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As the college students have been a most active user group in various social media, it remains significant to make effective sentiment analysis for college public opinions. Capturing the direction of public opinion in the student community in a timely manner and guiding students to develop the right values can help in the ideological management of universities. Universally, the recurrent neural networks have been the mainstream technology in terms of sentiment analysis. Nevertheless, the existing research works more emphasized semantic characteristics in vertical direction, yet failing to capture sematic characteristics in horizonal direction. In other words, it is supposed to increase more balance into sentiment analysis models. To remedy such gap, this paper presents a novel sentiment analysis method based on multi-scale deep learning for college public opinions. To fit for bidirectional semantic characteristics, a typical sequential neural network with two propagation paths is selected as the backbone. It is then extended with more layers in horizonal direction. Such design is able to balance both model depth and model breadth. At last, some experiments on a real-world social media dataset are conducted for evaluation, well acknowledging efficiency of the proposed analysis model.

Overexpression in Arabidopsis of the maize shikimate kinase-like genes SKL1 and SKL2 enhances tolerance to drought stress. The shikimate pathway has been reported to play an important role in plant signaling, reproduction, and development. However, its role in abiotic stress has not yet been reported. Here, two shikimate kinase-like genes, SKL1 and SKL2, were cloned from maize and their functions in mediating drought tolerance were investigated. Transcript levels of ZmSKL1 and ZmSKL2 in roots and leaves were strongly induced by drought stress. Both proteins were localized in the chloroplast. Furthermore, compared to the wild-type, transgenic Arabidopsis plants overexpressing ZmSKL1 or ZmSKL2 exhibited improved drought stress tolerance through increases in relative water content and stomatal closure. Additionally, the transgenic lines showed reduced accumulation of reactive oxygen species as a results of increased antioxidant enzyme activity. Interestingly, overexpression of ZmSKL1 or ZmSKL2 also increased sensitivity to exogenous abscisic acid. In addition, the ROS-related and stress-responsive genes were activated in transgenic lines under drought stress. Moreover, ZmSKL1 and ZmSKL2 were found to separately interact with ZmASR3, which is an important regulatory protein in mediating drought tolerance, suggesting that ZmSKL1 and ZmSKL2, together with ZmASR3, are proteins that may confer drought tolerance as candidates in plant genetic breeding manipulations.

The mutation of tumor suppressor gene liver kinase B1 (LKB1) has a prevalence of about 20% in non-small cell lung cancer (NSCLC). LKB1-mutant lung cancer is characterized by enhanced aggressiveness and immune escape, and is associated with poor prognosis. Therefore, it is urgent to develop effective therapeutic methods for LKB1-mutant NSCLC. Recently, apatinib, a VEGFR-TKI, was found to significantly improve the outcome of LKB1-mutant NSCLC, but the mechanism is not completely clear. In this study, AMP-activated protein kinase (AMPK), the crucial down-stream kinase of LKB1 was excavated as the potential target of apatinib. Biochemical experiments verified that apatinib is a direct AMPK activator. Moreover, clinically available VEGFR-TKIs were found to regulate AMPK differently that, apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. Activation of AMPK by apatinib leads to the phosphorylation of acetyl-CoA carboxylase (ACC) and inhibition of de novo fatty acid synthesis (FAsyn), which is up-regulated in LKB1-null cancers. Moreover, the killing effect of apatinib was obviously enhanced under delipidated condition, and the combination of exogenous FA restriction with apatinib treatment can be a promising method for treating LKB1-mutant NSCLC. This study discovered AMPK as an important off-target of apatinib, and elucidated different effects of this cluster of VEGFR-TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic, and highlights the subset of VEGFR-TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1-mutant NSCLC.

Increasing evidence shows that depression is associated with rheumatoid arthritis (RA). However, the causality and direction of this association remain unclear, because links between the two diseases might be caused by shared environmental confounding factors. Our study aims to understand a putative causal link between the two diseases.We retrieved summary statistics from meta-analyses of non-overlapping genome-wide association studies (GWASes) for depression (n = 807,553, 246,363 cases and 561,190 controls) and RA (n = 58,284, 14,361 cases and 42,923 controls). We combined Mendelian randomization (MR) estimates from each genetic instrument using inverse-variance weighted (IVW) meta-analysis, with alternate methods (e.g., simple median approach, weighted median approach, and MR-Egger regression) and conducted sensitivity analyses to assess the robustness of MR analyses.We found no evidence of causal relationships between depression and RA across all MR methods (IVW OR, 1.028 for RA; 95% CI, 0.821-1.287; P = 0.810) or vice versa (IVW OR, 0.999 for depression; 95% CI, 0.984-1.014; P = 0.932), indicating the links between the two diseases might be due to confounders.Despite the results, to optimize treatment outcomes of RA patients, we still emphasize depression should be managed as part of routine clinical care to optimize treatment outcomes of RA.

