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Abstract Emergency capability assessment is a complex system with multiple factors, variables and levels. Incomplete and uncertain assess information often occurs during assessment. Based on this, a method combining D-number theory and fuzzy analytic Hierarchy process (FAHP) is proposed to study the emergency capacity of coal enterprises in Longdong area. On the basis of analyzing the limitation of D-S evidence theory, the D-number theory was optimized and improved. According to the principles of systematicness, feasibility, scientificity and timeliness, a hierarchical structure model of enterprise emergency capability assessment was constructed from the perspective of pre-incident, mid-incident and post-incident, which consisted of 4 first-level indicators and 18 s-level indicators. The weight and importance of the assessment index of emergency response capability are calculated by organically integrating the D-number preference relation with the hierarchy structure. Combined with the assessment results of experts, a quantitative analysis and evaluation of the emergency response capacity of a coal enterprise was conducted by using FAHP. The comprehensive score of the enterprise's emergency response capability was 80.45, and the level of emergency response capacity was "good". The research results show that the D-FAHP method has high reliability in evaluating the emergency response capability of coal enterprises, avoiding the impact of uncertain and incomplete information on the assessment results. This can not only effectively identify the weak links in emergency management, but also meet the emergency decision-making needs of enterprises in the emergency state, which has important guiding significance to improve the ability and level of enterprise emergency management.

Sickle cell disease (SCD) is a pathophysiological condition of chronic hemolysis, oxidative stress, and elevated inflammation. The transcription factor Nrf2 is a master regulator of oxidative stress. Here, we report that the FDA-approved oral agent simvastatin, an inhibitor of hydroxymethyl-glutaryl coenzyme A reductase, significantly activates the expression of Nrf2 and antioxidant enzymes. Simvastatin also induces fetal hemoglobin expression in SCD patient primary erythroid progenitors and a transgenic mouse model. Simvastatin alleviates SCD symptoms by decreasing hemoglobin S sickling, oxidative stress, and inflammatory stress in erythroblasts. Particularly, simvastatin increases cellular levels of cystine, the precursor for the biosynthesis of the antioxidant reduced glutathione, and decreases the iron content in SCD mouse spleen and liver tissues. Mechanistic studies suggest that simvastatin suppresses the expression of the critical histone methyltransferase enhancer of zeste homolog 2 to reduce both global and gene-specific histone H3 lysine 27 trimethylation. These chromatin structural changes promote the assembly of transcription complexes to fetal γ-globin and antioxidant gene regulatory regions in an antioxidant response element-dependent manner. In summary, our findings suggest that simvastatin activates fetal hemoglobin and antioxidant protein expression, modulates iron and cystine/reduced glutathione levels to improve the phenotype of SCD, and represents a therapeutic strategy for further development.

Background Circular RNAs (circRNAs) have been closely implicated in competing endogenous RNA (ceRNA) network among human cancers including non‐small cell lung cancer (NSCLC). However, the role of most circRNAs in NSCLC remains to be determined. Here, we aimed to investigate the role of hsa_circ_0007385 (circ_0007385) in NSCLC cells. Methods Expression of hsa_circ_0007385 (circ_0007385), miRNA (miR)‐519d‐5p and high‐mobility group box 1 (HMGB1) was measured by real‐time quantitative PCR and western blotting. Functional experiments were evaluated by cell counting kit (CCK)‐8, flow cytometry, fluorescein active caspase‐3 staining kit, transwell assays, western blotting, and xenograft experiment. The relationship among circ_0007385,miR‐519d‐5p and HMGB1 was testified by dual‐luciferase reporter assay. Kaplan‐Meiersurvival curve identified overall survival in NSCLC patients. Results circ_0007385 expression was higher in NSCLC tissues and cell lines, and was associated with poor overall survival. Silencing circ_0007385 could suppress cell proliferation, migration and invasion in A549 and H1975 cells, as well as cisplatin (DDP) resistance. Moreover, circ_0007385 silence retarded tumor growth of A549 cells in vivo. Molecularly, there was a direct interaction between miR‐519d‐3p and either circ_0007385 or HMGB1; expression of miR‐519d‐3p was downregulated in NSCLC tumors in a circ_0007385‐correlated manner, and circ_0007385 could indirectly regulate HMGB1 via miR‐519d‐3p. Functionally, both inhibiting miR‐519d‐3p and restoring HMGB1 could overturn the suppressive effect of circ_0007385 knockdown on cell proliferation, migration, invasion, and DDP resistance. Conclusions Collectively, circ_0007385 deletion could function anti‐tumor role in NSCLC by suppressing malignant behaviors and DDP resistance in vitro and in vivo via circ_0007385/miR‐519d‐3p/HMGB1 axis. These outcomes might enhance our understanding of the molecular mechanisms underlying the malignant progression of NSCLC. Key points Significant findings of the study circ_0007385 was upregulated in NSCLC tissues and cells, and was associated with poor overall survival. Silenced circ_0007385 suppressed NSCLC cell proliferation, migration, invasion, and DDP resistance in vitro, and tumor growth in vivo. circ_0007385 was upregulated in NSCLC tissues and cells, and was associated with poor overall survival. What this study adds miR‐519d‐3p could directly interact with circ_0007385 and HMGB1 in NSCLC cells. A promising circ_0007385/miR‐519d‐3p/HMGB1 regulatory pathway was determined in NSCLC cells.

Reducing cadmium (Cd) accumulation in wheat is an effective way to decrease the potential threats of Cd to human health. The application of lanthanum (La) in agricultural fields is eliciting extensive attention due to its beneficial effects on improving yields and inhibiting Cd accumulation in edible parts of crops. However, the potential mechanism of La-restricted Cd accumulation in crop grains is not entirely understood. Here, we investigated the effects of La and Cd accumulation in wheat grains by implementing application at the shooting and heading stages. Some associated mechanisms were explored. Results showed that La application at the shooting and heading stages considerably promoted the thousand-grain weight. La application at the shooting and heading stages increased Cd accumulation in the first node beneath the panicle (N1) but reduced Cd levels in the other tissues. La application at the heading stage exerted greater effects on Cd storage in N1 while reducing Cd concentrations in the other tissues compared with La application at the shooting stage. La addition substantially decreased the translocation of Cd from the lower nodes to the upper internodes, but increased Cd translocation from the lower internodes to the upper nodes. The expression of TaZIP7 in N1 was downregulated by La treatment. These results suggest that the effective reduction in Cd in wheat grains by La application at the heading stage is probably a consequence of the successful promotion of Cd storage in nodes by downregulating the expression of TaZIP7 during the grain-filling stage, thereby hindering the redirection Cd from nodes to grains.

