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Fluconazole-resistant clade 4 Candida tropicalis causing candidemia in humans has been detected in tropical/subtropical areas, including those in China, Singapore, and Australia. We analyzed 704 individual yeasts isolated from fruits, soil, water, and farmers at 80 orchards in Taiwan. The most common pathogenic yeast species among 251 isolates recovered from farmers were Candida albicans (14.7%) and C. parapsilosis (11.6%). In contrast, C. tropicalis (13.0%), C. palmioleophila (6.6%), and Pichia kudriavzevii (6.0%) were prevalent among 453 environmental isolates. Approximately 18.6% (11/59) of C. tropicalis from the environment were resistant to fluconazole, and 81.8% (9/11) of those belonged to the clade 4 genotype. C. tropicalis susceptibility to fluconazole correlated with susceptibilities to the agricultural azole fungicides, difenoconazole, tebuconazole, and triadimenol. Tandem gene duplications of mutated ERG11 contributed to azole resistance. Agriculture environments are a reservoir for azole-resistant C. tropicalis; discontinuing agricultural use of azoles might reduce emergence of azole-resistant Candida spp. strains in humans.

Abstract We aimed to build a deep learning-based pathomics model to predict the early recurrence of non-muscle-infiltrating bladder cancer (NMIBC) in this work. A total of 147 patients from Xuzhou Central Hospital were enrolled as the training cohort, and 63 patients from Suqian Affiliated Hospital of Xuzhou Medical University were enrolled as the test cohort. Based on two consecutive phases of patch level prediction and WSI-level predictione, we built a pathomics model, with the initial model developed in the training cohort and subjected to transfer learning, and then the test cohort was validated for generalization. The features extracted from the visualization model were used for model interpretation. After migration learning, the area under the receiver operating characteristic curve for the deep learning-based pathomics model in the test cohort was 0.860 (95% CI 0.752–0.969), with good agreement between the migration training cohort and the test cohort in predicting recurrence, and the predicted values matched well with the observed values, with p values of 0.667766 and 0.140233 for the Hosmer–Lemeshow test, respectively. The good clinical application was observed using a decision curve analysis method. We developed a deep learning-based pathomics model showed promising performance in predicting recurrence within one year in NMIBC patients. Including 10 state prediction NMIBC recurrence group pathology features be visualized, which may be used to facilitate personalized management of NMIBC patients to avoid ineffective or unnecessary treatment for the benefit of patients.

Abstract Background The global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH. Methods We obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages. Results We observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation. Conclusion We identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K–AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

Abstract Tuberculosis (TB) remains a significant global health threat, necessitating effective strategies for diagnosis, prognosis, and treatment. This study employs a multi-cohort analysis approach to unravel the immune microenvironment of TB and delineate distinct subtypes within pulmonary TB (PTB) patients. Leveraging functional gene expression signatures (Fges), we identified three PTB subtypes (C1, C2, and C3) characterized by differential immune-inflammatory activity. These subtypes exhibited unique molecular features, functional disparities, and cell infiltration patterns, suggesting varying disease trajectories and treatment responses. A neural network model was developed to predict PTB progression based on a set of biomarker genes, achieving promising accuracy. Notably, despite both genders being affected by PTB, females exhibited a relatively higher risk of deterioration. Additionally, single-cell analysis provided insights into enhanced major histocompatibility complex (MHC) signaling in the rapid clearance of early pathogens in the C3 subgroup. This comprehensive approach offers valuable insights into PTB pathogenesis, facilitating personalized treatment strategies and precision medicine interventions.

Chromium, being among the most toxic heavy metals, continues to demand immediate attention in the remediation of Cr-contaminated environments. In this study, a strain of LBA36 (Bacillus toyonensis) was isolated from heavy metal contaminated soil in Luanchuan County, Luoyang City, China. The reduction and adsorption rates of LBA36 in 30 mg·L−1 Cr-containing medium were 97.95% and 8.8%, respectively. The reduction mechanism was confirmed by Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy (XPS). Cr(VI) reduction by this strain predominantly occurred outside the cell, with hydroxyl, amide, carboxyl, C-N group, carbonyl, and sulfur carbonyl as the main reaction sites. XPS analysis revealed the presence of Cr2p1/2 and Cr2p3/2. Furthermore, the hydroponic experiment showed that the fresh weight and plant height of radish seedlings increased by 87.87% and 37.07%, respectively, after inoculation with LBA36 strain under 7 mg·L−1 Cr(VI) stress. The levels of chlorophyll, total protein, malondialdehyde, superoxide dismutase and catalase were also affected to different degrees. In conclusion, this study demonstrated the potential of microbial and phytoremediation in the treatment of heavy metal toxicity, and laid the foundation for the development of effective bioremediation methods for Cr(VI) pollution.

Abstract Background Global myopia prevalence poses a substantial public health burden with vision-threatening complications, necessitating effective prevention and control strategies. Precise prediction of spherical equivalent (SE), myopia, and high myopia onset is vital for proactive clinical interventions. Methods We reviewed electronic medical records of pediatric and adolescent patients who underwent cycloplegic refraction measurements at the Eye & Ear, Nose, and Throat Hospital of Fudan University between January 2005 and December 2019. Patients aged 3–18 years who met the inclusion criteria were enrolled in this study. To predict the SE and onset of myopia and high myopia in a specific year, two distinct models, random forest (RF) and the gradient boosted tree algorithm (XGBoost), were trained and validated based on variables such as age at baseline, and SE at various intervals. Outputs included SE, the onset of myopia, and high myopia up to 15 years post-initial examination. Age-stratified analyses and feature importance assessments were conducted to augment the clinical significance of the models. Results The study enrolled 88,250 individuals with 408,255 refraction records. The XGBoost-based SE prediction model consistently demonstrated robust and better performance than RF over 15 years, maintaining an R 2 exceeding 0.729, and a Mean Absolute Error ranging from 0.078 to 1.802 in the test set. Myopia onset prediction exhibited strong area under the curve (AUC) values between 0.845 and 0.953 over 15 years, and high myopia onset prediction showed robust AUC values (0.807–0.997 over 13 years, with the 14th year at 0.765), emphasizing the models' effectiveness across age groups and temporal dimensions on the test set. Additionally, our classification models exhibited excellent calibration, as evidenced by consistently low brier score values, all falling below 0.25. Moreover, our findings underscore the importance of commencing regular examinations at an early age to predict high myopia. Conclusions The XGBoost predictive models exhibited high accuracy in predicting SE, onset of myopia, and high myopia among children and adolescents aged 3–18 years. Our findings emphasize the importance of early and regular examinations at a young age for predicting high myopia, thereby providing valuable insights for clinical practice.