An efficient and scalable process for the synthesis of 19-hydroxyprogesterone was obtained through seven steps with 34.5% total yield, which is much higher than the process reported in the literature (11.0% total yield). The plausible ring-opening mechanism of 6,19-epoxy bridge in compound

Cancer-derived exosomes are involved in the development of cancer cachexia. Carnosol, which exhibited ameliorating effects on cancer cachexia of C26 tumour-bearing mice in our previous study, alleviated atrophy of C2C12 myotubes induced by exosomes of C26 tumour cells in the present study. MiR-183-5p was found to be rich in C26 cells and C26 exosomes, and miR-183-5p mimic could directly induce atrophy of C2C12 myotubes. Carnosol at 5 to 20 μM could dose-dependently ameliorate the myotube atrophy induced by miR-183-5p. Four and a half LIM domain protein 1 (FHL1) was shown to be the direct target of miR-183-5p. Increase in myostatin, p-Smad3, MuRF-1, Atrogin-1, HIF-1α and p-STAT3 and decrease in mitochondrial respiration were also induced by miR-183-5p mimic in C2C12 myotubes. Carnosol could not affect the decrease in FHL-1 and the activation of STAT3 pathway but could significantly alleviate the increase in myostatin, p-Smad3, MuRF-1, Atrogin-1 and the decrease in mitochondrial respiration induced by miR-183-5p. The protective effects of carnosol on myotubes against atrophy of C2C12 myotubes induced by miR-183-5p, based on both its inhibiting effects on MuRF-1 and Atrogin-1-mediated protein degradation and its ability of keeping the mitochondrial respiration, might contribute to its ameliorating effects on cancer cachexia.

Hepatocellular carcinoma, as a common liver cirrhosis complication, has become the sixth most common cancer worldwide, and its increasing incidence has resulted in considerable medical and economic burdens. As a natural polyphenolic compound, kaempferol has exhibits a wide range of antitumor activities against multiple cancer targets. In this study, the Autodock software was used for molecular docking to simulate the interaction process between kaempferol and HCC targets and the PyMOL software was used for visualization. Proliferation of kaempferol HepG2 cells under the effect of kaempferol was detected using Cell Counting Kit-8 (CCK-8) assay, and the apoptosis rate of HepG2 cells was detected using flow cytometry. The expressions of proteins BAX, CDK1, and JUN protein expressions were detected by Western blot. Molecular docking found that the kaempferol ligand has 3 rotatable bonds, 6 nonpolar hydrogen atoms, and 12 aromatic carbon atoms, and can form complexes with the kaempferol targets P53, BAX, AR, CDK1, and JUN through electrostatic energy. GO (Gene Ontology) enrichment analysis suggests that kaempferol regulates the biological function of hepatocellular carcinoma cells and is related to apoptosis. Cell Counting Kit-8 assay suggested that Kaempferol can significantly inhibited HepG2 cell proliferation, and the inhibition rate increased with the increase in drug concentration and incubation time. Moreover, kaempferol can promoted HepG2 cell apoptosis in a dose-dependent manner. This compound upregulated BAX and JUN expression and downregulated CDK1 expression. Thus, Kaempferol can promote HepG2 cell apoptosis, and the regulatory mechanism may be related to the regulation of the expression levels of the apoptosis-related proteins BAX, CDK1, and JUN.

Background. Long noncoding RNAs (lncRNAs) have been widely suggested to bind with the microRNA (miRNA) sites and play roles of competing endogenous RNAs (ceRNAs), which can thus affect and regulate target gene and mRNA expression. Such lncRNA-related ceRNAs are identified to exert vital parts in vascular disease. Nonetheless, it remains unknown about how the lncRNA-miRNA-mRNA network functions in the varicose great saphenous veins. Methods. This study acquired the lncRNA and mRNA expression patterns from the GEO database and identifies the differentially expressed mRNAs and lncRNAs by adopting the R software “limma” package. Then, miRcode, miRDB, miRTarbase, and TargetScan were used to establish the miRNA-mRNA pairs and lncRNA-miRNA pairs. In addition, the lncRNA-miRNA-mRNA ceRNA network was constructed by using Cytoscape. Protein-protein interaction, Gene Ontology functional annotations, and Kyoto Encyclopedia of Genes and Genomes enrichment were carried out to examine the candidate hub genes, the functions of genes, and the corresponding pathways. Results. In line with the preset theory, we constructed ceRNA network comprising 12 lncRNAs, 38 miRNAs, and 149 mRNAs. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the PI3K/Akt signaling pathway played a vital part in the development of varicose great saphenous veins. AC114730, AC002127, and AC073342 were significant biomarkers. At the same time, we predicted the potential miRNA, which may exert a significant influence on the varicose great saphenous veins, namely, miR-17-5p, miR-129-5p, miR-1297, miR-20b-5p, and miR-33a-3p. Conclusion. By performing ceRNA network analysis, our study detects new lncRNAs, miRNAs, and mRNAs, which can be applied as underlying biomarkers of varicose great saphenous veins and as therapeutic targets for the treatment of varicose great saphenous veins.

