Erratum: CircNT5E promotes the proliferation and migration of bladder cancer via sponging miR-502-5p: Erratum.

[This corrects the article DOI: 10.7150/jca.53385.].

Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.

The cyclic-oligonucleotide-based anti-phage signalling system (CBASS) is a type of innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS uses cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homologue of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, using biochemical, genetic, cryo-electron microscopy and mass spectrometry investigations, we discover that the E2 enzyme from Serratia marcescens regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.

Integrated pharmacokinetic-pharmacodynamic modeling and metabolomic research on polyphenol-rich fraction of Thymus quinquecostatus Celak. Alleviating cerebral ischemia-reperfusion injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Thymus quinquecostatus Celak., a member of thymus genus in Lamiaceae family, has been used as a folk medicine for relieving exterior syndrome and alleviating pain in China. The polyphenol-rich fraction (PRF) derived from Thymus quinquecostatus Celak. had been validated that it can protect cerebral ischemia-reperfusion injury (CIRI) by activating Keap1/Nrf2/HO-1 signaling pathway. AIM OF THIS STUDY: To explore effective components and their pharmacokinetic and pharmacodynamic characteristics as well as possible mechanisms of PRF in treating CIRI. MATERIALS AND METHODS: Normal treated group (NTG) and tMCAO model treated group (MTG) rats were administrated PRF intragastrically. The prototype components and metabolites of PRF in plasma and brain were analyzed by the UPLC-Q-Exactive Orbitrap MSn method. Subsequently, the pharmacokinetics properties of indicative components were performed based on HPLC-QQQ-MS/MS. SOD and LDH activities were determined to study the pharmacodynamic (PD) properties of PRF. The PK-PD relationship of PRF was constructed. In addition, the effect of PRF on endogenous metabolites in plasma and brain was investigated using metabolomic method. RESULTS: Salvianic acid A, caffeic acid, rosmarinic acid, scutellarin, and apigenin-7-O-glucuronide were selected as indicative components based on metabolic analysis. The non-compartmental parameters were calculated for indicative components in plasma and brain of NTG and MTG rats. Furthermore, single-component and multi-component PK-PD modeling involved Emax, Imax PD models for effect indexes were fitted as well as ANN models were established, which indicated that these components can work together to regulate SOD and LDH activities in plasma and SOD activity in brain tissue to improve CIRI. Additionally, PRF may ameliorate CIRI by regulating the disorder of endogenous metabolites in lipid metabolism, amino acid metabolism, and purine metabolism pathways in vivo, among which lipid metabolism and purine metabolism are closely related to oxidative stress. CONCLUSION: The PK-PD properties of effect substances and mechanisms of PRF anti-CIRI were further elaborated. The findings provide a convincing foundation for the application of T. quinquecostatus Celak. in the maintenance of human health disorders.

Comparison of the Biomechanical Properties between Healthy and Whole Human and Porcine Stomachs.

Gastric cancer poses a societal and economic burden, prompting an exploration into the development of materials suitable for gastric reconstruction. However, there is a dearth of studies on the mechanical properties of porcine and human stomachs. Therefore, this study was conducted to elucidate their mechanical properties, focusing on interspecies correlations. Stress relaxation and tensile tests assessed the hyperelastic and viscoelastic characteristics of porcine and human stomachs. The thickness, stress-strain curve, elastic modulus, and stress relaxation were assessed. Porcine stomachs were significantly thicker than human stomachs. The stiffness contrast between porcine and human stomachs was evident. Porcine stomachs demonstrated varying elastic modulus values, with the highest in the longitudinal mucosa layer of the corpus and the lowest in the longitudinal intact layer of the fundus. In human stomachs, the elastic modulus of the longitudinal muscular layer of the antrum was the highest, whereas that of the circumferential muscularis layer of the corpus was the lowest. The degree of stress relaxation was higher in human stomachs than in porcine stomachs. This study comprehensively elucidated the differences between porcine and human stomachs attributable to variations across different regions and tissue layers, providing essential biomechanical support for subsequent studies in this field.

The hidden diet: Synthetic antioxidants in packaged food and their impact on human exposure and health.