Abstract Atherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.

Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.

Background This study aimed to investigate the effect and mechanism of Pentraxin 3 (PTX3) on myocardial injury in sepsis. Methods Thirty male C57BL/6 mice were randomly assigned to Groups A, B, or C. Mice in Groups A and B were injected with unloaded lentivirus, while mice in Group C were injected with lentivirus encoding PTX3 overexpression. Seven days after injection, septic myocardial injury mouse models were constructed following intraperitoneal injection with LPS in Groups B and C, and mice in Group A were intraperitoneally injected with normal saline. Cardiac function was examined using echocardiography; pathological variation of myocardial cells was measured through HE staining, transmission electron microscopy, and TUNEL staining; and Western blot was used to measure the expression of PI3K/AKT/mTOR pathway-related, autophagy-related, and apoptosis-related proteins in mice myocardial cells. Results PTX3 significantly improved cardiac function and structure in sepsis-stricken mice, and PTX3 alleviated cardiac damage caused by sepsis. PTX3 reduced the relative protein expression of p-PI3K, p-AKT, mTOR, LC3I/II, Beclin, ATG5, Bax, Caspase-3, and Caspase-9 in septic mouse cardiomyocytes and increased the relative protein expression of Bcl-2. Conclusion PTX3 can attenuate myocardial injury in sepsis due to the down-regulation of apoptosis and autophagy induced by the PI3K/AKT/mTOR pathway.

Abstract Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an important role in the pathogenesis of RIF. However, the underlying exact mechanism of lncRNA MALAT1 in RIF remains barely known. Here, the aim of our study was to investigate the dysregulate expression of lncRNA MALAT1 in TGF-β1 treated HK2/NRK-49F cells and unilateral ureteral obstruction (UUO) mice model, defining its effects on HK2/NRK-49F cells and UUO mice fibrosis process through the miR-124-3p/ITGB1 signaling axis. It was found that lncRNA MALAT1 and ITGB1 was significantly overexpression, while miR-124-3p was downregulated in HK2/NRK-49F cells induced by TGF-β1 and in UUO mice model. Moreover, knockdown of lncRNA MALAT1 remarkably downregulated the proteins level of fibrosis-related markers, ITGB1, and upregulated the expression of epithelial marker E-cadherin. Consistently, mechanistic studies showed that miR-124-3p can directly binds to lncRNA MALAT1 and ITGB1. And the protect effect of Len-sh-MALAT1 on fibrosis related protein levels could be partially reversed by co-transfected with inhibitor-miR-124-3p. Moreover, the expression trend of LncRNA MALAT1/miR-124-3p/ITGB1 in renal tissues of patients with obstructive nephropathy (ON) was consistent with the results of cell and animal experiments. Taken together, these results indicated that lncRNA MALAT1 could promote RIF process in vitro and in vivo via the miR-124-3p/ITGB1 signaling pathway. These findings suggest a new regulatory pathway involving lncRNA MALAT1, which probably serves as a potential therapeutic target for RIF.

Abstract Urban green technology innovation (UGTI) is strongly tied to environmental regulations, which can successfully balance economic and environmental benefits. Selecting the panel data for 280 Chinese cities during 2006–2019, we take the energy saving and emission reduction (ESER) demonstration city policy as a quasi-natural experiment, then employ the difference-in-differences model to examine the effect and its mechanisms of ESER policy on UGTI. Empirical results show that the ESER policy can significantly promote UGTI, especially in the western region, the northern region, and cities with weak government environmental attention. At the same time, China’s ESER policy has a stronger promoting effect on UGTI in cities where environmental targets are more stringent. Mechanism analysis shows that the policy mainly promotes UGTI through two channels: increasing the proportion of science and technology expenditure in fiscal expenditure and upgrading the structure of the industry. In addition, we find that the development of UGTI has positive environmental effects by lowering carbon emissions and air pollution. The findings not only enrich the literature on environmental regulation policies and UGTI at the theoretical level, but also provide references for policymakers to specific implementation methods in further enforcing environmental regulation policies to improve UGTI.

Objective This meta-analysis aimed to demonstrate the effect of methylene blue (MB) in patients with distributive shock.Design Meta-analysis.Methods According to the Prospective International Register of Systematic Reviews (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched the relevant randomised controlled trials (RCTs) via PubMed, Embase and Cochrane Library from the date of database inception to 19 April 2023. The primary outcome was mortality during follow-up, and secondary outcomes included mean arterial pressure (mm Hg), mechanical ventilation time (hours), intensive care unit (ICU) length of stay (LOS) (days), hospital LOS (days) and heart rate (times/min).Results This study included six RCTs with 265 participants. The study showed no significant difference in mortality between the MB and placebo groups (ORs: 0.59; 95% CI 0.32 to −1.06). However, MB reduced the duration of mechanical ventilation (mean difference (MD): −0.68; 95% CI −1.23 to −0.14), ICU LOS (MD: −1.54; 95% CI −2.61 to −0.48) and hospital LOS (MD: −1.97; 95% CI −3.92 to −0.11).Conclusions The use of MB may not reduce mortality in patients with distributive shock, but may shorten the duration of mechanical ventilation, ICU LOS and hospital LOS. More clinical studies are needed to confirm these findings in the future.Trial registration number CRD42023415938.