This study aimed to investigate the effects of transport stress on the physiological responses and immunity of Megalobrama amblycephala (blunt snout bream). Fish (109.67 ± 1.51 g) were sampled at nine time points: before transport (control), at 0 h, 1 h, 3 h, 6 h, 12 h, 24 h, 3 days, and 7 days after 4 h of medium-distance transportation, and four fish were sampled in each time point. The results showed that plasma cortisol, triiodothyronine (T

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.

Oocyte death is a severe clinical phenotype that causes female infertility and recurrent in vitro fertilization and intracytoplasmic sperm injection failure. We aimed to identify pathogenic variants in a female infertility patient with oocyte death phenotype.Sanger sequencing was performed to screen PANX1 variants in the affected patient. Western blot analysis was used to check the effect of the variant on PANX1 glycosylation pattern in vitro.We identified a novel PANX1 variant (NM_015368.4 c.86G A, (p. Arg29Gln)) associated with the phenotype of oocyte death in a non-consanguineous family. This variant displayed an autosomal dominant inheritance pattern with reduced penetrance. Western blot analysis confirmed that the missense mutation of PANX1 (c.86G A) altered the glycosylation pattern in HeLa cells. Moreover, the mutation effects on the function of PANX1 were weaker than recently reported variants.Our findings expand the inheritance pattern of PANX1 variants to an autosomal dominant mode with reduced penetrance and enrich the variational spectrum of PANX1. These results help us to better understand the genetic basis of female infertility with oocyte death.

The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has a good efficacy in advanced biliary tract cancer (BTC). The multi-target TKI lenvatinib and NGS-guided targeted therapy are also promising in BTC treatment. This study aimed to explore the performance of GemOX plus sintilimab and TKI (either lenvatinib or by NGS-guided targeted therapy) for local advanced or metastatic BTCs.This prospective single-arm study included patients with local advanced or metastatic BTCs and applied intravenous infusion of standard GemOX plus sintilimab and lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR amplification, lenvatinib for PDGFR and KIT mutation, and lenvatinib for FGFR/KIT mutation).From November 2020 to December 2021, 22 patients BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA cases) were enrolled, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6%). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeted therapy and there were 1 SD and 4 PR cases. For four patients with positive PD-L1 expression, the ORR was 100%. While among the three patients with super-progression markers such as RET, MDM2 and FGF14/STK24, there were two SD and one PD cases.In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.

Alkaloids exist in various herbal medicine widely and exhibit diverse biological and pharmacological activities. p-Sulphonatocalix[6]arenes (SC6A) and p-sulphonatocalix[8]arenes (SC8A) are water-soluble supramolecular macrocycles and are applied to the extraction of alkaloids from herbal products.In this study, an innovative method of SC6A/SC8A assisted extraction of the alkaloids from herbs was established.SC6A and SC8A were designed to extract 27 alkaloids from seven herbal medicines. Based on the significant solubilisation and extraction effect, Stephaniae Tetrandrae Radix (Fangji, FJ) was selected to obtain the optimal extraction process by adopting single factor test and orthogonal experiment. Then, the alkaloids and SC6A/SC8A were separated by one-step alkalisation and SCnA were reused. The host-guest complexes between alkaloids and SCnA were determined by competitive fluorescence titration, differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) and proton nuclear magnetic resonance (The optimum condition for SC6A assisted extraction was 5:1:80 (g/g/mL) for herbs/SC6A/solution ratio, 355-250 μm particle size and ultrasonicate 0.5 h, whilst 10:1:40 (g/g/mL) for herbs/SC8A/solution ratio, 355-250 μm particle size and ultrasonicate 0.5 h for SC8A assisted extraction. The total yield of alkaloids (fangchinoline and tetrandrine) from FJ was increased by 4.87 times and 5.97 times with SC6A and SC8A. Moreover, a good reusability of SC6A/SC8A was achieved by alkalisation dissociation. Host-guest complexes were determined by competitive fluorescence titration at a molar ratio of 1:1 between most alkaloids (25/27, except evodiamine and rutaecarpine) and SC6A/SC8A. The complex structure was proved by DSC, FTIR andThe study provided an effective eco-friendly and energy-saving extraction method of alkaloids from herbal medicine.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate ATG14- and Beclin1-mediated mitophagy and play key roles in the development of diabetic nephropathy (DN). DsbA-L is mainly located in MAMs and plays a role in renoprotection, but whether it activates mitophagy by maintaining MAM integrity remains unclear. In this study, we found that renal tubular damage was further aggravated in diabetic DsbA-L-/- mice compared to diabetic mice and that this damage was accompanied by disrupted MAM integrity and decreased mitophagy. Furthermore, notably decreased expression of ATG14 and Beclin1 in MAMs extracted from the kidneys of diabetic DsbA-L-/- mice was observed. In vitro, overexpression of DsbA-L reversed the disruption of MAM integrity and enhanced mitophagy in HK-2 cells, a human proximal tubular cell line, after exposure to high-glucose (HG) conditions. Additionally, compared to control mice, DsbA-L-/- mice were exhibited downregulated expression of helicase with zinc finger 2 (HELZ2) in their kidneys according to transcriptome analysis; HELZ2 serves as a cotranscription factor that synergistically functions with PPARα to promote the expression of mitofusin 2 (MFN-2). Treatment of HK-2 cells with MFN-2 siRNA resulted in MAM uncoupling and decreased mitophagy. Moreover, HG notably reduced the expression of HELZ2 and MFN-2 and inhibited mitophagy, and these effects were partially blocked by overexpression of DsbA-L and altered upon cotreatment with HELZ2 siRNA, HELZ2 overexpression or MK886 (PPARα inhibitor) treatment. These data indicate that DsbA-L alleviates diabetic tubular damage by activating mitophagy through maintenance of MAM integrity via the HELZ2/MFN-2 pathway.