Synthetic antioxidants (AOs) are commonly used in everyday items and industrial products to inhibit oxidative deterioration. However, the presence of AOs in food packaging and packaged foods has not been thoroughly documented. Moreover, studies on human exposure to AOs through skin contact with packaging or ingesting packaged foods are limited. In this study, we analyzed twenty-three AOs-including synthetic phenolic antioxidants (SPAs) and organophosphite antioxidants (OPAs)-along with six transformation products in various food samples and their packaging materials. We found AOs in food products at concentrations ranging from 1.30 × 103 to 1.77 × 105 ng/g, which exceeded the levels in both outer packaging (6.05 × 102-3.07 × 104 ng/g) and inner packaging (2.27 × 102-1.09 × 105 ng/g). The most common AOs detected in foodstuffs were tris(2,4-di-tert-butylphenyl) phosphate (AO168O), butylated hydroxytoluene (BHT), and octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (AO1076), together constituting 95.7 % of the total AOs found. Our preliminary exposure assessment revealed that dietary exposure-estimated at a median of 2.55 × 104 ng/kg body weight/day for children and 1.24 × 104 ng/kg body weight/day for adults-is a more significant exposure route than dermal contact with packaging. Notably, four AOs were identified in food for the first time, with BHT making up 76.8 % and 67.6 % of the total BHT intake for children and adults, respectively. These findings suggest that food consumption is a significant source of BHT exposure. The estimated daily intakes of AOs via consumption of foodstuffs were compared with the recommended acceptable daily intake to assess the risks. This systematic investigation into AOs contributes to understanding potential exposure and health risks associated with AOs in packaged foods. It emphasizes the need for further evaluation of human exposure to these substances.

Methylated ctDNA predicts early recurrence risk in patients undergoing resection of initially unresectable colorectal cancer liver metastases.

Background: Patients with initially unresectable colorectal cancer liver metastases (IU-CRLM) might benefit from using an effective systemic treatment followed by resection of liver metastases but the curative success rate is quite low. Indeed, nearly one-third of patients exhibit early recurrence within the first 6 months after surgery, and these individuals often have poor overall survival. Objectives: This study aims to clarify the application value of serial circulating tumor DNA (ctDNA) analysis in predicting the clinical outcome of IU-CRLM patients following liver metastasectomy. Design: A retrospective study was conducted on a cohort of patients with IU-CRLM between February 2018 and April 2021. Methods: Plasma samples at different time points during CRLM treatment [baseline (BL), preoperation (PRE), postoperation (POST), end-of-treatment (EOT), and progressive disease (PD)] were retrospectively collected from patients with initially unresectable CRLM enrolled at the Sun Yat-sen University Cancer Center. Dynamic changes of SEPTIN 9 (SEPT9) and Neuropeptide Y (NPY) methylated circulating tumor DNA (MetctDNA) levels in serial plasma samples were detected using droplet-digital PCR (ddPCR). Results: SEPT9 and NPY genes were hypermethylated in colon cancer cell lines and tissues while no difference was observed between primary and metastatic tumors. Patients with MetctDNA positive at POST or EOT had significantly lower recurrence-free survival (RFS) compared to patients with MetctDNA negative at these time points [POST: Hazard ratio (HR) 9.44, 95% confidence interval (CI) 5.15-17.30, p < 0.001; EOT: HR 11.48, 95% CI 3.27-40.31, p < 0.001]. Multivariate analysis demonstrated that POST (OR 33.96, 95% CI 4.03-286.10, p = 0.001) and EOT (OR 18.36, 95% CI 1.14-295.71, p = 0.04) MetctDNA was an independent risk factor for early recurrence. Time-dependent receiver operating characteristic curve (T-ROC) analysis revealed that area under the curve (AUC) value was greatest at the relapse time point of 6 months post-intervention, with POST-AUC and EOT-AUC values of 0.74 (95% CI 0.66-0.81) and 0.73 (95% CI 0.53-0.94), respectively. Serial MetctDNA analysis showed that RFS was significantly lower in patients with no MetctDNA clearance compared with those with MetctDNA clearance (HR 26.05, 95% CI 4.92-137.81, p < 0.001). Conclusion: Our study confirmed that serial ctDNA analysis of NPY and SEPT9 gene methylation could effectively predict early recurrence in IU-CRLM patients, especially at POST and EOT.

Protective effects of human urinary kallidinogenase against corticospinal tract damage in acute ischemic stroke patients.