AbstractBackground Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock.Methods This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis.Results Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups.Conclusion Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Abstract Heat stress (HS) is a long-standing hurdle that animals face in the living environment. Alpha-lipoic acid (ALA) is a strong antioxidant synthesized by plants and animals. The present study evaluated the mechanism of ALA action in HS-induced early porcine parthenotes development. Parthenogenetically activated porcine oocytes were divided into three groups: control, high temperature (HT) (42 °C for 10 h), and HT + ALA (with 10 µM ALA). The results show that HT treatment significantly reduced the blastocyst formation rate compared to the control. The addition of ALA partially restored the development and improved the quality of blastocysts. Moreover, supplementation with ALA not only induced lower levels of reactive oxygen species and higher glutathione levels but also markedly reduced the expression of glucose regulatory protein 78. The protein levels of heat shock factor 1 and heat shock protein 40 were higher in the HT + ALA group, which suggests activation of the heat shock response. The addition of ALA reduced the expression of caspase 3 and increased the expression of B-cell lymphoma-extra-large protein. Collectively, this study revealed that ALA supplementation ameliorated HS-induced apoptosis by suppressing oxidative and endoplasmic reticulum stresses via activating the heat shock response, which improved the quality of HS-exposed porcine parthenotes.

Brain hemorrhage: Causes of fluid build-up on the brain Inhibiting a key inflammatory protein and thereby protecting the blood-brain barrier following brain hemorrhage may prevent the build-up of fluid on the brain (hydrocephalus). Using rat models and cell cultures, Yujie Chen and Hua Feng at the Third Military Medical University in Chongqing, China, and co-workers examined how posthemorrhagic hydrocephalus occurs. They found that the acute inflammatory response activated immediately after a brain hemorrhage, which is driven by a critical protein complex involved in innate immunity called the NLRP3 inflammasome, triggers the formation of lipid droplets in the choroid plexus, a part of the brain adjacent to the blood-brain barrier. The lipid droplets interact with mitochondria, increasing the release of reactive oxygen species and damaging the blood-brain barrier. This barrier dysfunction triggers hydrocephalus. Blocking NLRP3 activity improved the function of the barrier following hemorrhage.

Background Poor adherence to antihypertensive drugs is a major cause of unsatisfactory blood pressure control. Hypertension doctors play an integral role in improving medication adherence in hypertensive patients. Although most existing studies have recognized the status quo and influencing factors of medication adherence, little attention has been paid to hypertension doctors’ awareness and practice in hypertension management. Therefore, in this study, we aimed to investigate hypertension doctors’ awareness and practice of medication adherence in hypertensive patients. Methods This is a cross-sectional survey. A self-reported questionnaire was developed and sent to hypertension doctors in Hunan province, China, between May 1, 2022 and July 1, 2022. Univariate and generalized linear models were used to identify the factors influencing hypertension doctors’ awareness and practice. The correlation between awareness and practice was determined using Spearman’s correlation coefficient. Results In total, 236 valid questionnaires were collected (valid response rate, 73.5%). Of the respondents, 44.1% were chief physicians and 64.4% were females. Approximately half of the respondents were ≥40 years old and had over 14 years of working experience. Most respondents (87.7%) did not have hypertension, but 54.2% had a family history of hypertension. The average awareness and practice scores were 29.8 ± 8.8 and 39.4 ± 7.1, respectively, out of 50, with higher scores indicating higher levels of awareness or practice. More hypertension consultations and more antihypertensive prescriptions issued were associated with better awareness and practice among respondents (ps < 0.05). Respondents with higher education and professional titles had higher awareness (ps < 0.05). Moreover, respondents with 6–13 years of work experience had better practice than those with

PCIF1 can mediate the methylation of N6,2′-O-dimethyladenosine (m6Am) in mRNA. Yet, the detailed interplay between PCIF1 and the potential cofactors and its pathological significance remain elusive. Here, we demonstrated that PCIF1-mediated cap mRNA m6Am modification promoted head and neck squamous cell carcinoma progression both in vitro and in vivo. CTBP2 was identified as a cofactor of PCIF1 to catalyze m6Am deposition on mRNA. CLIP-Seq data demonstrated that CTBP2 bound to similar mRNAs as compared with PCIF1. We then used the m6Am-Seq method to profile the mRNA m6Am site at single-base resolution and found that mRNA of TET2, a well-known tumor suppressor, was a major target substrate of the PCIF1-CTBP2 complex. Mechanistically, knockout of CTBP2 reduced PCIF1 occupancy on TET2 mRNA, and the PCIF1-CTBP2 complex negatively regulated the translation of TET2 mRNA. Collectively, our study demonstrates the oncogenic function of the epitranscriptome regulator PCIF1-CTBP2 complex, highlighting the importance of the m6Am modification in tumor progression.

Abstract Selenium is an essential micronutrient element. For the extremely biotoxic of selenite, Selenium nanoparticles (SeNPs) is gaining increasing interest. In this work, a selenium-enriched strain with highly selenite-resistant (up to 173 mmol/L) was isolated from the local specialty food of longevity area and identified as Paenibacillus motobuensis (P. motobuensis) LY5201. Most of the SeNPs were accumulated extracellular. SeNPs were around spherical with a diameter of approximately 100 nm. The X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy showed that the purified SeNPs consisted of selenium and proteins. Our results suggested that P. motobuensis LY5201could be a suitable and robust biocatalyst for SeNPs synthesis. In addition, the cytotoxicity effect and the anti-invasive activity of SeNPs on the HepG2 showed an inhibitory effect on HepG2, indicating that SeNPs could be used as a potential anticancer drug.

Abstract This study aimed to investigate the risk factors of patients with postpartum hemorrhage (PPH) after cesarean delivery (CD) and to develop a risk-factor model for PPH after CD. Patients were selected from seven affiliated medical institutions of Chongqing Medical University from January 1st, 2015, to January 1st, 2020. Continuous and categorical variables were obtained from the hospital’s electronic medical record systems. Independent risk factors were identified by univariate analysis, least absolute shrinkage and selection operator and logistic regression. Furthermore, logistic, extreme gradient boosting, random forest, classification and regression trees, as well as an artificial neural network, were used to build the risk-factor model. A total of 701 PPH cases after CD and 2797 cases of CD without PPH met the inclusion criteria. Univariate analysis screened 28 differential indices. Multi-variable analysis screened 10 risk factors, including placenta previa, gestational age, prothrombin time, thrombin time, fibrinogen, anemia before delivery, placenta accreta, uterine atony, placental abruption and pregnancy with uterine fibroids. Areas under the curve by random forest for the training and test sets were 0.957 and 0.893, respectively. The F1 scores in the random forest training and test sets were 0.708. In conclusion, the risk factors for PPH after CD were identified, and a relatively stable risk-factor model was built.