Introduction: Diabetic peripheral neuropathy (DN) is the most common complication of type 2 diabetes mellitus (T2DM). Objective: This study aimed to explore the role of fibrinogen (FIB) in T2DM neuropathy and its preliminary mechanism. Methods: Ten male Sprague–Dawley rats were divided into a normal control group (NC group) and a T2DM neuropathy model group (DN group). The DN group was given a high-energy diet and streptozotocin, while the NC group was given a normal diet and a citric acid buffer. The expression levels of related proteins were analysed. Results: Electrophysiology: Compared with the NC group, the conduction latency of the somatosensory-evoked potential and nerve conduction velocity was prolonged in the DN group, while the motor nerve action potential was decreased. As seen under a light microscope, the peripheral nerve fibres in the DN group were swollen, and the nerve fibres in the posterior funiculus of the spinal cord were loose or missing. Moreover, as seen under an electron microscope, the peripheral nerve demyelination of the DN group was severe, with microvascular blood coagulation, luminal stenosis, and collapse. Compared with the NC group, in the DN group, the expression of FIB was positively correlated with the expression of both ionised calcium-binding adaptor molecule-1 and glial fibrillary acidic protein. Compared with the NC group, in the DN group, the expression of platelet/endothelial cell adhesion molecule-1 and B-cell lymphoma 2 was negatively correlated. Conclusion: The increased concentration of FIB may be the cause of neuropathy, and its mechanism may be related to its promotion of inflammatory response, blood coagulation, and vascular stenosis.

Objective The objective of this study was to evaluate the safety and efficacy of pneumovesicoscopic Cohen surgery with an adjustable suspension technique through the urethra for the treatment of primary vesicoureteral reflux disease in infants. Methods This study retrospectively analysed the clinical data of 31 infants who underwent pneumovesicoscopic Cohen surgery with an adjustable suspension technique through the urethra in our hospital from January 2019 to December 2020. We also collected the clinical data of 29 infants who underwent open Cohen surgery in our hospital from January 2015 to December 2018 as a control variable. The clinical efficacy of the two groups was compared. Result All pneumovesicoscopic Cohen surgeries were successfully completed and no patients were converted to open surgery. The amount of bleeding, duration of postoperative analgesia, duration of postoperative haematuria, incision size and length of hospital stay in the pneumovesicoscopic surgery group were significantly lower than those in the open surgery group (P 0.05). Conclusion Pneumovesicoscopic Cohen surgery with an adjustable suspension technique through the urethra for the treatment of primary vesicoureteral reflux disease in infants was safe and effective. This procedure had the advantages of less trauma, quick recovery and good cosmetic effects.

Background Circumscribed Choroidal hemangioma (CCH) is a kind of hamartoma that is caused by congenital vascular malformation. And, polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy. There is no literature indicating that there is a correlation between the occurrences of CCH and PCV. Case presentation A 66-year-old male presented with decreased vision of his left eye for 4 years. Fundus photograph showed that the branches of blood vessels at the supratemporal retina were occluded in white lines, an orange lesion could be seen in the subnasal retina and mottled, yellowish white lesions were accompanied by punctate hard exudation in the macular in the left eye. The Fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and Spectral domain optical coherence tomography (OCT) were done. There was a diagnosis of CCH, PCV and branch retinal vein occlusion accompanied with retinoschisis of the left eye. Conclusion This article reports on a case of an elderly male Chinese patient with CCH and PCV accompanied by branch retinal vein occlusion with retinoschisis in the left eye. The common lesions are choroidal vascular abnormalities. Whether hypertension is related to CCH, PCV and branch retinal vein occlusion remains to be further studied.

Background The aim of this study was to analyze the relationship of the estimated glomerular filtration rate (eGFR) to hydroxychloroquine (HCQ) blood concentrations in systemic lupus erythematosus (SLE) patients. Method Patients with SLE who had been taking HCQ for more than 12 months were recruited. All subjects gave written informed consent. Various clinical characteristics and laboratory values were examined. The blood concentration of HCQ was measured by high-performance liquid chromatography, and the relationship of eGFR to HCQ blood concentration was mainly investigated. Result In total, 115 patients with SLE receiving long-term HCQ therapy were included in the study. The median concentration of HCQ was 1096 ng/ml (range 116–8240 ng/ml). The eGFR was strongly associated with blood concentration of HCQ (P = 0.011, P Conclusion We provided novel evidence that impaired renal function influenced the blood concentration of HCQ. Patients with low eGFR need to adjust the HCQ dosage according to the monitoring results of HCQ blood concentrations. Key points• A higher HCQ blood concentration was associated with low eGFR.• This finding reinforces the importance of routine HCQ measurement to maintain normal blood concentrations.• HCQ blood monitoring will be useful for dose modification in patients with renal dysfunction.