BackgroundA proper evaluation on the intention of using nutrition label in patients with coronary heart disease (CHD) is crucial to design and formulate of behavior-based interventions. A valid and reliable instrument based on theoretical basis is needed to measure individual intention toward nutrition label use and identify underlying socio-cognitive factors.ObjectTo develop and test validity and reliability of the theoretically based nutrition label use (NLU) scale and to promote the use of nutrition labels in CHD patients.MethodsA questionnaire was developed based on the theory of planned behavior (TPB), empirical literatures, expert review and pilot tested. A total of 460 CHD patients in a hospital in Changsha were investigated using this questionnaire from April 2021 to August 2021. The items and dimensions in the scale were explored and confirmed using item-analysis, content validity, exploratory factor analytical (EFA), confirmatory factor analytical (CFA), internal consistency and split-half reliability tests.ResultsA total of 33 items with 4 structural factors were identified, including 10 items of attitude, 6 items of subjective norm, 12 items of perceived behavior control, and 5 items of intention. The total variance explained by the EFA model was 68.563%. The model was further tested with CFA. The measurement model fitted the data well (Ratio of chi-square minimum and degree of freedom (CMIN/DF) =1.743, goodness of fit index (GFI) =0.814, incremental fit index (IFI) =0.946, Tuker-Lewis index (TLI) =0.940, the comparative fit index (CFI) =0.945, the root mean square error of approximation (RMSEA) =0.057). The content validation index (CVI) of the scale was 0.82, and the CVI of the items ranged from 0.8 to 1.00. The reliability of the scale was 0.976 (p

In this study, authors identified neutralizing antibodies by isolating B cells from SARS-CoV-2 Delta infected patients and detect altered structural features, likely introduced by somatic hypermutation, that are involved in epitope binding and increase neutralization breadth against virus variants.

Abstract Background To evaluate the effectiveness of enhanced check to the duration of the central venous catheters associated bloodstream infections (CABSIs), and the impact on infection rates. Methods A before-after, real-world study in six adult intensive care units was conducted. All adult patients who had only one central venous catheter were included during two consecutive periods. The intervention period, added cross-check that all patients with central venous catheter (CVC) need to be performed, and included nurses' checks for insertion practices and doctors' checks for maintenance practices. Propensity scores matching were used to account for potential confounding, and restricted cubic spline was served as visualizing the CABSI risk. Results A total of 2906 patients with 26,157 CVC-days were analyzed. After intervention, the density incidence of CABSI decreased from 10.24 to 6.33/1,000 CVC-days (P

ObjectiveThe relationship between excessive daytime sleepiness (EDS) and cognitive performance of older adults remains unclear, especially when a healthy lifestyle is considered. The study aimed to explore the association between EDS in passive and active situations and general cognitive function among community-dwelling older adults.MethodsTwo hundred and seventy-one older adults aged 60 and above were recruited from the community cohort in Shangrao. All study participants were free of depression and dementia. The Chinese version of the Epworth Sleepiness Scale (CESS) was used to evaluate EDS. Using the item scores of CESS, the presence of EDS among all study participants were grouped as non-EDS, passive situation-related EDS (PSR-EDS), active situation-related EDS (ASR-EDS), and high sleep propensity (HSP). The Hong Kong Brief Cognitive Test (HKBC) was used to assess cognitive function. Chinese healthy lifestyle metrics were scored based on AHA Life Simple-7. The multivariate logistic regression model was used to estimate the association between the presence of EDS and cognitive function.ResultsThe PSR-EDS (n = 29, 20.8 ± 5.3) and the HSP groups (n = 21, 19.8 ± 4.8) scored lower with HKBC than in the non-EDS group (n = 213, 23.2 ± 4.9). The subdomain performance of language in the HSP group was poorer than in the non-EDS group (ps < 0.05). Relative to non-EDS, HSP (OR = 3.848, 95% CI = 1.398-10.591) was associated with an increased risk of poor cognitive performance after adjusting age, sex, education, and healthy lifestyle metrics.ConclusionHigh propensity for excessive daytime sleepiness, irrespective of lifestyle, is associated with poorer cognitive performance among community-dwelling older adults. The findings may provide empirical evidence to support sleepiness intervention for reducing the risk of cognitive decline.

Abstract Alkali metal–carbon dioxide (Li/Na/K‐CO2) batteries are emerging electrochemical energy storage technologies in the context of the energy crisis and the urgent demand for carbon neutrality. Alkali metal–CO2 batteries offer a new strategy for CO2 fixation and utilization, and thus has been receiving considerable attention in recent years. Considerable progress has been achieved since alkali metal–CO2 batteries were invented, especially in terms of development of new electrode materials, and yet, research is lacking on the underlying mechanisms of the systems. This is the first typical review focusing on the electrochemical mechanisms of metal–CO2 batteries that summarizes the current understanding of and provides insights into the thermodynamic reaction pathways, the kinetic characteristics, and the crucial factors determining the reaction mechanisms in alkali metal–CO2 batteries. The review starts with the fundamental concepts of alkali metal–CO2 batteries, followed by a comprehensive discussion of the working mechanisms on cathodes and anodes. Moreover, the operation mechanisms of state‐of‐the‐art electrolytes, including liquid and (quasi‐)solid‐state electrolytes, are also described. Finally, we identify the unsolved problems in current alkali metal–CO2 batteries and propose potential topics for future research.