Abstract Net ecosystem productivity (NEP), the difference between gross primary productivity (GPP) and ecosystem respiration (ER), is the basis of forest carbon sinks. Revealing NEP differences between naturally regenerating forests (NF) and planted forests (PF) can benefit for making carbon neutrality strategies. Based on 35 eddy covariance measurements in China, we analyzed NEP differences in values and spatial patterns between NF and PF. The results showed that NF had slightly lower NEP than PF, resulting from the high stand age (SA) and soil fertilizer, while their differences were not significant (p > 0.05). The increasing latitude decreased mean annual air temperature thus decreased GPP both in NF and PF. However, the higher SA and soil fertilizer in NF made most GPP release as ER thus induced no significant NEP spatial variation, while lower SA and soil fertilizer in PF made NEP spatially couple with GPP thus showed a decreasing latitudinal pattern. Therefore, stand characteristics determined the differences in NEP values but indirectly affected the differences in NEP spatial variations through altering GPP allocation. The decreasing latitudinal pattern of NEP in PF indicates a higher sequestration capacity in the PF of South China. Our results provide a basis for improving the forest carbon sequestration.

BI-X, a therapeutic protein under development for the treatment of human ocular disease via intravitreal administration, binds to its therapeutic targets and endogenous albumin in the vitreous humor. A monkey ocular pharmacokinetic (PK) study following BI-X administration was conducted to measure drug and albumin levels in plasma, the vitreous humor, the aqueous humor, and retina tissue at various timepoints post-dose. A comprehensive bioanalytical approach was implemented in support of this study. Five immunocapture-LC-MS/MS assays were developed and qualified for quantitating BI-X in different matrices, while ELISA was used for albumin measurement. Immunocapture at the protein or peptide level was evaluated to achieve adequate assay sensitivity. Drug and albumin assays were applied for the analysis of the monkey study samples.

Abstract Cases of arthroscopic surgery have increased over the past two decades, and arthroscopic shaver systems have become a commonly used orthopedic tool. Nevertheless, most shavers generally have problems such as the cutting edge is not sharp enough and easy to wear. This paper aims to discuss the structural characteristics of BJKMC’s (Bojin◊ Kinetic Medical) novel arthroscopic shaver, the double serrated blade. The product's design and verification process are outlined. BJKMC’s articular arthroscopy shaver has a “tube in a tube” structure, comprising a stainless steel outer sleeve and a rotating hollow inner tube. The outer sleeve and inner tube have corresponding suction and cutting windows, and there are serrated teeth on the inner and outer casing. To verify the design rationality, it was compared to Dyonics◊’s equivalent product, the Incisor◊ Plus Blade. The appearance, cutting tool hardness, metal pipe roughness, cutting tool wall thickness, tooth profile, and angle, overall structure, and the key dimensions were examined and compared. Compared with Dyonics◊’s Incisor◊ Plus Blade, BJKMC’s Double Serrated Blade had a smoother working surface, harder and thinner blade head. Therefore, BJKMC’s product may have satisfactory performance when it comes to surgery.

Objective To demonstrate the therapeutic effect of vasopressin as an alternative treatment for cardiac arrest.Design Systematic review and meta-analysis.Methods PubMed, EMBASE, the Cochrane Library and Web of Science were searched for randomised controlled trials. The intervention included administration of vasopressin alone or vasopressin combined with epinephrine or vasopressin, steroids and epinephrine (VSE) versus epinephrine combined with placebo as control group. The primary outcome was the return of spontaneous circulation (ROSC). The secondary outcomes included mid-term survival and mid-term good neurological outcome. We conducted subgroup analyses of the primary outcome based on different settings, different study drug strategies and different types of initial rhythm.Results Twelve studies (n=6718) were included, of which eight trials (n=5638) reported the data on patients with out-of-hospital cardiac arrest and four trials (n=1080) on patients with in-hospital cardiac arrest (IHCA). There were no significant differences between intravenous vasopressin and placebo in the outcomes of ROSC (relative risk (RR): 1.11; 95% CI: 0.99 to 1.26), mid-term survival (RR: 1.23; 95% CI: 0.90 to 1.66) and mid-term good neurological outcome (RR: 1.20; 95% CI: 0.77 to 1.87). However, in the subgroup analysis, intravenous vasopressin as part of VSE can significantly improve the rate of ROSC (RR: 1.32; 95% CI: 1.18 to 1.47) but not the rate of mid-term survival (RR: 2.15; 95% CI: 0.75 to 6.16) and mid-term good neurological outcome (RR: 1.80; 95% CI: 0.81 to 4.01) for patients with IHCA.Conclusions Our study failed to demonstrate increased benefit from vasopressin with or without epinephrine compared with the standard of care. However, vasopressin as a part of VSE is associated with the improvement of ROSC in patients with IHCA, and the benefit on mid‐term survival or mid-term good neurological outcome is uncertain. Larger trials should be conducted in the future to address the effect of vasopressin only, vasopressin plus epinephrine or VSE on cardiac arrest.PROSPERO registration number CRD42021293347.

Abstract Phenolic compounds (PCs) could be applied to reduce reactive oxygen species (ROS) levels, and are used to prevent and treat diseases related to oxidative stress. QSAR study was applied to elucidate the relationship between the molecular descriptors and physicochemical properties of polyphenol analogues and their DPPH radical scavenging capability, to guide the design and discovery of highly-potent antioxidant substances more efficiently. PubMed database was used to collect 99 PCs with antioxidant activity, whereas, 105 negative PCs were found in ChEMBL database; their molecular descriptors were generated with Python's Rdkit package. While the molecular descriptors significantly related to the antioxidant activity of PCs were filtered by t-test. The prediction QSAR model was then established by discriminant analysis, and the obtained model was verified by the back-substitution and Leave-One-Out cross-validation methods along with heat map. It was revealed that the anti-DPPH radical activity of PCs was correlated with the drug-likeness and molecular fingerprints, physicochemical, topological, constitutional and electronic property. The established QSAR model could explicitly predict the antioxidant activity of polyphenols, thus were applicable to evaluate the potential of candidates as antioxidants.