Background Apurinic/apyrimidinic endonuclease 1 (APE1) imparts radio-resistance by repairing isolated lesions via the base excision repair (BER) pathway, but whether and how it is involved in the formation and/or repair of DSBs remains mostly unknown. Methods Immunoblotting, fluorescent immunostaining, and the Comet assay were used to investigate the effect of APE1 on temporal DSB formation. Chromatin extraction, 53BP1 foci and co-immunoprecipitation, and rescue assays were used to evaluate non-homologous end joining (NHEJ) repair and APE1 effects. Colony formation, micronuclei measurements, flow cytometry, and xenograft models were used to examine the effect of APE1 expression on survival and synergistic lethality. Immunohistochemistry was used to detect APE1 and Artemis expression in cervical tumor tissues. Results APE1 is upregulated in cervical tumor tissue compared to paired peri-tumor, and elevated APE1 expression is associated with radio-resistance. APE1 mediates resistance to oxidative genotoxic stress by activating NHEJ repair. APE1, via its endonuclease activity, initiates clustered lesion conversion to DSBs (within 1 h), promoting the activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key kinase in the DNA damage response (DDR) and NHEJ pathway. APE1 then participates in NHEJ repair directly by interacting with DNA- PKcs. Additionally, APE1 promotes NHEJ activity by decreasing the ubiquitination and degradation of Artemis, a nuclease with a critical role in the NHEJ pathway. Overall, APE1 deficiency leads to DSB accumulation at a late phase following oxidative stress (after 24 h), which also triggers activation of Ataxia-telangiectasia mutated (ATM), another key kinase of the DDR. Inhibition of ATM activity significantly promotes synergistic lethality with oxidative stress in APE1-deficient cells and tumors. Conclusion APE1 promotes NHEJ repair by temporally regulating DBS formation and repair following oxidative stress. This knowledge provides new insights into the design of combinatorial therapies and indicates the timing of administration and maintenance of DDR inhibitors for overcoming radio-resistance.

Aim: We conducted a meta-analysis to evaluate the prognostic and clinicopathological relevance of DKC1 in various cancers. Methods: We searched Web of Science, Embase, PubMed, Wanfang and CNKI. Stata SE15.1 was used to calculate the hazard ratio and relative risk with 95% CIs to assess the possible correlations between DKC1 expression levels and overall and disease-free survival, as well as with clinicopathological parameters. Results: We included nine studies, with a total of 2574 patients. There was a meaningful link between elevated DKC1 and poorer disease-free (p

The adsorption of fatty acid, kerosene and fatty acid-kerosene on fluorapatite (001) surface were investigated by density functional theory (DFT) calculations. The results showed that the single fatty acid could form stable chemisorption on fluorapatite (001) surface by the O of fatty acids bonding with Ca1 site. The single kerosene could not be stably adsorbed on fluorapatite (001) surface because the H of kerosene did not form hydrogen bond with the O of PO43- on (001) surface (Osurf). For the coadsorption conformation, the chemisorption of fatty acid-kerosene on fluorapatite (001) surface was contributed by the interaction between O of fatty acids and Ca1, the H of kerosene did not bond with the Osurf, but the carbon chain length of kerosene has a large influence on the coadsorption. Compared with the coadsorption of fatty acid-decane, the adsorption of butyric acid-tetradecane and octanoic acid-tetradecane on fluorapatite (001) surface have greater adsorption energies and overlapping region of DOS between O 2p and Ca 4d, indicating that there is a synergistic effect between fatty acid and tetradecane. Meanwhile, the collaborative effects exist between the molecules of fatty acids. The interpenetrating adsorption of fatty acid and kerosene on the fluorapatite surface could improve the adsorption strength and density. The flotation test further confirmed that the single kerosene could not collect fluorapatite, but it could be collected by the single fatty acid. Besides, the synergistic effect between fatty acid and kerosene could increase the flotation recovery of fluorapatite.

Mesenchymal stem cells (MSCs) have been widely used as functional components in tissue engineering. However, the immunogenicity and limited pro-angiogenic efficacy of MSCs greatly limited their pro-regenerative ability in allogenic treatment. Herein, utilizing a chemically defined cocktail in the culture system, including cytokines, small molecules, structural protein, and other essential components, we generated the immunoprivileged and pro-angiogenic cells (IACs) derived from human adipose tissues. Conventional adipose-derived MSCs (cADSCs) were used as a control in all the experiments. IACs show typical MSC properties with enhanced stemness capacity and a robust safety profile. IACs induce a significantly milder immune response of allogenic peripheral blood mononuclear cells in an H3K27me3-HLA axis-dependent manner. IACs, through superior paracrine effects, further promote nitric oxide production, anti-apoptotic ability, and the tube formation of human vein endothelial cells. Embedded in a photo-reactive hydrogel (Gel) termed as GelMA/HA-NB/LAP for tissue engineering treatment, IACs promote faster tissue regeneration in a xenogeneic full-thickness skin defect model, eliciting a milder immune response and enhanced blood vessel formation in IACs-treated defect areas. Together with its excellent pro-regenerative potential and robust safety, our findings suggest that IACs may be a promising candidate for clinically relevant stem cell and tissue engineering therapeutics.