Abstract Aims This study explores the current occupational well‐being status of male nurses in Chengdu, China, and identifies the concomitant protective and risk factors. Design This study has a cross‐sectional survey design. Methods From 13 July to 21 July 2019, a cross‐sectional survey involving 209 male nurses in 7 tertiary hospitals in Chengdu, China, was conducted using a general information questionnaire, the Mindfulness Attention Awareness Scale, the Acceptance and Action Questionnaire‐II, the Professional Identity Scale and the Nurses' Occupational Well‐being Scale. Results The score of male nurses' occupational well‐being was 78.7 ± 14.2. The higher the mindfulness and professional identity (p = .002, p

Abstract Background The prevention of peripherally inserted central catheters (PICC)-associated BSI and central venous catheters (CVC)-associated BSI have been a topic of national importance in China. Therefore, we aimed to explore the epidemiological characteristics of central line-associated bloodstream infection (CLABSI), and to evaluate whether PICCs were associated with a protective effect for CLABSI. Methods A retrospective cohort study was conducted in teaching hospital in Western China. All adult patients received a CVC or PICC during their hospital stay were included from January 2017 to December 2020. Primary endpoint was CLABSI up to 30 days after CVC or PICC placement. Propensity scores with a 2:1 match was used to account for potential confounders, and restricted cubic spline was used to visualize the risk of CLABSI at different time points during the catheterization. Results A total of 224687 devices (180522 PICCs and 45965 CVCs) in 24879 patients were included. The overall incidence was 1.8 CLABSIs per 1000 catheter-days. The odds ratio (OR) value increased day by day after PICC insertion, reached a relatively high point on the 4th day, and decreased from days 5 through 8. From the 9th day of intubation the OR value began to gradually increase day by day again. After covariate adjustment using propensity scores, CVCs were associated with higher risk of CLABSI (adjHR = 3.27, 95% CI 2.38–4.49) compared with PICCs. Conclusions PICCs have a protective role and the effect of fluctuation curve feature in CLABSI when compared to CVCs, and the first 8 calendar days after CVC insertion are the acute stage of CVC-associated BSI.

Introduction: The correct pairing and separation of homologous chromosomes during meiosis is crucial to ensure both genetic stability and genetic diversity within species. In allodiploid organisms, synapsis often fails, leading to sterility. However, a gynogenetic allodiploid hybrid clone line (GDH), derived by crossing red crucian carp (Carassius auratus ♀) and common carp (Cyprinus carpio ♂), stably produces diploid eggs. Because the GDH line carries 100 chromosomes with 50 chromosomes from the red crucian carp (RCC; ♀, 2n = 2x = 100) and 50 chromosomes from the common carp (CC; C. carpio L., ♂, 2n = 2x = 100), it is interesting to study the mechanisms of homologous chromosome pairing during meiosis in GDH individuals.Methods: By using fluorescence in situ hybridization (FISH) with a probe specific to the red crucian carp to label homologous chromosomes, we identified the synaptonemal complex via immunofluorescence assay of synaptonemal complex protein 3 (SCP3).Results: FISH results indicated that, during early ovarian development, the GDH oogonium had two sets of chromosomes with only one set from Carassius auratus, leading to the failure formation of normal bivalents and the subsequently blocking of meiosis. This inhibition lasted at least 5 months. After this long period of inhibition, pairs of germ cells fused, doubling the chromosomes such that the oocyte contained two sets of chromosomes from each parent. After chromosome doubling at 10 months old, homologous chromosomes and the synaptonemal complex were identified.Discussion: Causally, meiosis proceeded normally and eventually formed diploid germ cells. These results further clarify the mechanisms by which meiosis proceeds in hybrids.

BackgroundBeing a nurse with non-altruistic orientation exists and altruism decline is being challenged as never before, which would be a disaster for medicine if left unnoticed.PurposeTo describe the meaning of altruism and altruistic behaviors in nursing, and to discuss dilemmas we face today.MethodCochrane, PROSPERO, PubMed, Web of Science, CINAHL, Scopus, Embase, ProQuest, and CNKI were searched for original research published in English or Chinese from 2012 to February 2022.ResultsBy screening 13 studies came from 12 different countries described altruism and altruistic behavior together were included in. Altruism has been described as value, vocation, or professionalism in nursing which can reflect nurses' compassion, level of expertise, and quality of care. Altruistic nursing care, body donation, financial endowment, volunteering, sharing, benefiting patients maximum, and helping colleagues represented most of the altruistic behaviors in nursing. There is a vacant that not any assessment tool designed for measuring altruism in nurse groups. Interventions from curriculums in class and support of organizations with psychological methods could be helpful to improve the nurses' level of altruism.ConclusionAltruism and altruistic behaviors in the past decades were described. A new concept of altruism in nursing was proposed based on the original meaning and the current changes, and interventions for promoting altruism and some of the dilemmas faced today were synthesized.

The basic leucine zipper transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a critical role in the cellular antioxidant response under oxidative stress conditions. In this study, we investigated the role of NRF2 in fetal hemoglobin expression and the pathophysiology of sickle cell disease (SCD) in a NRF2 knockout (SCD/NRF2-/-) transgenic mouse model. NRF2 loss impaired survival of SCD pups during gestation and in the first 2 months of life. Furthermore, fetal hemoglobin expression was inhibited during erythropoiesis in embryonic day 13.5 and embryonic day 18.5 fetal liver and adult spleen and bone marrow cells, respectively. Examination of peripheral red blood cells revealed an increase of reactive oxygen species (ROS) and sickling under hypoxic conditions. Loss of NRF2 function in SCD/NRF2-/- mice produced greater splenomegaly with red pulp expansion and obscured architecture. In addition, NRF2 knockout reduced the expression of its target antioxidant proteins, leading to increased levels of ROS, proinflammatory cytokines, and adhesion molecules in SCD mice. Genetic knockout of NRF2 demonstrates its role in developmentally regulated g-globin gene expression and the ability to control oxidative stress and the phenotypic severity of SCD. [ABSTRACT FROM AUTHOR]

BackgroundThe COVID-19 pandemic has spread across the world. Nurses have inevitably been influenced by it.PurposeTo investigate the prevalence and influencing factors of psychological distress among nurses in Sichuan, China over the COVID-19 outbreak.MethodsThis study used a cross-sectional survey design. Thousand eight hundred and seventy nurses who worked in COVID-19-designated hospitals participated in the study during the pandemic. Data was collected online between February 8 and February 13, 2020. The self-designed General Information Questionnaire, the General Health Questionnaire-12, the Perception of Hospital Safety Climate Scale, and the Simplified Coping Style Questionnaire were used. The binomial logistic regression model was applied to assess the association between psychological distress and potential explanatory variables.FindingsAt the beginning of the epidemy of the COVID-19 outbreak, 12% of nurses were found to experience psychological distress. The main influencing factors were personal precautionary measures at work, discomfort caused by protective equipment, perception of the hospital safety climate, coping style, and professional title.ConclusionsIn the pandemic, wearing protective equipment correctly, a safe hospital climate, and positive coping style for nurses could be beneficial for nurses' mental health. Nurse managers should take measures to build a safe hospital climate.