This study aimed to assess the effects of human urinary kallidinogenase (HUK) on motor function outcome and corticospinal tract recovery in patients with acute ischemic stroke (AIS). This study was a randomized, controlled, single-blinded trial. Eighty AIS patients were split into two groups: the HUK and control groups. The HUK group was administered HUK and standard treatment, while the control group received standard treatment only. At admission and discharge, the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and muscle strength were scored. The primary endpoint was the short-term outcomes of AIS patients under different treatments. The secondary endpoint was the degree of corticospinal tract fiber damage under different treatments. There was a significant improvement in the NIHSS Scale, BI and muscle strength scores in the HUK group compared with controls (Mann-Whitney U test; P  < 0.05). Diffusion tensor tractography classification and intracranial arterial stenosis were independent predictors of short-term recovery by linear regression analysis. The changes in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) decline rate were significantly smaller in the HUK group than in the control group ( P <  0.05). Vascular endothelial growth factor (VEGF) increased significantly after HUK treatment ( P  < 0.05), and the VEGF change was negatively correlated with changes in ADC. HUK is beneficial for the outcome in AIS patients especially in motor function recovery. It may have protective effects on the corticospinal tract which is reflected by the reduction in the FA and ADC decline rates and increased VEGF expression. The study was registered on ClinicalTrials.gov (unique identifier: NCT04102956).

Data on hematological parameters and generalized severe periodontitis in the United States.

This article describes an ensemble of datasets used to understand the relationship between generalized severe periodontitis and hematological parameters. This dataset combines public periodontal examination data, hematological parameters data, and demographic data from the National Center for Health Statistics from 2009 to 2014. The stage of periodontitis was identified by attachment loss conducted by dental examiners, who were dentists (D.D.S./ D.M.D.) licensed in at least one U.S. state, while matching current classification criteria from the American Academy of Periodontology and the European Federation of Periodontology. Based on the NHANES database, information on age, gender, education level (< 9th grade, 9-11th grade, high school, college, graduate), race/ethnicity (Mexican American, Hispanic, non-Hispanic White, non-Hispanic Black, and other races), PIR (poverty income ratio) were acquired from the demographic data. Hematological parameters (including HB, HCT, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, red cell distribution width, platelet count, mean platelet volume, and red blood cell count) and glucose data had been obtained from laboratory data. Smoking data had been obtained from questionnaire data.

Effect of endoscopic mucosal resection and endoscopic submucosal dissection on postoperative wound complications in patients with gastric cancer: A meta-analysis.

Endoscopic submucosa dissection (ESD) allows complete excision of the whole lesion, which results in a higher percentage of complete excision and an improved quality of life by minimizing the amount of excision as opposed to an endoscopic mucosal resection (EMR). Although ESD is now being carried out in the majority of hospitals, ESD's possible complications (such as trauma and perforation) have given rise to doubts about ESD practices in patients with early-stage stomach cancer when deciding on therapy and reimbursement. This study was designed to evaluate the effectiveness and safety of ESD over EMR in treating early-stage stomach cancer. Four main databases have been searched, including EMBASE and published. The ROBINS-I tool suggested in the Cochrane Handbook has been applied to evaluate the quality of the chosen trials. It may better reflect the risk of bias in the included studies. The meta-analyses were carried out with ReMan 5.3, and the results were treated with endote. Seven cohort studies have been completed. Meta analysis indicated that EMR and ESD surgery did not differ significantly from each other in terms of postoperative haemorrhage (OR, 0.76; 95%CI, 0.56,1.04 p = 0.09); EMR, however, was associated with a lower rate of postoperative perforation than ESD surgery (OR, 0.36; 95%CI, 0.24,0.54 p < 0.0001). Taking into account that ESD and EMR did not differ significantly in the risk of wound bleeding, even though the risk of perforation is not likely to result in life-threatening illness. In the analysis of these data, however, the potential advantages of EMR might be greater than ESD.

Molecular basis of threonine ADP-ribosylation of ubiquitin by bacterial ARTs.