This study aimed to evaluate the effect of supplementation with inulin-type fructans (ITFs) on the intestinal immune function in the context of dysbiosis resulting from antibiotic cocktail (ABx) treatment. BALB/c mice (8-9 weeks of age) were treated with an ABx for 3 weeks and then allowed to recover spontaneously or with ITF supplementation (5%) for 4 weeks. Our results showed that ABx treatment can induce gut microbiota dysbiosis and intestinal inflammation in mice. After 4 weeks of recovery, ITF supplementation restored the composition of the intestinal microbial community. However, compared with spontaneous recovery, ITF supplementation delayed inflammation recovery in the intestine and upregulated diamine oxidase (DAO) activity and increased lipopolysaccharide (LPS) content in serum. In addition, ITF supplementation delayed the regulatory T (Treg) cell and B cell recovery in the lamina propria (LP). Furthermore, compared with spontaneous recovery, ITF supplementation inhibited the relative expression of certain proinflammatory genes, such as for inducible nitric oxide synthase (iNOS) and tumour necrosis factor α (Tnf-α), in the colon, but it reduced the secretion of the anti-inflammatory mediator transforming growth factor β1 (TGF-β1) in serum, reduced the secretion of secretory immunoglobulin A (SIgA) in the colon and promoted the secretion of the proinflammatory cytokine interleukin (IL)-17A. In conclusion, these data supported the hypothesis that the influence of ITFs on the host's intestinal status is not always beneficial in the context of ABx-induced biological disorder. However, the significance of these findings needs to be determined by advanced studies KEY POINTS: • ITFs did not promote the recovery of microbial community composition. • ITFs delayed the recovery of ABx-induced colonic inflammation. • ITFs reduced the secretion of TGF-β1 and SIgA. • ITFs delayed the recovery of Treg and B cells in the LP.

Although endoscopic dacryocystorhinostomy (DCR) is a standard procedure for nasolacrimal duct obstruction (NLDO), the failure rate remains approximately 10%. A small lacrimal sac is considered the main reason for surgical failure. We explored the efficacy of endoscopic DCR for the treatment of NLDO with a small lacrimal sac.The clinical data of 72 patients (88 eyes) diagnosed with NLDO and undergoing endoscopic DCR from 2012 to 2020, with at least 24 months of follow-up were retrospectively collected. Intraoperatively, the Rosenmüller valves were fully exposed, mucosal flaps were preserved to cover the naked bone, and a silicone tube was implanted if necessary. Postoperative intervention was performed if necessary. The main outcome measures were symptomatic improvement and objective ostium patency.Eighty-eight eyes of 72 patients were divided into two groups: the refractory group (34 patients, 47 eyes), with a small lacrimal sac (≤ 5 mm in diameter), and the simple group (38 patients, 41 eyes). Patients with small lacrimal sacs were more prone to bilateral eye disease than those in the simple group (P = 0.014) and required a longer postoperative follow-up (P 0.001). Refractory NLDO and simple NLDO had a success rate of 91.5% and 95.1%, respectively, with no significant difference.Endoscopic DCR for refractory NLDO with a small lacrimal sac could achieve a beneficial result by exposing the Rosenmüller valves, preserving mucosal flaps, implanting necessary intubation, and intervening postoperatively. Thus, a small lacrimal sac should not be regarded as a contraindication to surgery.

Mitochondria homeostasis plays an important role in acute kidney injury (AKI). In this study, we aimed at identifying the mechanism of mitophagy regulation in AKI. Activation of mitophagy after ischemic kidney injury was visualized with increased expression of LC3, PINK1, PARKIN expression and with a subsequent decline in p62 levels. Immuohistochemistry staining showed higher LC3 levels in ischemic kidney injury mice. Further, differential expression of PARKIN targeting miRNAs revealed that miR-140-5p was significantly downregulated followed by ischemic kidney injury. miR-140-5p mimics suppressed PARKIN expressions and their mitochondrial translocation. Further, miR-140-5p mimics under hypoxia prevented mitophagosome formation. These effects on hypoxia-induced PARKIN expression and LC3/TOMM20 levels were reversed by antagomiR miR-140-5p treatment. Dual-luciferase reporter assay revealed that miR-140-5p had significant interaction with 3'UTR of PARKIN. Our findings show that HIF-1α is bound to miR-140-5p promoter and down regulates its expression and thereby promotes mitophagy process under hypoxic conditions. These results cumulatively show that HIF-1α regulates mitophagy during AKI through the regulation of miR-140-5p/PARKIN axis.