Abstract Objectives Toll-like receptors (TLRs) on neutrophils play a crucial role in detecting pathogens and organ/tissue injury in acute-on-chronic liver failure (ACLF). However, little is known about the exact mechanisms and potential signalling pathways. The aim of this study was to investigate alterations in TLR signalling pathways in neutrophils of ACLF patients. Methods Twenty-seven patients with compensated cirrhosis (n = 9), decompensated cirrhosis (n = 9) and ACLF (n = 9) were enrolled in the study. Neutrophils were isolated, and alterations in TLR signalling pathways were evaluated using an RT2 Profiler™ PCR Array. The fold change for each gene (2(−∆∆CT)) was compared among the groups. Genes with a fold change ratio of ≥ 2 or ≤ 0.5 along with a p value of

Abstract Magnetic achiral planar microswimmers can be massively fabricated at low cost and are envisioned to be useful for in vivo biomedical applications. To understand locomotion in representative in vivo environments, we investigated the swimming performance of achiral planar microswimmers in methylcellulose solutions. We observed that these microswimmers displayed very similar swimming characteristics in methylcellulose solutions as in water. Furthermore, this study indicated that the range of precession angles increased as the concentration of MC solution increased. Last, it was demonstrated that achiral planar microswimmers with similar precession angles exhibited nearly the same dimensionless speeds in different concentrations of the methylcellulose solutions. Upon understanding swimmer kinematics, more effective control over the achiral planar microswimmers can be achieved to perform multiple biomedical tasks in in vivo environments.

Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively correlated with the expression of KRAS-GTP, the active form of KRAS, in various human cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung adenocarcinomas and was associated with poor patient survival. Mechanistically, the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated BCL6 expression. BCL6 maintained the global expression of prereplication complex components; therefore, BCL6 inhibition induced stalling of the replication fork, leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells. Importantly, BCL6-specific knockout in lungs significantly reduced the tumor burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.

Abstract Oxygen (O2) is the most abundant molecule in the atmosphere after nitrogen. Previous studies have documented that oxygen concentration remains nearly constant (20.946%) at all altitudes. Here we show for the first time that oxygen concentration varies significantly from earlier consensus and shows strong spatial and seasonal differences. Field observations on the Qinghai-Tibetan Plateau (QTP) indicate oxygen concentration of 19.94–20.66% (2018, n = 80), 19.98–20.78% (2019, n = 166) and 19.97–20.73% (2020, n = 176), all statistically different from earlier reports (p

Abstract Background Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from damaged mitochondria into the cytosol. mtDNA stress may contribute to cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway activation in infectious diseases. Odontoblasts are the first cells challenged by cariogenic bacteria and involved in maintenance of the pulp immune and inflammatory responses to dentine-invading pathogens. In this study, we investigated that mtDNA as an important inflammatory driver participated in defending against bacterial invasion via cGAS-STING pathway in odontoblasts. Methods The normal tissues, caries tissues and pulpitis tissues were measured by western blotting and immunohistochemical staining. Pulpitis model was built in vitro to evaluated the effect of the cGAS-STING pathway in odontoblast-like cell line (mDPC6T) under inflammation. Western blot and real-time PCR were performed to detect the expression of cGAS-STING pathway and pro-inflammatory cytokines. The mitochondrial function was evaluated reactive oxygen species (ROS) generated by mitochondria using MitoSOX Red dye staining. Cytosolic DNA was assessed by immunofluorescent staining and real-time PCR in mDPC6T cells after LPS stimulation. Furthermore, mDPC6T cells were treated with ethidium bromide (EtBr) to deplete mtDNA or transfected with isolated mtDNA. The expression of cGAS-STING pathway and pro-inflammatory cytokines were measured. Results The high expression of cGAS and STING in caries and pulpitis tissues in patients, which was associated with inflammatory progression. The cGAS-STING pathway was activated in inflamed mDPC6T. STING knockdown inhibited the nuclear import of p65 and IRF3 and restricted the secretion of the inflammatory cytokines CXCL10 and IL-6 induced by LPS. LPS caused mitochondrial damage in mDPC6T, which promoted mtDNA leakage into the cytosol. Depletion of mtDNA inhibited the cGAS-STING pathway and nuclear translocation of p65 and IRF3. Moreover, repletion of mtDNA rescued the inflammatory response, which was inhibited by STING knockdown. Conclusion Our study systematically identified a novel mechanism of LPS-induced odontoblast inflammation, which involved mtDNA leakage from damaged mitochondria into the cytosol stimulating the cGAS-STING pathway and the inflammatory cytokines IL-6 and CXCL10 secretion. The mtDNA-cGAS-STING axis could be a potent therapeutic target to prevent severe bacterial inflammation in pulpitis. Video Abstract Graphic abstract

Objective(s): Sirt3 may regulate ROS production and might be involved in β‑cell apoptosis, which plays an important role in the progression of type 2 diabetes mellitus (T2DM). Quercetin is a potent anti-oxidative bioflavonoid, but its effects on T2DM remain to be explored. This study aimed to investigate the effects of quercetin on β‑cell apoptosis and explore its mechanisms.Materials and Methods: The effects of quercetin were conducted on db/db mice and INS1 cells. Fasting blood glucose was determined by the colorimetric method, serum insulin was measured by enzyme‑linked immunosorbent assay (ELISA). Meanwhile, Sirt3 in INS1 cells was knocked down by plasmid transfection. The antioxidant proteins (SOD2 and CAT), apoptosis proteins (cleaved Caspase-3, Bax, and BCL-2), and Sirt3 protein in pancreases and INS1 cells were determined by western blotting. Results: When INS1 cells and diabetic mice were treated with quercetin, the levels of SOD2, CAT, and Sirt3 proteins were increased, the levels of cleaved Caspase-3 and the ratio of Bax to BCL-2 were decreased at different degrees, along with reduced blood glucose levels and elevated insulin levels in diabetic mice. When Sirt3 was knocked down in INS1 cells, increase of two antioxidants and decrease of cell apoptosis generated by quercetin could not occur. Conclusion: Quercetin protected islet β‑cells from oxidation-induced apoptosis via Sirt3 in T2DM, which would be beneficial to develop new strategies for preventing β‑cell failure in T2DM.