Ubiquitination plays essential roles in eukaryotic cellular processes. The effector protein CteC from Chromobacterium violaceum blocks host ubiquitination by mono-ADP-ribosylation of ubiquitin (Ub) at residue T66. However, the structural basis for this modification is unknown. Here we report three crystal structures of CteC in complexes with Ub, NAD+ or ADP-ribosylated Ub, which represent different catalytic states of CteC in the modification. CteC adopts a special 'D-E' catalytic motif for catalysis and binds NAD+ in a half-ligand binding mode. The specific recognition of Ub by CteC is determined by a relatively separate Ub-targeting domain and a long loop L6, not the classic ADP-ribosylating turn-turn loop. Structural analyses with biochemical results reveal that CteC represents a large family of poly (ADP-ribose) polymerase (PARP)-like ADP-ribosyltransferases, which harbors chimeric features from the R-S-E and H-Y-E classes of ADP-ribosyltransferases. The family of CteC-like ADP-ribosyltransferases has a common 'D-E' catalytic consensus and exists extensively in bacteria and eukaryotic microorganisms.

Recurrent Cerebral Infarction Due to Moyamoya Disease Complicated With Systemic Lupus Erythematosus: A Case Report and Literature Review.

INTRODUCTION: We report a rare case of moyamoya disease caused by an RNF213 mutation, complicated with systemic lupus erythematosus. CASE REPORT: A 32-year-old woman experienced 4 cerebral ischemia stroke events within 6 months. The main symptom was left limb weakness with blurred vision in the right eye. Results of digital subtraction angiography conducted at another hospital were consistent with moyamoya disease. On genetic testing, we found that the patient carried 2 mutations in the moyamoya disease-related gene RNF213 (p.R4810K, p.T1727M). On the basis of the laboratory immunologic indicators, such as positive antibodies and abnormal immunoglobulin levels and imaging examinations, the patient was finally diagnosed as moyamoya disease complicated with systemic lupus erythematosus. She was treated with aspirin, butylphthalide, urinary kallidinogenase, and sodium methylprednisolone. CONCLUSIONS: This was a 32-year-old young patient diagnosed with moyamoya disease carrying RNF213 gene mutation and accompanied by lupus with cerebral ischemic event as the first occurrence. The patient's condition was complex; therefore, comprehensive analysis and in-depth consideration were needed to avoid a missed diagnosis and misdiagnosis. When the primary disease cannot be identified, genetic testing can help to clarify the diagnosis of moyamoya disease.

Comprehensive molecular findings in primary malignant melanoma of the esophagus: A multicenter study.

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture-based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co-occurred with KIT mutation and amplification. The most common pathways affected were the mitogen-activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression-free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32-19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22-15.30). Treatment with immune-checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01-0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs.

Unveiling the crucial role of iron mineral phase transformation in antimony(V) elimination from natural water.

Antimony (Sb) in natural water has long-term effects on both the ecological environment and human health. Iron mineral phase transformation (IMPT) is a prominent process for removing Sb(V) from natural water. However, the importance of IMPT in eliminating Sb remains uncertain. This study examined the various Sb-Fe binding mechanisms found in different IMPT pathways in natural water, shedding light on the underlying mechanisms. The study revealed that the presence of goethite (Goe), hematite (Hem), and magnetite (Mag) significantly affected the concentration of Sb(V) in natural water. Elevated pH levels facilitated higher Fe content in iron solids but impeded the process of removing Sb(V). To further our understanding, polluted natural water samples were collected from various locations surrounding Sb smelter sites. Results confirmed that converting ferrihydrite (Fhy) to Goe significantly reduced Sb levels (<5 µg/L) in natural water. The emergence of secondary iron phases resulted in greater electrostatic attraction and stabilized surface complexes, which was the most likely cause of the decline of Sb concentration in natural water. The comprehensive findings offer new insights into the factors governing IMPT as well as the Sb(V) behavior control.

Housing Environmental Factors Driving Falls Among Middle-Aged and Older Adults: A National Cohort Study.