Prostate cancer (PCa) is one of the most common male malignancies with frequent remote invasion and metastasis, leading to high mortality. Epithelial-mesenchymal transition (EMT) is a fundamental process in embryonic development and plays a key role in tumor proliferation, invasion and metastasis. Numerous long non-coding RNAs (lncRNAs) could regulate the occurrence and development of EMT through various complex molecular mechanisms involving multiple signaling pathways in PCa. Given the importance of EMT and lncRNAs in the progression of tumor metastasis, we recapitulate the research progress of EMT-related signaling pathways regulated by lncRNAs in PCa, including AR signaling, STAT3 signaling, Wnt/β-catenin signaling, PTEN/PI3K/AKT signaling, TGF-β/Smad and NF-κB signaling pathways. Furthermore, we summarize four modes of how lncRNAs participate in the EMT process of PCa via regulating relevant signaling pathways.

A simple method has been developed for the synthesis of ­3-(2-oxo-2-phenylethylidene)-3,4-dihydroquinoxalin-2(1H)-one and ­3-aryl-quinoxalin-2(1H)-one derivatives through C–H activation of quinoxalin-2(1H)-ones by peroxides and iodide. In this protocol, the per­oxide (TBPB) serves as both the radical initiator and aryl source, realizing arylation of quinoxalin-2(1H)-one in a one-step reaction. The methodology has the advantages of being a metal-free strategy and having broad functional group tolerance.

Abstract Background The association between allogeneic blood transfusion and healthcare-associated infection (HAI) is considered dose-dependent. However, this association may be confounded by transfusion duration, as prolonged hospitalization stay increases the risk of HAI. Also, it is not clear whether specific blood products have different dose–response risks. Methods In this retrospective cohort study, a logistic regression was used to identify confounding factors, and the association between specific blood products and HAI were analyzed. Then Cox regression and restricted cubic spline regression was used to visualize the hazard of HAI per transfusion product. Results Of 215,338 inpatients observed, 4.16% were transfused with a single component blood product. With regard to these transfused patients, 480 patients (5.36%) developed a HAI during their hospitalization stay. Logistic regression showed that red blood cells (RBCs) transfusion, platelets transfusion and fresh-frozen plasmas (FFPs) transfusion were risk factors for HAI [odds ratio (OR) 1.893, 95% confidence interval (CI) 1.656–2.163; OR 8.903, 95% CI 6.646–11.926 and OR 1.494, 95% CI 1.146–1.949, respectively]. However, restricted cubic spline regression analysis showed that there was no statistically dose–response relationship between different transfusion products and the onset of HAI. Conclusions RBCs transfusion, platelets transfusion and FFPs transfusion were associated with HAI, but there was no dose–response relationship between them.

Abstract Aqueous zinc-based batteries (AZBs) attract tremendous attention due to the abundant and rechargeable zinc anode. Nonetheless, the requirement of high energy and power densities raises great challenge for the cathode development. Herein we construct an aqueous zinc ion capacitor possessing an unrivaled combination of high energy and power characteristics by employing a unique dual-ion adsorption mechanism in the cathode side. Through a templating/activating co-assisted carbonization procedure, a routine protein-rich biomass transforms into defect-rich carbon with immense surface area of 3657.5 m2 g−1 and electrochemically active heteroatom content of 8.0 at%. Comprehensive characterization and DFT calculations reveal that the obtained carbon cathode exhibits capacitive charge adsorptions toward both the cations and anions, which regularly occur at the specific sites of heteroatom moieties and lattice defects upon different depths of discharge/charge. The dual-ion adsorption mechanism endows the assembled cells with maximum capacity of 257 mAh g−1 and retention of 72 mAh g−1 at ultrahigh current density of 100 A g−1 (400 C), corresponding to the outstanding energy and power of 168 Wh kg−1 and 61,700 W kg−1. Furthermore, practical battery configurations of solid-state pouch and cable-type cells display excellent reliability in electrochemistry as flexible and knittable power sources.

Hybridization is a traditional and effective strategy to alter the genotypes and phenotypes of the offspring, and distant hybridization is a useful strategy to generate polyploids in fish. In this study, goldfish (Carassius auratus, GF, 2n = 100) and Bleeker’s yellow tail (Xenocypris davidi Bleeker, YT, 2n = 48), which belong to different subfamilies, were crossed with each other. The cross of female GF × male YT successfully obtained hybrid offspring (GFYT hybrids), while the cross of female YT × male GF was lethal, and all the fertilized eggs stopped developing before the neurula stage of embryogenesis. All GFYT hybrids possessed 124 chromosomes (3n = 124) with two sets from GF and one set from YT. The measurable and countable traits of GFYT hybrids were identified, and the genetic characteristics of 5S rDNA between GFYT hybrids and their parents were also revealed. There were, respectively, four and three different 5S rDNA types in GF (assigned as GF-Ⅰ∼Ⅳ) and YT (assigned as YT-Ⅰ∼Ⅲ), and GFYT hybrids specifically inherited YT-Ⅰ and YT-Ⅱ 5S rDNA types from YT and GF-Ⅲ and GF-Ⅳ from GF. In addition, there were only testis-like and fat-like gonads been found in GFYT hybrids. Interestingly, there were pyknotic and heteromorphous chromatin and invaginated cell membrane observed in the spermatids of testis-like gonads, but no mature sperm were found. Furthermore, TUNEL assays indicated that, compared with control, apparent apoptotic signals, which were mainly distributed around spermatid regions, were detected in the testis-like gonads, and the expression of apoptosis pathway-related genes including p53, bcl-2, bax, and caspase9 was significantly upregulated. Moreover, the expression of meiosis-related genes including spo11, dmc1, and rad51 showed an abnormally high expression, but mns1 and meig1, two key genes involved in the maturation of spermatid, were extremely downregulated. In brief, this is the first report of allotriploid via distant hybridization between GF and YT that possessing different chromosome numbers in vertebrates. The obtainment of GFYT hybrids not only harbors potential benefits and application in aquaculture but also further extends the understanding of the influence of hybridization and polyploidization on the genomic constitution of the hybrid offspring. Furthermore, they can be used as a model to test the origin and consequences of polyploidization and served as a proper resource to study the underlying mechanisms of spermatogenesis dysfunctions.

