Search

Abstract Objective Clinically significant portal hypertension (CSPH) seriously affects the feasibility and safety of surgical treatment for hepatocellular carcinoma (HCC) patients. The aim of this study was to establish a new surgical scheme defining risk classification of post-hepatectomy liver failure (PHLF) to facilitate the surgical decision-making and identify suitable candidates for individual hepatectomy among HCC patients with CSPH. Backgrounds Hepatectomy is the preferred treatment for HCC. Surgeons must maintain a balance between the expected oncological outcomes of HCC removal and short-term risks of severe PHLF and morbidity. CSPH aggravates liver decompensation and increases the risk of severe PHLF thus complicating hepatectomy for HCC. Methods Multivariate logistic regression and stochastic forest algorithm were performed, then the independent risk factors of severe PHLF were included in a nomogram to determine the risk of severe PHLF. Further, a conditional inference tree (CTREE) through recursive partitioning analysis validated supplement the misdiagnostic threshold of the nomogram. Results This study included 924 patients, of whom 137 patients (14.8%) suffered from mild-CSPH and 66 patients suffered from (7.1%) with severe-CSPH confirmed preoperatively. Our data showed that preoperative prolonged prothrombin time, total bilirubin, indocyanine green retention rate at 15 min, CSPH grade, and standard future liver remnant volume were independent predictors of severe PHLF. By incorporating these factors, the nomogram achieved good prediction performance in assessing severe PHLF risk, and its concordance statistic was 0.891, 0.850 and 0.872 in the training cohort, internal validation cohort and external validation cohort, respectively, and good calibration curves were obtained. Moreover, the calculations of total points of diagnostic errors with 95% CI were concentrated in 110.5 (range 76.9-178.5). It showed a low risk of severe PHLF (2.3%), indicating hepatectomy is feasible when the points fall below 76.9, while the risk of severe PHLF is extremely high (93.8%) and hepatectomy should be rigorously restricted at scores over 178.5. Patients with points within the misdiagnosis threshold were further examined using CTREE according to a hierarchic order of factors represented by the presence of CSPH grade, ICG-R15, and sFLR. Conclusion This new surgical scheme established in our study is practical to stratify risk classification in assessing severe PHLF, thereby facilitating surgical decision-making and identifying suitable candidates for individual hepatectomy.

Abstract Backgrounds To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone . Methods A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups. Results After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P

Endothelial cell specific-1 (ESM-1), also known as endocan, is a soluble dermatan sulfate proteoglycan that is mainly secreted by endothelial cells. Endocan is associated with tumorigenesis and cancer progression and is also related to cardiovascular disorders, autoimmune diseases, and sepsis. The phenylalanine-rich region and linear polysaccharide of endocan are necessary for the protein to exert its biological functions. Elevated plasma endocan levels reflect endothelial activation and dysfunction. In addition, endocan participates in complex inflammatory responses and proliferative processes. Here, we reviewed current research on endocan, elaborated the protein’s structure and biological functions, and speculated on its possible clinical value in nervous system diseases. We conclude that endocan may be a glycoprotein that plays an important role in neurological disorders.

Age and gender have been recognized as two pivotal covariates affecting the composition of the gut microbiota. However, their mediated variations in microbiota seem to be inconsistent across different countries and races. In this study, 613 individuals, whom we referred to as the “healthy” population, were selected from 1,018 volunteers through rigorous selection using 16S rRNA sequencing. Three enterotypes were identified, namely, Escherichia–Shigella, mixture (Bacteroides and Faecalibacterium), and Prevotella. Moreover, 11 covariates that explain the differences in microbiota were determined, with age being the predominant factor. Furthermore, age-related differences in alpha diversity, beta diversity, and core genera were observed in our cohort. Remarkably, after adjusting for 10 covariates other than age, abundant genera that differed between age groups were demonstrated. In contrast, minimal differences in alpha diversity, beta diversity, and differentially abundant genera were observed between male and female individuals. Furthermore, we also demonstrated the age trajectories of several well-known beneficial genera, lipopolysaccharide (LPS)-producing genera, and short-chain fatty acids (SCFAs)-producing genera. Overall, our study further elucidated the effects mediated by age and gender on microbiota differences, which are of significant importance for a comprehensive understanding of the gut microbiome spectrum in healthy individuals.