Background and Objectives: Housing is one of the main places where falls occur; however, few studies have examined housing environmental factors driving fall risk. This study aimed to explore the associations between housing environmental factors and falls in China. Research Design and Methods: The study included data of middle-aged and older adults aged ≥45 years from 4 waves of the China Health and Retirement Longitudinal Study. We assessed 7 housing environmental factors: building materials, toilet types, household tidiness, household cooking fuels, and access to electricity, running water, and bathing facilities. Based on these, we divided housing environments into 3 types: good (0-2 poor factors), moderate (3-5 poor factors), and poor (6-7 poor factors). Falls incidence (yes or no) was self-reported during the survey period. We applied the Cox proportional hazard model to estimate the associations, adjusting for a set of covariates such as sociodemographic characteristics, lifestyles, and disease status. Results: A total of 12,382 participants were analyzed, and the incidence of falls was 31.7%. According to the fully adjusted model, having a squatting toilet (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.03-1.26), household untidiness (HR = 1.09, 95% CI = 1.01-1.18), and solid fuel use for cooking (HR = 1.10, 95% CI = 1.02-1.18) were associated with a higher risk of falls (ps < .05), compared to their counterparts. We found a linear relationship between housing environments and falls (p for trend = .001). Specifically, moderate (HR = 1.16, 95% CI = 1.06-1.27) and poor housing environments (HR = 1.21, 95% CI = 1.08-1.34) were associated with a higher risk of falls compared to a good housing environment. Discussion and Implications: Among middle-aged and older Chinese adults, a better household environment, including sitting toilets, tidy living conditions, and clean fuel use for cooking, may reduce the risk of falls. The evidence from our study suggests the need to implement age-friendly housing environments to prevent falls and disability in an aging society.

Dietary rumen-protected L-arginine or N-carbamylglutamate enhances placental amino acid transport and suppresses angiogenesis and steroid anabolism in underfed pregnant ewes.

This study aimed to investigate the effects of dietary supplementation of underfed Hu ewes from d 35 to 110 of gestation with either rumen-protected L-arginine (RP-Arg) or N-carbamylglutamate (NCG) on placental amino acid (AA) transport, angiogenic gene expression, and steroid anabolism. On d 35 of gestation, 32 Hu ewes carrying twin fetuses were randomly divided into four treatment groups, each consisting of eight ewes, and were fed the following diets: A diet providing 100% of NRC's nutrient requirements for pregnant ewes (CON); A diet providing 50% of NRC's nutrient requirements for pregnant ewes (RES); RES diet plus 5 g/d NCG (RES + NCG); or RES diet plus 20 g/d RP-Arg (RES + ARG). On the d 110 of pregnancy, blood samples were taken from the mother, and samples were collected from type A cotyledons (COT; the fetal portions of the placenta). The levels of 17ß-estradiol and progesterone in the maternal serum and both the capillary area density (CAD) and capillary surface density (CSD) in type A COT were decreased in response to Arg or NCG supplementation when compared to the RES group. The concentrations of arginine, leucine, putrescine and spermidine in type A COT were higher (P < 0.05) in the RES + ARG or RES + NCG group than in the RES group. The mRNA expression levels of inducible nitric oxide synthase (iNOS) and solute carrier family 15, member 1 (SLC15A1) were increased (P < 0.05) while those of progesterone receptor (PGR) and fibroblast growth factor 2 (FGF2) were decreased in type A COT by supplementation with either NCG or RP-Arg compared to the RES group. The results suggest that providing underfed pregnant ewes from d 35 to 110 of gestation with a diet supplemented with NCG or RP-Arg improves placental AA transport, and reduces the expression of angiogenic growth factor genes and steroid anabolism, leading to better fetal development.

The mitochondrial energy metabolism pathway-related signature predicts prognosis and indicates immune microenvironment infiltration in osteosarcoma.

BACKGROUND: Abnormalities in the mitochondrial energy metabolism pathways are closely related to the occurrence and development of many cancers. Furthermore, abnormal genes in mitochondrial energy metabolism pathways may be novel targets and biomarkers for the diagnosis and treatment of osteosarcoma. In this study, we aimed to establish a mitochondrial energy metabolism-related gene signature for osteosarcoma prognosis. METHODS: We first obtained differentially expressed genes based on the metastatic status of 84 patients with osteosarcoma from the TARGET database. After Venn analysis of differentially expressed genes and mitochondrial energy metabolism pathway-related genes (MMRGs), 2 key genes were obtained using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Next, we used these 2 genes to establish a prognostic signature. Subsequent analyses elucidated the correlation between these 2 key genes with clinical features and 28 types of immune cells. Pathway changes in osteosarcoma pathogenesis under different metastatic states were clarified using gene set enrichment analysis (GSEA) of differentially expressed genes. RESULTS: A gene signature composed of 2 key prognosis-related genes (KCNJ5 and PFKFB2) was identified. A risk score was calculated based on the gene signature, which divided osteosarcoma patients into low- or high-risk groups that showed good and poor prognosis, respectively. High expression of these 2 key genes is associated with low-risk group in patients with osteosarcoma. We constructed an accurate nomogram to help clinicians assess the survival time of patients with osteosarcoma. The results of immune cell infiltration level showed that the high-risk group had lower levels of immune cell infiltration. GSEA revealed changes in immune regulation and hypoxia stress pathways in osteosarcoma under different metastatic states. CONCLUSION: Our study identified an excellent gene signature that could be helpful in improving the prognosis of patients with osteosarcoma.

