysis was applied to examine the interrelationships among these study variables based on the hypothesized model. Results The proposed model achieved a good model fit. Job satisfaction had a direct negative effect on turnover intention (β = − 0.38, P β = 0.37, P Conclusions Our study elucidated the pathways linking professional identity, job satisfaction, and burnout to turnover intention of GPs. This revealed that turnover intention was significantly affected by job satisfaction and burnout, and the effects of professional identity on turnover intention can be mediated by job satisfaction and burnout.

Stringent COVID-19 control measures were imposed in Wuhan between January 23 and April 8, 2020. Estimates of the prevalence of infection following the release of restrictions could inform post-lockdown pandemic management. Here, we describe a city-wide SARS-CoV-2 nucleic acid screening programme between May 14 and June 1, 2020 in Wuhan. All city residents aged six years or older were eligible and 9,899,828 (92.9%) participated. No new symptomatic cases and 300 asymptomatic cases (detection rate 0.303/10,000, 95% CI 0.270–0.339/10,000) were identified. There were no positive tests amongst 1,174 close contacts of asymptomatic cases. 107 of 34,424 previously recovered COVID-19 patients tested positive again (re-positive rate 0.31%, 95% CI 0.423–0.574%). The prevalence of SARS-CoV-2 infection in Wuhan was therefore very low five to eight weeks after the end of lockdown. Large-scale population screening can provide insights to levels of ongoing SARS-CoV-2 transmission. Here, the authors report a citywide screening of ~10,000,000 residents of Wuhan and show that SARS-CoV-2 infection prevalence was very low five to eight weeks after the end of lockdown.

Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Containing 1 (CTHRC1) in primary CRC served as a metastasis-associated gene. Animal experiments verified that CTHRC1 secreted by CRC cells promoted hepatic metastasis, which was closely correlated with macrophage infiltration. Depletion of macrophages by liposomal clodronate largely abolished the promoting effect of CTHRC1 on CRC liver metastasis. Furthermore, we demonstrated that CTHRC1 modulated macrophage polarization to M2 phenotypes through TGF-β signaling. A mechanistic study revealed that CTHRC1 bound directly to TGF-β receptor II and TGF-β receptor III, stabilized the TGF-β receptor complex, and activated TGF-β signaling. The combination treatment of CTHRC1 monoclonal antibody and anti-PD-1 blocking antibody effectively suppressed CRC hepatic metastasis. Taken together, our data demonstrated that CTHRC1 is an intrinsic marker of CRC metastasis and further revealed that CTHRC1 promoted CRC liver metastasis by reshaping infiltrated macrophages through TGF-β signaling, suggesting that CTHRC1 could be a potential biomarker for the early prediction of and a therapeutic target of CRC hepatic metastasis.

Background Obesity and osteoporosis frequently coexist, and might have a causal relationship. Gut microbiota, associated with both lipid and bone metabolism, plays an important role in the pathogenesis of excessive fat accumulation and bone loss. The improvement of intestinal flora by prebiotics was a promising strategy for ameliorating obesity-related bone loss. Methods Obesity model was established by feeding mice with high fat diet (HFD) for 16 weeks. Fructooligosaccharides (FOS) and/or galactooligosaccharides (GOS) were daily gavaged to mice. Osteoblastic, adipocytic, and osteoclastic differentiation was performed on primary cells isolated from experimental mice. The composition of gut flora was evaluated by 16s rDNA sequencing. Expression of intestinal junction proteins was assessed by qPCR and immunohistochemistry. Cytokine levels were measured by qPCR. Results Long-term HFD caused decreased bone mass in mice, which was associated with decreased osteogenesis, increased osteoclastogenesis, and excessive adipogenesis. FOS/GOS treatment significantly alleviated HFD-induced bone loss and reversed the imbalanced differentiation of osteoblasts, adipocytes, and osteoclasts. In addition, our study showed that FOS/GOS administration ameliorated microbiota dysbiosis (manifested as enhanced Firmicutes:Bacteriodetes ratio and reduced biodiversity), downregulated expression of intestinal junction proteins (including Claudin1, Claudin15, ZO-1, and JAM-A), and increased inflammatory cytokines (including TNFα, IL6, and IL17) in HFD-fed mice. Conclusion Long-term HFD led to decreased bone mass, with microbiota dysbiosis, leaky gut, and systemic inflammation. The administration of FOS/GOS could significantly increase biodiversity and SCFA concentrations of intestinal flora in HFD fed mice, then reverse high gut permeability and inflammatory cytokines, in the end protect against HFD induced osteopenia.

The overarching view of current tumor therapies simplifies cancer to a cell-biology problem in which neoplasms are caused solely by malignant cells and the exploration of carcinogenesis and tumor progression largely focuses on somatic mutations and other genetic abnormalities of cancer cells. The limited therapeutic response indicates that cancer is driven not only by endogenous oncogenic factors and reciprocal interactions within the tumor microenvironment, but also by complex systemic processes. Homeostasis is the fundamental premise of health, and is maintained by systemic regulation of neuro-endocrine-immune axis. Cancer is also a systemic disease that manifested by dysfunction of the nervous, endocrine, and immune systems. Multiple axes of regulation exist in cancer, including central-, organ-, and microenvironment-level manipulation. At each specific regulatory level, the tridirectional communication among the nervous, endocrine, and immune factors transmit flexible signaling to induce proliferation, invasion, reprogrammed metabolism, therapeutic resistance, and other malignant phenotypes of cancer cells, resulting in the extremely poor prognosis of this lethal disease. Understanding this coordinated signaling network will enable the development of new approaches for cancer treatment via behavioral and pharmacological interventions.

Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

BACKGROUND Adiposity is an established risk factor for diabetes. The different measurements of adiposity for predicting diabetes have been compared in recent studies in Western countries. However, similar researches among Chinese adults are limited. METHODS Data were collected from a national survey conducted during September 2014 and May 2015 Among Chinese adults aged 40 years and older across 30 China's provinces. Multilevel model analysis was performed to examine the impacts of different obesity indices [body mass index (BMI), waist circumference (WC), lipid accumulation product index (LAP), visceral adiposity index (VAI), and body adiposity index (BAI)] on the risk of diabetes. RESULTS A total of 162 880 participants were included in this study. Of them, 54.47% were female. With an increase in BMI, WC, LAP, VAI, and BAI, the prevalence of diabetes significantly grew (P

Besides the function of preventing metamorphosis in insects, the juvenile hormone (JH) plays a role in female reproduction; however, the underlying mechanism is largely unknown. The methoprene-tolerant (Met) protein belongs to a family of basic helix-loop-helix–Per-Arnt-Sim (bHLH-PAS) transcription factors and functions as the JH intracellular receptor. In this study, two full length cDNAs encoding Met (CsMet1 and CsMet2) were isolated from the rice stem borer, Chilo suppressalis. Structural analysis revealed that both CsMet1 and CsMet2 exhibited typical bHLH, PAS-A, PAS-B, and PAC (PAS C terminal motif) domains. Comparative analysis of transcript level using reverse transcription-quantitative PCR (RT-qPCR) revealed that CsMet1 was predominant in almost all examined developmental stages and tissues. Treatment with methoprene in vivo induces the transcription of both CsMet1 and CsMet2. Notably, injection of dsCsMet1 and dsCsMet2 suppressed the expression levels of vitellogenin (CsVg) and Vg receptor (CsVgR). These findings revealed the potential JH signaling mechanism regulating C. suppressalis reproduction, and provided evidence that RNAi-mediated knockdown of Met holds great potential as a control strategy of C. suppressalis.