Abstract Blood urea nitrogen (BUN) is a nitrogenous end product of protein metabolism. This study aims to explore the age- and sex-specific distribution of BUN among healthy Chinese adults. A total of 24,006 BUN values from healthy adults (14,148 males and 9858 females) were included in the cross-sectional study. Males had a higher median BUN value compared to females (4.6 mmol/L vs. 4.1 mmol/L). BUN values showed a positive correlation with body mass index (BMI), cholesterol, and blood sugar (P

Objective To study the neuroprotective effect of levetiracetam (LEV) with hypoxia ischemia brain-damage (HIBD) model of neonatal rats. Methods The rats were randomly divided into three groups: model group, LEV low, medium and high concentration groups [gavage with 10, 30, 50 mg/(kg·d) LEV], with 10 rats in each, and another 10 rats in sham operation group. Twenty four hours after the last administration, HE staining was used to observe the pathological changes of rat brain, TUNEL method was used to detect the apoptosis of neurons, the expression of inflammatory factors interleukin-6 (IL-6), tumor necrosis factor α(TNF-α), and oxidative stress factors malondialdehyde(MDA), the content and activity of superoxide dismutas (SOD) in serum were detected by ELISA, and the protein expression of caspase-3, B-cell lymphoma-2(Bcl-2), nuclear factor erythroid 2-related factor 2(Nrf2), heme oxygenase(HO-1) in rat brain tissue were detected by Western blot. Results Compared with the sham operation group, the morphology of brain tissue cell in the model group were disordered, showed diffuse distribution, increased vacuolation and inflammatory infiltration, the apoptosis rate of neurons, the expression of IL-6, TNF-α, MDA in serum and caspase-3 in brain tissue were significantly higher(P＜0.05), and the expression of SOD in serum, Bcl-2, Nrf2 and HO-1 in brain tissue were significantly lower(P＜0.05); Compared with the model group, the above changes of LEV in low, medium and high concentration groups were significantly reduced(P＜0.05). Conclusions LEV can alleviate inflammatory reaction and oxidative stress, and play a neuroprotective role in HIBD newborn rats.

Abstract Magnetic micro/nanorobots attracted much attention in biomedical fields because of their precise movement, manipulation, and targeting abilities. However, there is a lack of research on intelligent micro/nanorobots with stimuli-responsive drug delivery mechanisms for cancer therapy. To address this issue, we developed a type of strong covalently bound tri-bead drug delivery microrobots with NIR photothermal response azobenzene molecules attached to their carboxylic surface groups. The tri-bead microrobots are magnetic and showed good cytocompatibility even when their concentration is up to 200 µg/mL. In vitro photothermal experiments demonstrated fast NIR-responsive photothermal property; the microrobots were heated to 50 °C in 4 min, which triggered a significant increase in drug release. Motion control of the microrobots inside a microchannel demonstrated the feasibility of targeted therapy on tumor cells. Finally, experiments with lung cancer cells demonstrated the effectiveness of targeted chemo-photothermal therapy and were validated by cell viability assays. These results indicated that tri-bead microrobots have excellent potential for targeted chemo-photothermal therapy for lung cancer cell treatment.

Abstract Background Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. Methods A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan–Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. Results Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan–Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. Conclusions We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.

ABSTRACT BACKGROUND: For critically ill patients, physicians tend to administer sufficient or even excessive oxygen to maintain oxygen saturation at a high level. However, the credibility of the evidence for this practice is unclear. OBJECTIVE: To determine the effects of different oxygen therapy strategies on the outcomes of mechanically ventilated intensive care unit (ICU) patients. DESIGN AND SETTING: Systematic review of the literature and meta-analysis conducted at Jiangxi Provincial People’s Hospital, Affiliated to Nanchang University, Nanchang, China. METHODS: We systematically searched electronic databases such as PubMed and Embase for relevant articles and performed meta-analyses on the effects of different oxygen therapy strategies on the outcomes of mechanically ventilated ICU patients. RESULTS: A total of 1802 patients from five studies were included. There were equal numbers of patients in the conservative and liberal groups (n = 910 in each group). There was no significant difference between the conservative and liberal groups with regard to 28-day mortality (risk ratio, RR = 0.88; 95% confidence interval, CI = 0.59-1.32; P = 0.55; I2 = 63%). Ninety-day mortality, infection rates, ICU length of stay, mechanical ventilation-free days up to day 28 and vasopressor-free days up to day 28 were comparable between the two strategies. CONCLUSIONS: It is not necessary to use liberal oxygen therapy strategies to pursue a higher level of peripheral oxygen saturation for mechanically ventilated ICU patients. Conservative oxygen therapy was not associated with any statistically significant reduction in mortality.

Introduction The expression of MiR-135b-5p was up-regulated while Krüppel-like factor 4 (KLF4) expression was extremely low in human gastric carcinoma (GC) tissues. This study aimed to explore the role of miR-135b-5p in GC cells and its influence on various cell capacity and viability by targeting KLF4. Material and methods The dual-luciferase reporter assay was first performed and the target relationship between miR-135b-5p and KLF4 was confirmed. Then three GC cell lines and the human normal gastric epithelial cell line (GES1) were analyzed for the expression level of miR-135b-5p and KLF4 mRNA by RT-qPCR. The BGC-823 GC cell line was chosen for subsequent assays. Results The expression of miR-135b-5p and KLF4 was manipulated via transfection. The changes of proliferation, invasion, migration, viability, cycle and apoptosis of GC cells were evaluated by MTS, colony formation assay, transwell assay, wound healing assay and flow cytometry assay, respectively. Overexpression of MiR-135b-5p enhanced viability, proliferation, invasion and migration of GC cells, increased cell viability and reduced cell apoptosis. Replenishing of KLF4 functioned oppositely. Conclusions The inhibitory effects of ectopic KLF4 could be attenuated by co-transfection of miR-135b-5p. Collective data suggested that miR-135b-5p has a tumor-promoting role in GC cells via downregulating KLF4. Hence, inhibition of miR-135b-5p could be valuable for treatment of gastric cancer.