Abstract Background MiR-199a-3p (miR-199a) can enhance the chemosensitivity of hepatocellular carcinoma (HCC). Because of the easy degradation of miRNA by direct infusion, effective vehicle-mediated delivery of miR-199a may represent a new strategy for improving HCC chemotherapy. Considering mesenchymal stem cell (MSC)-derived exosomes as promising natural nanovectors for drug and molecule delivery, we aimed to determine whether exosomes from adipose tissue-derived MSCs (AMSCs) could be used to deliver miR-199a and improve HCC chemosensitivity. Methods MiR-199a-modified AMSCs (AMSC-199a) were constructed by miR-199a lentivirus infection and puromycin selection. MiR-199-modified exosomes (AMSC-Exo-199a) were isolated from the supernatant of AMSC-199a and were assessed by transmission electron microscopy, nanoparticle tracking analysis, and flow cytometry analysis. The expression levels of miR-199a in HCC samples, AMSCs, exosomes, and HCC cells were quantified by real-time PCR. The effects of AMSC-Exo-199a on HCC chemosensitivity were determined by cell proliferation and apoptosis assays and by i.v. injection into orthotopic HCC mouse models with doxorubicin treatment. MTOR, p-4EBP1 and p-70S6K levels in HCC cells and tissues were quantified by Western blot. Results AMSC-Exo-199a had the classic characteristics of exosomes and could effectively mediate miR-199a delivery to HCC cells. Additionally, AMSC-Exo-199a significantly sensitized HCC cells to doxorubicin by targeting mTOR and subsequently inhibiting the mTOR pathway. Moreover, i.v.-injected AMSC-Exo-199a could distribute to tumor tissue and markedly increased the effect of Dox against HCC in vivo. Conclusions AMSC-Exo-199a can be an effective vehicle for miR-199a delivery, and they effectively sensitized HCC to chemotherapeutic agents by targeting mTOR pathway. AMSC-Exo-199a administration may provide a new strategy for improving HCC chemosensitivity.

BackgroundPost-stroke fatigue (PSF) is a frequent complication of stroke. Serum uric acid (SUA) is frequently thought to be a risk factor for stroke. This study aimed to investigate whether SUA also played a role in PSF.MethodsSubjects with ischemic stroke were screened from The First Affiliated Hospital of Wenzhou Medical University between January 2020 and October 2020. Patients' fatigue symptoms were assessed by the Fatigue severity scale (FSS). To investigate the relationship between SUA and PSF, binary logistic regression analysis was conducted, with the confounders being controlled. SUA levels were divided into four layers (Q1 ≤ 245 μmol/L; Q2 246–308 μmol/L; Q3 309–365 μmol/L; Q4 ≥366 μmol/L) based on the quartiles.ResultsSUA levels were significantly higher in the PSF group (345.96 ± 73.78 μmol/L) than the non-PSF group (295.97 ± 87.8 μmol/L, P < 0.001). There were no differences in any other variables between these two groups. After adjusting the confounders, the risk of PSF in the Q4 layer (≥366 μmol/L) was 6.05 times (95% CI 1.79–20.43, P = 0.004) higher than that in Q1 (≤245 μmol/L).ConclusionHigh SUA at admission was an independent risk factor for fatigue 1 year after stroke onset. High SUA (≥366 μmol/L) during stroke deserves more attention, and active control of high SUA levels may be beneficial to reduce the incidence of PSF in the chronic stage following stroke.

WRKYs play important roles in plant metabolism, but their regulation mechanism in Rehmannia glutinosa remains elusive. In this study, 37 putative WRKY transcription factors (TFs) with complete WRKY domain from R. glutinosa transcriptome sequence data were identified. Based on their conserved domains and zinc finger motif, the R. glutinosa WRKY TFs were divided into five groups. Structural feature analysis shows that the 37 RgWRKY proteins contain WRKYGQK/GKK domains and a C2H2/C2HC-type zinc finger structure. To identify the function of RgWRKY members involved in acteoside biosynthesis, transcriptional profiles of 37 RgWRKYs in hairy roots under salicylic acid (SA), methyl jasmonate (MeJA), and hydrogen peroxide (H2O2) treatments were systematically established using RNA-seq analysis. Based on the correlationship between the expression levels of RgWRKY genes and acteoside content, RgWRKY7, RgWRKY23, RgWRKY34, RgWRKY35, and RgWRKY37 were suggested to be involved in acteoside biosynthesis in R. glutinosa, and RgWRKY37 was selected for gene functional research. Overexpression of RgWRKY37 increased the content of acteoside and total phenylethanoid glycosides (PhGs) in hairy roots and enhanced the transcript abundance of seven enzyme genes involved in the acteoside biosynthesis pathway. These results strongly suggest the involvement of the WRKY transcription factor in the regulation of acteoside biosynthesis.

CD96 is one of the immune superfamily members and it is identified as a T cell-specific receptor. In this study, we cloned a CD96 from Nile tilapia (Oreochromis niloticus, named OnCD96). The open reading frame of OnCD96was 1371 bp, encoding a protein of 456 amino acids. Sequence alignment analysis indicated that OnCD96 contained two Ig-like domains in entodomain, proline-rich motif, and ITIM motif in the cytoplasm. Subcellular localization studies showed that OnCD96 was distributed mainly in the cytoplasm and on the cytoplasmic membrane. In healthy tilapia, OnCD96 was distributed in all the tested tissues and relatively higher in the liver. After Streptococcus agalactiae infection, the expression of OnCD96 in the thymus, brain, and spleen reached its peak at 72 h, 48 h, and 24 h, respectively. After stimulation with poly I:C, the expression of OnCD96 in thymus and spleen reached its peak at 6 h and 24 h respectively. While, the expression in the brain had double peaks, which were at 24 h and 96 h. After stimulation with Keyhole limpet hemocyanin (KLH), a classical T cell-dependent antigen, the expression of OnCD96 was significantly up-regulated in blood and head kidney. Moreover, compared with the first challenge, OnCD96 was up-regulated earlier after the second challenge. Yeast two-hybrid assay indicated that there might be interaction between OnCD96 and OnNecl5. These results suggested that OnCD96 plays an important role during pathogens infection, and the interaction between CD96 and Necl5 is conserved in Nile tilapia.