Whether high-speed rail (HSR) can promote the coordination between the economy and environment is a critical issue that needs to be investigated. We used balanced panel data of 281 prefecture-level or above cities in China from 2005 to 2017 to consider the opening of HSR as a quasi-natural experiment. We integrated the difference-in-differences (DID) model, the spatial difference-in-differences (SDID) model, and social network analysis (SNA) to empirically investigate the impact of HSR on urban environmental efficiency (UEE). The results showed that HSR significantly improved UEE by 4.6% annually during the study period, although the effect of HSR on UEE exhibited a time lag and varied dramatically in different cities. An analysis of the mechanism showed that the effect of technological innovation and the structural effect brought by the opening of HSR were the main contributors to the improved UEE. Further analysis showed that HSR service centrality also significantly improved UEE and HSR opening and HSR service centrality both had positive spatial spillover effects on the UEE of neighboring cities. Several policy implications are proposed accordingly to make full use of the advantages of HSR to improve UEE for China.

Background: Studies have demonstrated that immune cell activation and their infiltration in the myocardium can have adverse effects on the heart, contributing to the pathogenesis of heart failure (HF). The purpose of this study is used by bioinformatics analysis to determine the potential diagnostic markers of heart failure and establish an applicable model to predict the association between heart failure and immune cell infiltration. Methods: Firstly, gene expression profiles of dilated heart disease GSE3585 and GSE120895 were obtained in Gene Expression Omnibus (GEO) database. This study then selected differentially expressed genes (DEGs) in 54 patients with HF and 13 healthy controls. In this study, biomarkers were identified using Least Absolute Shrinkage and Selector Operation (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE). Additionally, we evaluated the prognostic discrimination performance by the receiver operating characteristic (ROC) curve. Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) was used for analyzing immune cell infiltration in HF tissues. Lastly, immune biomarkers were correlated with each other. Result: After 24 DEGs were analyzed using a combinatorial model of LASSO regression and SVM-RFE analysis, four key genes were obtained, namely NSG1, NPPB, PHLDA1, and SERPINE2.The area under the curve (AUC) of these four genes were greater than 0.8. Subsequently, using CIBERPORT, we also found that compared with normal people, the proportion of M1 macrophages and activated mast cells in heart failure tissues decreased. In addition, correlation analysis showed that NPPB, PHLDA1 and SERPINE2 were associated with immune cell infiltration. Conclusion: NSG1, NPPB, PHLDA1 and SERPINE2 were identified as potential biomarkers of heart failure. It reveals the comprehensive role of relevant central genes in immune infiltration, which provides a new research idea for the treatment and early detection in heart failure.

Objectives To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. Methods A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. Results There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p

Lentinula edodes (L. edodes), one of the most popular edible mushrooms in China, is adversely affected by high temperature. Heat shock proteins (HSPs) play a crucial role in regulating the defense responses against the abiotic stresses in L. edodes. Some HSPs in L. edodes have been described previously, but a genome-wide analysis of these proteins is still lacking. Here, the HSP genes across the entire genome of the L. edodes mushroom were identified. The 34 LeHSP genes were subsequently classified into six subfamilies according to their molecular weights and the phylogenetic analysis. Sequence analysis showed that LeHSP proteins from the same subfamily have conserved domains and one to five similar motifs. Except for Chr 5 and 9, 34 LeHSPs genes were distributed on the other eight chromosomes. Three pairs of paralogs were identified because of sequence alignment and were confirmed as arising from segmental duplication. In LeHSPs’ promoters, different numbers of heat shock elements (HSEs) were predicted. The expression profiles of LeHSPs in 18N44 and 18 suggested that the thermo-tolerance of strain 18N44 might be related to high levels of LeHSPs transcript in response to heat stress. The quantitative real-time PCR (qRT-PCR) analysis of the 16 LeHSP genes in strains Le015 and Le027 verified their stress-inducible expression patterns under heat stress. Therefore, these comprehensive findings provide useful in-depth information on the evolution and function of LeHSPs and lay a theoretical foundation in breeding thermotolerant L. edodes varieties.

Infertility has become a global public health issue. In vitro fertilization and embryo transfer (IVF-ET) is widely performed as an infertility treatment. However, a significant number of infertile women continue to experience serial implantation failure, despite the high quality of the transferred embryos. Jian-Pi-An-Tai formula is an experience formula in treating threatened abortion in our team. It has also been used to treat infertile women after embryo transfer and shows superiority compared to single use of conventional western medicine. However, the of evidence on its effective in treating infertile women undergo IVF-ET is lacking.This randomized controlled trial (RCT) will be carried out in Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University planning to recruit 180 infertile patients undergoing IVF-ET with the type of deficiency of both the spleen and kidney. The control group will be treated by conventional western medicine and the treatment group will use conventional western medicine plus Jian-Pi-An-Tai formula. The primary outcomes will include Embryo implantation rate, Clinical pregnancy rate, Persistent pregnancy rate; and the secondary outcomes will include TCM symptom score and reproductive hormones. Safety evaluation will be recorded during the whole study. All data in this RCT will be analyzed by SPSS 23.0 software. This study has been approved by the Research Ethics Committee of the Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University (2022KY130).The results of this RCT will contribute to provide scientific and rigorous evidence for the efficacy and safety of Jian-Pi-An-Tai formula in treating infertile women undergo IVF-ET. And the results from this RCT will be published in a relevant journal after finished.