Abstract Leaf functional traits have attracted the attention of ecologists for several decades, but few studies have systematically assessed leaf morphological traits (termed “economic traits”), stomatal (termed “hydraulic”), and anatomical traits of entire forest communities, thus it is unclear whether their relationships are consistent among trees, shrubs, and herbs, and which anatomical traits should be assigned to economical or hydraulic traits. In this study, we collected leaf samples of 106 plant species in temperate forests and 164 plant species in subtropical forests and determined nine key functional traits. We found that functional traits differed between temperate and subtropical forests. Leaf traits also differed between different plant functional groups, irrespective of forest type; dry matter content, stomatal density, and cell tense ratio followed the order trees > shrubs > herbs, whereas specific leaf area and sponginess ratio showed the opposite pattern. The correlations of leaf traits were not consistent among trees, shrubs, and herbs, which may reflect different adaptive strategies. Principal component analysis indicated that leaf economics and hydraulic traits were uncoupled in temperate and subtropical forests, and correlations of anatomical traits and economic and hydraulic traits were weak, indicating anatomical traits should be emphasized in future studies.

Abstract Background and aims Prostaglandin E receptor 2 (EP2) is an immune modulatory molecule that regulates the balance of immunity. Here we investigated the role of EP2 in immune dysregulation in patients with acute-on-chronic liver failure (ACLF). Methods Plasma Progstaglandin E2 (PGE2) levels and EP2 expression on immune cells were determined in blood samples collected from patients with chronic hepatitis B related ACLF(HB-ACLF), patients with chronic hepatitis B (CHB), acute decompensated cirrhosis without ACLF (AD) and healthy controls (HC). Cytokine production, bacterial phagocytosis and reactive oxygen species (ROS) production were detected to explore the role of EP2 in regulating immune cell functions. Results The plasma PGE2 levels were increased and EP2 expression on CD8+ T cells was decreased in HB-ACLF compared with those in controls. The levels of PGE2 and EP2 were associated with systemic inflammation and disease severity. Small molecular chemicals against EP2 increased both cytokine secretion in PBMCs and ROS production in neutrophils and monocytes, but decreased monocytic phagocytosis. By contrast, an EP2-selective agonist reduced the production of a series of cytokines in PBMCs, but increased G-CSF. Conclusion Altered PGE2-EP2 augmented the excessive inflammation of innate and adaptive immune cells in response to LPS or E. coli in HB-ACLF. EP2 might be a new potential target for HB-ACLF treatment.

Regional differences and regulatory mechanisms of vegetation productivity response to changing environmental conditions constitute a core issue in macroecological researches. To verify the main limiting factors of different macrosystems [temperature-limited Tibetan Plateau (TP), precipitation-limited Mongolian Plateau (MP), and nutrient-limited Loess Plateau (LP)], we conducted a comparative survey of the east-west grassland transects on the three plateaus and explored the factors limiting regional productivity and their underlying mechanisms. The results showed that aboveground net primary productivity (ANPP) of LP (109.10 ± 16.76 g m-2 yr-1) was significantly higher than that of MP (66.71 ± 11.11 g m-2 yr-1) and TP (57.02 ± 10.59 g m-2 yr-1). The response rate of ANPP with environmental changes was different among different plateaus, being closely related to the main limiting factors. On MP, this was precipitation, on LP it was temperature and nutrients, and on TP, it was non-specific, reflecting restriction by the extremely low temperature. After autocorrelation screening of environmental factors, different regions exhibited different productivity response mechanisms. MP was mainly influenced by temperature and precipitation, LP was influenced by temperature and nutrient, and TP was influenced by nutrient, reflecting the modifying effect of the main limiting factors. The effect of each regional environment on ANPP was 72.56% on average and only 27.18% after simple regional integration. The regional model could optimize the simulation error of the integrated model, and the relative deviations in MP, LP, and TP were reduced by 31.76%, 17.22%, and 2.23%, respectively. These findings indicate that the grasslands on the three plateaus may have different or even the opposite mechanisms to control productivity.

At the intersection of research areas on health and employment, little attention has been paid on employment quality among people living with HIV (PLWH). The objective of the current study is to identify critical factors and empirically examine their effects on employment quality among PLWH. Based on the social-ecological perspective, we identified negative self-image, workplace discrimination, social support, and policy support as critical factors associated with employment quality among PLWH. Thereafter, a questionnaire survey was conducted to gather information from 339 employed PLWH in China. Hierarchical regression analyses were further performed to analyze the effects of the identified factors on employment quality among PLWH. We obtained three main findings. First, negative self-image and workplace discrimination are detrimental to employment quality among PLWH; whereas social support and policy support are conducive to their employment quality. Second, older, male, and highly educated PLWH can better leverage the undesirable effects of negative self-image and workplace discrimination on employment quality compared with their peers. Third, male, and highly educated PLWH can better utilize social support and policy support to advance employment quality compared with their peers. However, the employment quality effects of the identified factors did not differ by marital status. Our findings provided some useful implications for PLWH, employers, community service providers, and policy makers to promote employment quality among PLWH.