Abstract Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by the formation of multiple benign cartilage-capped tumors, usually in the metaphyseal region of the long bones. Over 70% of HME cases arise from monoallelic mutations in either of the two genes encoding the heparan sulfate (HS) synthesis enzymes, ext1 and ext2. To identify more HME-associated mutations, genomic DNA from members of five independent consanguineous families with HME was sequenced with whole exome sequencing (WES). A novel heterozygous splice site mutation (c.1173+2T>A) in ext2 was detected in all three affected members of family V. Further study showed that the novel mutation caused exon 7 of ext2 mRNA to be skipped during splicing and caused a frameshift after the codon for Arg360, which results in the appearance of new 43 codons, followed by a termination codon. Although the resulting truncated protein was still localized to the Golgi, similar to the full-length EXT2, its HS synthesis activity decreased by 40%. In this study, a novel splice site mutation in ext2 was identified and suggested to be a pathogenic mutation of HME, which may expand the genetic etiology spectrum of HME and may be helpful for clinical genetic counseling and prenatal diagnosis.

Abstract Background Genetic components contribute significantly to the cause of hearing loss. Nonsyndromic hearing loss has been shown to have high genetic heterogeneity. For families who had given birth to two nonsyndromic deaf children in succession, it seems that their deafness was highly related to genetics. Objectives This study aimed to disclose the genetic causes of the subjects from the four Chinese families with two nonsyndromic deaf children in succession who failed to find the genetic etiology of the hearing loss by common deafness genetic screening (GJB2, GJB3, SLC26A4, and MT‐RNR1, including 20 hot variants in 4 genes). Methods Targeted next‐generation sequencing (NGS) of 127 known deafness genes was performed in probands of four families, followed by a series of comprehensive analyses of all family members combined with a literature review of related genes. Results We identified pathogenic variants in three families including c.919‐2A>G/c.1985G>A in SLC26A4; c.109G>A (p.V37I) in GJB2; and m.7505T>C in MT‐TS1. Sanger sequencing confirmed that these variants segregated with the hearing impairment of each family. We also identified c.331C>T/c.625‐5C>T/c.5717G>A in CDH23; c.138T>C in POU3F4 in two families, in which the pathogenicity in clinical was likely pathogenic or unknown. Conclusions Using the NGS detection technology, we found the genetic etiology of the HL in part of deaf families. Our study provided a useful piece of information for the variant spectrum of hearing loss in Chinese families with two deaf children in succession.

Owning to the extreme difficulty in identifying the primary generation (G0), the common ancestor of various twin-tail goldfish strains remains unclear. However, several authors have hypothesized that this ancestor may have been the crucian carp (Carassius auratus). Previously, we generated an experimental hybrid goldfish (EG) from the interspecific hybridization of red crucian carp (Carassius auratus ♀, RCC) × common carp (Cyprinus carpio ♂, CC). Unlike either parent, EG possessed twin caudal fins similar to those of natural goldfish (Carassius auratus, NG). The genetic characteristics of EG, as well as the mechanisms underlying its formation, are largely unknown. Here, we identified the genetic variation in the chordin gene that was associated with the formation of the twin-tail phenotype in EG: a stop codon mutation at the 127th amino acid. Furthermore, simple sequence repeat (SSR) genotyping indicated that, among the six alleles, all of the EG alleles were also present in female parent (RCC), but alleles specific to the male parent (CC) were completely lost. At some loci, EG and NG alleles differed, showing that these morphologically similar goldfish were genetically dissimilar. Collectively, our results demonstrated that genetic variations and differentiation contributed to the changes of morphological characteristics in hybrid offspring. This analysis of genetic variation in EG sheds new light on the common ancestor of NG, as well as on the role of hybridization and artificial breeding in NG speciation.

Objective This study aimed to compare the results of different graft materials in type I tympanoplasty for patients with a large perforation of the tympanic membrane. Methods We performed a retrospective study on 180 patients with type I tympanoplasty. The patients were divided into three groups according to the repair materials used. Age, sex, pre- and postoperative hearing levels, mean air–bone gap, rate of graft success, hearing gain, and the postoperative graft failure rate were evaluated. We continued to follow-up the patients to 1 year after surgery. Results The air conduction threshold was significantly higher before the operation than after the operation in the temporalis fascia, partial-thickness cartilage, and full-thickness cartilage groups. Although the hearing gain in the temporalis fascia group and the partial-thickness cartilage group was higher than that in the full-thickness cartilage group, there was no significant difference in the graft success rate among the groups. Conclusions Temporalis fascia, partial-thickness cartilage, and full-thickness cartilage can be used as appropriate transplantation materials for tympanoplasty type I in patients with a large perforation. Temporalis fascia and partial-thickness cartilage may be best for improvement of hearing.

In many Asian countries, herbs are used to treat disease. However, herbs also have adverse effects. Herb-induced liver injury has become a serious public health problem requiring urgent attention. The seeds of Swietenia macrophylla , a member of the family Polygonaceae, are often called skyfruit. We recently encountered a case of liver injury caused by skyfruit. The patient suffered from hepatocellular injury. We applied the updated Roussel Uclaf Causality Assessment Method (RUCAM) and the results indicated a highly probable relationship with skyfruit (total score 10). Moreover, we summarize another six cases of skyfruit-induced liver injury from the literature. The aim of our report is to help clinicians become more aware of the potential hepatotoxic effects of skyfruit and to accurately describe the clinical and laboratory characteristics of skyfruit-induced liver injury.

Background/Aims: CD133+CD44+ cancer stem cells previously isolated from laryngeal squamous cell carcinoma (LSCC) cell lines showed strong malignancy and tumorigenicity. However, the molecular mechanism underlying the enhanced malignancy remained unclear. Methods: Cell proliferation assay, spheroid-formation experiment, RNA sequencing (RNA-seq), miRNA-seq, bioinformatic analysis, quantitative real-time PCR, migration assay, invasion assay, and luciferase reporter assay were used to identify differentially expressed mRNAs, lncRNAs, circRNAs and miRNAs, construct transcription regulatory network, and investigate functional roles and mechanism of circRNA in CD133+CD44+ laryngeal cancer stem cells. Results: Differentially expressed genes in TDP cells were mainly enriched in the biological processes of cell differentiation, regulation of autophagy, negative regulation of cell death, regulation of cell growth, response to hypoxia, telomere maintenance, cellular response to gamma radiation, and regulation of apoptotic signaling, which are closely related to the malignant features of tumor cells. We constructed the regulatory network of differentially expressed circRNAs, miRNAs and mRNAs. qPCR findings for the expression of key genes in the network were consistent with the sequencing data. Moreover, our data revealed that circRNA hg19_circ_0005033 promotes proliferation, migration, invasion, and chemotherapy resistance of laryngeal cancer stem cells. Conclusions: This study provides potential biomarkers and targets for LSCC diagnosis and therapy, and provide important evidences for the heterogeneity of LSCC cells at the transcription level.