We explored the prognostic value of preoperative CA19-9 in α-fetoprotein (AFP)-positive and -negative HCC with hepatitis B virus (HBV) background (HBV-HCC), and explored the underlying mechanism. Recurrence-free survival (RFS) and overall survival (OS) were assessed in HBV-HCC patients who underwent curative resection (Cohort 1). Immunohistochemical staining of CA19-9 in HCC and liver parenchyma were quantified in another cohort of 216 patients with resected HCC (Cohort 2). Immunohistochemical staining of CA19-9 and serum CA19-9 level was also compared between patients with HCC and intrahepatic cholangiocarcinoma (ICC) (Cohort 3). In Cohort 1, CA19-9 ≥ 39 U/mL was an independent risk factor for RFS (HR = 1.507, 95% CI = 1.087-2.091, p = 0.014) and OS (HR = 1.646, 95% CI = 1.146-2.366, p = 0.007). CA19-9 ≥ 39 U/mL was also associated with significantly higher incidence of macrovascular invasion (MaVI) compared with CA19-939 U/mL (23.0% vs. 7.2%, p = 0.002), and elevated aminotransferase and aspartate aminotransferase to platelet ratio index (APRI), and lower albumin. Immunohistochemical staining of CA19-9 revealed that CA19-9 expression was found exclusively in the background liver but not in HCC tumor cells. In contrast, tumor tissue was the main source of CA19-9 in ICC patients. CA19-9 ≥ 39 U/mL was associated with worse OS and RFS in both AFP-positive and negative HCC patients. CA19-9 indicated more severe inflammation and cirrhosis in the liver of HCC patients.

Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir).A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%).Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

OBJECTIVE To examine whether serum procalcitonin (PCT) is useful for differentiating acute pyelonephritis (APN) from asymptomatic bacteriuria and acute cystitis during pregnancy. METHODS A multicenter prospective observational study was conducted to compare serum white blood cell (WBC) counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and PCT level among pregnant women with asymptomatic bacteriuria, acute cystitis, and APN and healthy pregnant women (controls). Utility of WBC count, ESR, CRP, and PCT biomarkers for the prediction of APN during pregnancy were measured. RESULTS Area under the curve (AUC) values of PCT, CRP, ESR, and WBC count for predicting asymptomatic bacteriuria were 0.576, 0.628, 0.542, and 0.532, respectively; those for predicting acute cystitis were 0.766, 0.735, 0.681, and 0.597, respectively; and those for predicting acute pyelonephritis 0.859, 0.763, 0.711, and 0.732, respectively. Compared with the other inflammatory markers used to predict APN, PCT exhibited the highest AUC (0.859 [95% confidence interval (CI) 0.711-0.935]). A cutoff value of >0.25 ng/ml had a sensitivity of 87% and a specificity of 79%. CONCLUSION Serum PCT can be a valuable addition to existing methods of differentiating asymptomatic bacteriuria, acute cystitis, and APN during pregnancy and can facilitate the early identification of APN during pregnancy.

Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.

This paper mainly discusses the problem of fast fixed-time bipartite synchronization in the complex networks with signed graph that is based on TS fuzzy system. By designing suitable and effective controller, the synchronization of the considered complex networks has been achieved successfully in this paper, whose convergence rate is superior to the great majority of existing results. With the assistance of a comparison system being built and using the theory of Lyapunov stability, this paper has established sufficient criteria successfully that are able to achieve fast fixed-time bipartite synchronization. And a numerical simulation example displays the performance of the obtained new results at the end of this paper.

HY072808 is a novel phosphodiesterase 4 inhibitor currently under clinical development to treat atopic dermatitis. The first step is to address the pharmacokinetics and safety after topical administration of HY072808 ointments in healthy humans. In this study, we developed a highly sensitive liquid chromatography-tandem mass spectrometry method to determine plasma HY072808 and its active metabolite, ZZ24, in tiny amounts. The plasma samples were prepared using a simple liquid-liquid extraction method. Liquid chromatographic separation was achieved by gradient elution. The MS/MS quantification was performed in positive ion mode via multiple reaction monitoring. The method showed satisfactory linearity from 10 to 4,000 pg/ml for HY072808 and ZZ24. There was no significant interference from blank plasma. The method was validated for accuracy and precision, matrix effect and extraction recovery, dilution integrity, injection carryover and stability according to the related guidelines of the regulatory authorities. The HY072808 and ZZ24 concentrations in human plasma from a clinical trial were determined using this method. In conclusion, the validated method was robust and could be utilized to support the clinical development of HY072808.