Background: Mesenchymal stem cell (MSC)-derived exosome administration has been considered as a novel cell-free therapy for liver diseases through cell-cell communication. This study was aimed to determine the effects and mechanisms of AMSC-derived exosomes (AMSC-Exo) for acute liver failure (ALF) treatment. Methods: AMSC-Exo were intravenously administrated into the mice immediately after lipopolysaccharide and D-galactosamine (LPS/GalN)-exposure and their effects were evaluated by liver histological and serum biochemical analysis. To elucidate its mechanisms in ALF therapy, the expression levels of miRNAs and inflammasome-related genes in macrophages were evaluated by qPCR and Western blot analysis, respectively. The exosomes from miR-17-knockdowned AMSCs (AMSC-ExomiR-17-KD) were used for further determine the role of miR-17 in AMSC-Exo-based therapy. Findings: AMSC-Exo administration significantly ameliorated ALF as determined by reduced serum alanine aminotransferase and aspartate aminotransferase levels and hepatic inflammasome activation. Further experiments revealed that AMSC-Exo were colocalized with hepatic macrophages and could reduce inflammatory factor secretion by suppressing inflammasome activation in macrophages. Moreover, miR-17, which can suppress NLRP3 inflammasome activation by targeting TXNIP, was abundant in AMSC-Exo cargo. While, the therapeutic effects of AMSC-ExomiR-17-KD on ALF were significantly abolished as they could not effectively suppress TXNIP expression and consequent inflammasome activation in vitro and in vivo.Interpretation: Exosome-shuttled miR-17 plays an essential role in AMSC-Exo therapy for ALF by targeting TXNIP and suppressing inflammasome activation in hepatic macrophages. AMSC-Exo-based therapy may present as a promising approach for TXNIP/NLRP3 inflammasome-related inflammatory liver diseases. Fund: Key R&D projects of Zhejiang province (2018C03019) and National Natural Science Fund (81470851 and 81500616). Keywords: Mesenchymal stem cells, Exosome, Macrophage, miR-17, TXNIP, NLRP3 inflammasome

Abstract Background To explore and summarize the reasons why urethral calculi cause a urethral fistula. Case presentation We retrospectively studied 1 patient in Xiangya hospital and all relevant literature published in English between 1989 and 2015. The patients (including those reported in the literature) were characterized by age, origin, location of calculus, size of calculus, fistulous track, and etiological factors. Most of urethral calculi associated with a urethral fistula were native generated. Urethral calculi can be formed in various locations of the urethra, and the size of the calculus ranged from small (multiple) calculi to giant stones. The fistula external orifice located at the root of the penis was relatively common, and there were various etiological factors, such as urethral strictures, urethral trauma induced by long-term catheterization, lumbar fractures, and congenital anomaly factors. They were managed by the excision of the fistulous tract, retrieval of the urethral stones, and/or debridement and pus drainage operations. Conclusion Some elements, such as trauma, recurrent urinary tract infections, abscess formation induced by long-term catheterization, and urethral calculus, may be the risk factors for a urethral fistula.

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.

Abstract To explore the impact of high-intensity focused ultrasound (HIFU) ablation of uterine fibroids in nulliparous women on subsequent pregnancy and delivery. A retrospective analysis was conducted of nulliparous women who received HIFU treatment at Chongqing Medical University, Chongqing,China, from January 1, 2010, to January 1, 2015. A total of 189 cases were enrolled, the median follow-up time was three years. Among them,there were 131 cases pregnancy with a total of 133 times,the pregnancy rate was 69.3% (131/189),and the spontaneous conception rate was 95.4% (125/131). Of 131 pregnant women, 19 were on-going pregnancy, terminated pregnancy 114 times,which include 93 times successfully delivery with a 76.3% (87/114) full-term birth rate,and the cesarean section rate was 72.0% (67/93). Of 94 newborns,the average birth weight was (3.3 ± 0.4)kg (range:1.5–4.8 kg), and a pair of them were identical twins. The incidence of complications during pregnancy and delivery were 10.8% (10/93) and 7.5% (7/93),respectively,except one woman failed on-going pregnancy and one woman suffered hysterectomy due to the complications,others all successful pregnant and delivered. Multiple-factor regression analysis found that age and infertility history were the important factors that may affect pregnancy after HIFU (P

Abstract Cell cycle progression in mammals is strictly controlled by a number of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), the expression of which is often dysregulated in cancer cells. Our previous work revealed that Cullin 4B (CUL4B), a critical component of the Cullin4B-RING E3 ligase complex (CRL4B), is overexpressed in human osteosarcoma cells through an unknown mechanism. Here, we demonstrated that CUL4B forms an E3 ligase with RBX1 (RING-box 1), DDB1 (DNA damage binding protein 1), and DCAF11 (DDB1 and CUL4 associated factor 11) in human osteosarcoma cells. In vitro and in vivo ubiquitination analyses indicated that CRL4BDCAF11 E3 ligase was able to specifically ubiquitinate a CDK inhibitor—p21Cip1 at K16, K154, K161 and K163 but not at K75 and K141. Knocking down any component of the CRL4BDCAF11 complex, including CUL4B, DDB1 or DCAF11, using short hairpin RNAs (shRNAs) attenuated the ubiquitination level of p21Cip1, inhibited osteosarcoma cell proliferation, led to cell cycle arrest at S phase, and decreased colony formation rate. Taken together, our data suggest that the CRL4BDCAF11 complex represents a unique E3 ligase that promotes the ubiquitination of p21Cip1 and regulates cell cycle progression in human osteosarcoma cells.

Asthma is a common chronic respiratory disease in childhood. The present study aims to assess the association between rhinovirus (RV) infection and acute wheezing in the occurrence of recurrent wheezing in 5-year old and younger children. A total of 109 children with recurrent wheezing and 70 children without wheezing (controls) were recruited from October 2013 to March 2015. Nasopharyngeal aspirate samples were obtained from all children. RV, human metapneumovirus (hMPV), and bocavirus (BoV) were tested by reverse transcription-polymerase chain reaction.Respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus (IV), and adenoviruses (ADV) were confirmed by detection of viral antigens via fluoroimmunoassay. Viral infection was more commonly detected in children with recurrent wheezing than in controls (odds ratio (OR): 6.10; 95% confidence interval (CI): 2.89–12.87). RV and RSV were found in both wheezing children and controls. However, RV was detected more in wheezing children than in controls (OR: 3.07; 95% CI: 1.37–6.90), followed by RSV (OR: 5.33; 95% CI: 1.53–18.62). Furthermore, RV more tended to infect wheezing children after infancy. Compared with children infected with other viruses, higher levels of eosinophil were found in wheezing children with RV infection ( P