ErbB2/Neu oncogene is overexpressed in 25% of invasive/ metastatic breast cancers. We have found that deletion of heat shock factor Hsf1 in mice overexpressing ErbB2/Neu significantly reduces mammary tumorigenesis and metastasis. Hsf1+/-ErbB2/Neu+ tumors exhibit reduced cellular proliferative and invasive properties associated with reduced activated ERK1/2 and reduced epithelial-mesenchymal transition (EMT). Hsf1+/+Neu+ mammary epithelial cells exposed to TGFβshow high levels of ERK1/2 activity and EMT; this is associated with reduced expression of E-cadherin and increased expression of Slug and vimentin, a mesenchymal marker. In contrast, Hsf1-/-Neu+ or Hsf1+/+Neu+ cells do not exhibit activated ERK1/2 and show reduced EMT in the presence of TGFβ. The ineffective activation of the RAS/RAF/MEK/ERK1/2 signaling pathway in cells with reduced levels of HSF1 is due to the low levels of HSP90 in complex with RAF1 that are required for RAF1 stability and maturation. These results indicate a powerful inhibitory effect conferred by HSF1 downstream target genes in the inhibition of ErbB2-induced breast cancers in the absence of the Hsf1 gene [ABSTRACT FROM AUTHOR]

Abstract DNA-damaging agents have been used in cancer chemotherapy for a long history. Unfortunately, chemotherapeutic treatment strategies against hepatocellular carcinoma (HCC) are still ineffective. We screened a novel DNA-damaging compound, designated as 0404, by using time-dependent cellular response profiling (TCRP) based on unique DNA-damage characteristics. We used human HCC cell lines and HCC xenograft mouse model to analyze the anti-cancer effects of 0404. Transcriptome and miRNA arrays were used to verify the anti-cancer mechanism of 0404. It was confirmed that p53 signaling pathway was crucial in 0404 anti-cancer activity and the expression of miR-34a, a key tumor-suppressive miRNA, was up-regulated in 0404-treated HepG2 cells. MiR-34a expression was also down-regulated in HCCs compared with corresponding non-cancerous hepatic tissues. We further identified the mechanisms of 0404 in HepG2 cells. 0404 increased miR-34a expression and acylation p53 protein levels and decreased SIRT1 protein levels in a concentration-dependent manner. The sensitivity of HepG2 cells to 0404 was significantly decreased by transfection with miR-34a inhibitors and SIRT1 protein levels were up-regulated by miR-34a inhibition. Our findings show that 0404 is probably an attractive agent for treating HCC, especially in HCC with wide type (WT) p53, through forming a p53/miR-34a/SIRT1 signal feedback loop to promote cell apoptosis.

Mobile devices, such as smartphones, can offload applications and data to the cloud via access points or base stations to reduce energy consumption and improve user experience. However, mobile offloading is vulnerable to smart attackers that use smart and programmable radio devices, such as universal software radio peripherals, to perform multiple types of attacks, such as spoofing and jamming, based on the radio environment and offloading transmissions. In this paper, a mobile offloading game is investigated that consists of three players: a mobile device that chooses its offloading rate, a smart attacker that determines its attack mode, and a security agent that decides whether or not to initiate full protection for the serving access point during the offloading. Nash and Stackelberg equilibria of the offloading game are derived and their existence conditions are discussed. A Q-learning-based mobile offloading strategy is proposed for mobile devices that are unaware of system parameters, such as the channel conditions, in dynamic radio environments. Simulation results show that the proposed offloading strategy can improve the utility of the mobile device and reduce the attack rate of smart attackers.

Hepatitis B is a major global health problem and a potentially life-threatening liver infection caused by hepatitis B virus (HBV). Many cytokines including interleukin 6 (IL-6) have been shown to be involved in the HBV infection process. IL-6 is a typical cytokine made up of 184 amino acids, and the gene is located in chromosome 7p21. For healthy people, serum IL-6 levels are usually too low to be detected. However, dysregulated synthesis of IL-6 has been discovered in chronic inflammatory diseases such as hepatitis B, Crohn's disease and rheumatoid arthritis. IL-6 also plays an important role in HBV replication and in the development of hepatitis B disease. This review aims to present the latest discoveries concerning the role of IL-6 in hepatitis B disease progression, and HBV entry and replication, and evaluate polymorphisms that are associated with the development of hepatitis B disease.

Background & Aims: The high expression levels of interferon-γ (IFN-γ)-inducible genes correlate positively with liver diseases. The present study aimed to explore the effect of isoliquiritigenin (ISL) on the expression of genes induced by IFN-γ in vitro, and to elucidate the underlying molecular mechanisms. Methods: HepG2 and L02 cells were divided into control, ISL, IFN-γ, and IFN-γ plus ISL groups. The cytotoxicity of compounds to cells was evaluated by Cell Counting Kit 8 (CCK8) assay; the expression levels of chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and interleukin-6 (IL-6) in cells and supernatant were measured by quantitative real time polymerase chain reaction (qRT-PCR) and ELISA, respectively. Moreover, western blot was used to examine the phosphorylated levels of janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1), nuclear factor (NF)-γB, interferon regulatory factor 3 (IRF3)/myeloid differentiation factor 88 (MyD88), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (Akt) in HepG2 and L02 cells exposed to ISL, IFN-γ and IFN-γ plus ISL. Results: The results showed that IFN-γ treatment induced the expression of CXCL9, CXCL10, CXCL11, and IL-6 in HepG2 and LO2 cells, which could be significantly and dose-dependently inhibited by ISL treatment (P Conclusion: We demonstrate that ISL inhibits IFN-γ-induced inflammation in hepatocytes via influencing the activation of JAK1/STAT1, IRF3/MyD88, ERK/MAPK, JNK/MAPK, and PI3K/Akt signaling pathways.