Supporting and retaining competent primary care workforce in low-resource settings: lessons learned from a prospective cohort study.

OBJECTIVE: Assess whether local health facilities can adequately support the performance of general practitioners (GPs) trained by China's national compulsory services programme (CSP). DESIGN: Prospective cohort study. SETTING: Health facilities in middle and western rural areas in China, 2015-2022. PARTICIPANTS: Cohorts of CSP graduates from 2015 to 2019 in four major medical universities. MAIN OUTCOMES: Job performance measured by a 12-item Job Performance Scale; productivity measured by outpatient volume per day; turnover measured by ever changing jobs within the past year. RESULTS: 91.2%, 92.0% and 90.5% GPs working in township health centres reported inadequate medication, equipment and external assistance from higher level hospitals, while CSP graduates working in secondary or tertiary hospitals reported a lower rate of less than 60%. The top three tests reported as lacking were blood gases (67.7%), microbiology (61.6%) and cancer biomarkers (49.7%); the top three lacked procedures were CT scan (64.8%), MRI scan (58.1%) and ambulatory BP monitoring (55.8%); and the top three lacked drugs were drugs for cardiovascular diseases (23.3%), systematic hormonal preparations (17.7%) and traditional Chinese medicines (13.0%). Multivariable analysis showed that facility support was positively associated with job performance-adequate medication increased job performance by 2.2 points (95% CI 0.7 to 3.8), and adequate external assistance increased job performance by 3.3 points (95% CI 1.8 to 4.8). Facility support was also positively associated with productivity-adequate medication increased outpatients seen per day by 20% (95% CI 0.1 to 0.3), and adequate equipment increased outpatients seen per day by 12% (95% CI 0.0 to 0.2). Facility support did not have significant impact on turnover, but GPs who changed jobs in the past year were 1.9-2.3 times more likely to report adequate facility support. CONCLUSION: GPs in township health centres experienced a high prevalence of shortage in facility support. The identification of a positive association between facility support and performance and productivity has implications for future research and resources deployment in primary healthcare.

The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium.

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in bidirectional crosstalk between pancreatic tumor epithelium and TME and results in a pro-|tumorigenic contexture.

Thiol-Based Modification of MarR Protein VnrR Regulates Resistance Toward Nitrofuran in Vibrio cholerae By Promoting the Expression of a Novel Nitroreductase VnrA and of NO-Detoxifying Enzyme HmpA.

Aims: Epidemiological investigations have indicated low resistance toward nitrofuran in clinical isolates, suggesting its potential application in the treatment of multidrug-resistant bacteria. Therefore, it is valuable to explore the mechanism of bacterial resistance to nitrofuran. Results: Through phenotypic screening of ten multiple antibiotic resistance regulator (MarR) proteins in Vibrio cholerae, we discovered that the regulator VnrR (VCA1058) plays a crucial role in defending against nitrofuran, specifically furazolidone (FZ). Our findings demonstrate that VnrR responds to FZ metabolites, such as hydroxylamine, methylglyoxal, hydrogen peroxide (H2O2), ß-hydroxyethylhydrazine. Notably, VnrR exhibits reversible responses to the addition of H2O2 through three cysteine residues (Cys180, Cys223, Cys247), leading to the derepression of its upstream gene, vnrA (vca1057). Gene vnrA encodes a novel nitroreductase, which directly contributes to the degradation of FZ. Our study reveals that V. cholerae metabolizes FZ via the vnrR-vnrA system and achieves resistance to FZ with the assistance of the classical reactive oxygen/nitrogen species scavenging pathway. Innovation and Conclusion: This study represents a significant advancement in understanding the antibiotic resistance mechanisms of V. cholerae and other pathogens. Our findings demonstrate that the MarR family regulator, VnrR, responds to the FZ metabolite H2O2, facilitating the degradation and detoxification of this antibiotic in a thiol-dependent manner. These insights not only enrich our knowledge of antibiotic resistance but also provide new perspectives for the control and prevention of multidrug-resistant bacteria.