The v-myb avian myeloblastosis viral oncogene homolog (MYB) superfamily constitutes one of the most abundant groups of transcription factors (TFs) described in plants. To date, little is known about the MYB genes in Rehmannia glutinosa. Forty unique MYB genes with full-length cDNA sequences were isolated. These 40 genes were grouped into five categories, one R1R2R3-MYB, four TRFL MYBs, four SMH MYBs, 25 R2R3-MYBs, and six MYB-related members. The MYB DNA-binding domain (DBD) sequence composition was conserved among proteins of the same subgroup. As expected, most of the closely related members in the phylogenetic tree exhibited common motifs. Additionally, the gene structure and motifs of the R. glutinosa MYB genes were analyzed. MYB gene expression was analyzed in the leaf and the tuberous root under two abiotic stress conditions. Expression profiles showed that most R. glutinosa MYB genes were expressed in the leaf and the tuberous root, suggesting that MYB genes are involved in various physiological and developmental processes in R. glutinosa. Seven MYB genes were up-regulated in response to shading in at least one tissue. Two MYB genes showed increased expression and 13 MYB genes showed decreased expression in the tuberous root under continuous cropping. This investigation is the first comprehensive study of the MYB gene family in R. glutinosa.

Rehmannia glutinosa is a common bulk medicinal material that has been widely used in China due to its active ingredients. Acteoside, one of the ingredients, has antioxidant, antinephritic, anti-inflammatory, hepatoprotective, immunomodulatory, and neuroprotective effects, is usually selected as a quality-control component for R. glutinosa herb in the Chinese Pharmacopeia. The acteoside biosynthesis pathway in R. glutinosa has not yet been clearly established. Herein, we describe the establishment of a genetic transformation system for R. glutinosa mediated by Agrobacterium rhizogenes. We screened the optimal elicitors that markedly increased acteoside accumulation in R. glutinosa hairy roots. We found that acteoside accumulation dramatically increased with the addition of salicylic acid (SA); the optimal SA dose was 25 μmol/L for hairy roots. RNA-seq was applied to analyze the transcriptomic changes in hairy roots treated with SA for 24 h in comparison with an untreated control. A total of 3,716, 4,018, and 2,715 differentially expressed transcripts (DETs) were identified in 0 h-vs.-12 h, 0 h-vs.-24 h, and 12 h-vs.-24 h libraries, respectively. KEGG pathway-based analysis revealed that 127 DETs were enriched in “phenylpropanoid biosynthesis.” Of 219 putative unigenes involved in acteoside biosynthesis, 54 were found to be up-regulated at at least one of the time points after SA treatment. Selected candidate genes were analyzed by quantitative real-time PCR (qRT-PCR) in hairy roots with SA, methyl jasmonate (MeJA), AgNO3 (Ag+), and putrescine (Put) treatment. All genes investigated were up-regulated by SA treatment, and most candidate genes were weakly increased by MeJA to some degree. Furthermore, transcription abundance of eight candidate genes in tuberous roots of the high-acteoside-content (HA) cultivar QH were higher than those of the low-acteoside-content (LA) cultivar Wen 85-5. These results will pave the way for understanding the molecular basis of acteoside biosynthesis in R. glutinosa, and can serve as a basis for future validation studies.

The effectors of the type IV secretion system (T4SS) of bacteria play important roles in mediating bacterial intracellular proliferation and manipulating host-related pathway responses to bacterial infection. Brucella Spp. inhibit the apoptosis of host cells to benefit their own intracellular proliferation. However, the underlying mechanisms between T4SS effectors and Brucella-inhibited apoptosis in goat trophoblast cells remain unclear. Here, based on Brucella suis vaccine strain 2, the VceC was deleted by allelic exchange. We show that ΔVceC was able to infect and proliferate to high titers in goat trophoblast cells (GTCs) and increase C/EBP-homologous protein (CHOP)-mediated apoptosis. GRP78 expression decreased upon ΔVceC infection. In addition, we discovered that the inositolrequiring enzyme 1 (IRE1) pathway was inhibited in this process. Changing endoplasmic reticulum (ER) stress affected Brucella intracellular replication in GTCs. The replication of ΔVceC was more sensitive under the different ERstress conditions in the GTC line after treatment with ER stress inhibitors 4 phenyl butyric acid (4-PBA) or ER stress activator Tm. Together, our findings show that VceC has a protective effect on the intracellular persistence of Brucella infection, and inhibits ER stress-induced apoptosis in the CHOP pathway. The present work provides new insights for understanding the mechanism of VceC in the establishment of chronic Brucella infection.

Rehmannia glutinosa L., a perennial plant of Scrophulariaceae, is one of the most commonly used herbs in traditional Chinese medicine (TCM) that have been widely cultivated in China. However, to date, the biosynthetic pathway of its two quality-control components, catalpol and acteoside, are only partially elucidated and the mechanism for their tissue-specific accumulation remains unknown. To facilitate the basic understanding of the key genes and transcriptional regulators involved in the biosynthesis of catalpol and acteoside, transcriptome sequencing of radial striation (RS) and non-radial striation (nRS) from four R. glutinosa cultivars was performed. A total of 715,158,202 (~107.27 Gb) high quality reads obtained using paired-end Illumina sequencing were de novo assembled into 150,405 transcripts. Functional annotation with multiple public databases identified 155 and 223 unigenes involved in catalpol and acteoside biosynthesis, together with 325 UGTs, and important transcription factor (TF) families. Comparative analysis of the transcriptomes identified 362 unigenes, found to be differentially expressed in all RS vs. nRS comparisons, with 143 upregulated unigenes, including those encoding enzymes of the catalpol and acteoside biosynthetic pathway, such as geranyl diphosphate synthase (RgGPPS), geraniol 8-hydroxylase (RgG10H), and phenylalanine ammonia-lyase (RgPAL). Other differentially expressed unigenes predicted to be related to catalpol and acteoside biosynthesis fall into UDP-dependent glycosyltransferases (UGTs), as well as transcription factors. In addition, 16 differentially expressed genes were selectively confirmed by real-time PCR. In conclusion, a large unigene dataset of R. glutinosa generated in the current study will serve as a resource for the identification of potential candidate genes for investigation of the tuberous root development and biosynthesis of active components.

Background: Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis.Methods: This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov, number NCT00611702.Findings: We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 ≥2). The gene set had high predictive capacity (area under the curve [AUC] 0·967), which was superior to that of baseline clinical variables (AUC 0·706) and clinical and pathological variables (AUC 0·806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0·754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0·916). The 13 genes also accurately predicted early allograft loss (AUC 0·842 at 2 years and 0·844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0·866) and two independent, publically available expression datasets (n=282, AUC 0·831 and n=24, AUC 0·972).Interpretation: Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis.Funding: National Institutes of Health. [ABSTRACT FROM AUTHOR]