AimsThis cohort study aimed to explore the effect of a one-day online continuing medical education (CME) on the improvement of physicians’ knowledge and clinical practice on functional dyspepsia (FD).MethodsPhysicians were invited to participate in this CME via medical education applications. FD training videos made in advance were sent to participants via a weblink. Before and after training, participants were required to finish the FD knowledge test and provide case information of FD patients. McNemar test, Wilcoxon rank-sum test, Freidman test, Chi-square test, quantile regression, and generalized estimating equations (GEE) were used to perform statistical analysis.ResultsThere were 397 of 430 (92.33%) physicians finished this CME program. The total score of the FD knowledge test after training was significantly higher compared with before training [488.3 (468.3–510.0) vs. 391.7 (341.7–450.0), p

Abstract Background Vonoprazan results in more potent acid suppression for gastroesophageal reflux disease (GERD) than proton pump inhibitors. It has only been approved for treating erosive esophagitis in China, but 30–40% of GERD patients cannot achieve the goal of treatment with vonoprazan 20 mg daily. This study aims to investigate whether vonoprazan could relieve the symptoms of Chinese patients with non-erosive reflux disease (NERD) and whether increased dosage or different times of dosing could increase the response rate of GERD. Methods This study is a pragmatic, open-label, crossover-cluster, randomized controlled trial with patient preference arms. Two thousand eight hundred eighty patients with GERD from 48 hospitals in China will be enrolled. These hospitals will be divided into a compulsory randomization cluster (24 hospitals) and a patient preference cluster (24 hospitals). Patients in the compulsory randomization cluster will be randomized to three regimens according to the crossover-cluster randomization. Patients in the patient preference cluster may choose to receive any regimen if they have a preference; otherwise, patients will be randomly assigned. The three treatment regimens will last 4 weeks, including (1) vonoprazan 20 mg p.o. after breakfast, (2) vonoprazan 20 mg p.o. after dinner, and (3) vonoprazan 20 mg p.o. after breakfast and after dinner. Patients will attend a baseline visit, a 4-week e-diary, a fourth-week visit, and a sixth-month visit online. The primary outcome is the symptom relief rate of all patients after 4-week therapy. Secondary outcomes include the healing rate of EE patients, the severity of symptoms, compliance with the therapy at the fourth-week follow-up visit, recurrent symptoms, and the frequency of self-conscious doctor visits at the sixth-month follow-up visit. Discussion This trial will explore the effectiveness of different regimens of vonoprazan that will be implemented with GERD patients in China. The randomization with patient preferences considered and the crossover-cluster component may improve the robustness and extrapolation of study conclusions. Trial registration https://www.chictr.org.cn ChiCTR2300069857. Registered on 28 March 2023. Protocol version: February 18, 2023, Version 2.

Abstract Background and Aim Both intestinal symptoms and comorbidities exist in irritable bowel syndrome (IBS) patients and influence their quality of life (QOL). More research is needed to determine how these variables impact the QOL of IBS patients. This study aimed to determine which specific factors had a higher influence on QOL and to further compare the effects of intestinal symptoms and comorbidities on QOL. Methods IBS patients were recruited from six tertiary hospitals in different regions of China. QOL, gastrointestinal symptoms, and comorbidities were assessed by different scales. Correlation analysis, multiple linear regression, and mediation model were used for statistics. Results Four hundred fifty‐three IBS patients (39.7% women, mean age 45 years) were included and no significant differences in QOL were found across demographic characteristics. Abnormal defecation (r = −0.398), fatigue (r = −0.266), and weakness (r = −0.286) were found to show higher correlation with QOL. More than 40% of IBS patients were found to suffer from varying degrees of anxiety or depression, and anxiety (r = −0.564) and depression (r = −0.411) were significantly negatively correlated with QOL (P

Background: Dysbiosis is associated with colorectal cancer (CRC) and adenomas (CRA). However, the robustness of diagnostic models based on microbial signatures in multiple cohorts remains unsatisfactory.Materials and Methods: In this study, we used machine learning models to screen metagenomic signatures from the respective cross-cohort datasets of CRC and CRA (selected from CuratedMetagenomicData, each disease included 4 datasets). Then select a CRC and CRA data set from the CuratedMetagenomicData database and meet the requirements of having both metagenomic data and clinical data. This data set will be used to verify the inference that integrating clinical features can improve the performance of microbial disease prediction models.Results: After repeated verification, we selected 20 metagenomic features that performed well and were stably expressed within cross-cohorts to represent the diagnostic role of bacterial communities in CRC/CRA. The performance of the selected cross-cohort metagenomic features was stable for multi-regional and multi-ethnic populations (CRC, AUC: 0.817–0.867; CRA, AUC: 0.766–0.833). After clinical feature combination, AUC of our integrated CRC diagnostic model reached 0.939 (95% CI: 0.932–0.947, NRI=30%), and that of the CRA integrated model reached 0.925 (95%CI: 0.917–0.935, NRI=18%).Conclusion: In conclusion, the integrated model performed significantly better than single microbiome or clinical feature models in all cohorts. Integrating cross-cohort common discriminative microbial features with clinical features could help construct stable diagnostic models for early non-invasive screening for CRC and CRA.

ABSTRACT Early identification of severe 2019 coronavirus disease (COVID-19) cases is of great significance. We included 92 COVID-19 patients and 22 healthy controls and collected their laboratory test data and stool for metagenomic sequencing analysis. We found that the proportion of severe COVID-19 cases was significantly increased in patients with reduced lymphocytes and elevated neutrophils and had unique intestinal microbiota. Pseudothermotoga hypogea and Lachnospiraceae bacterium GAM79 were the species of bacteria that markedly decreased in COVID-19 patients compared to control individuals. For COVID-19 patients, Enterococcus sp. DA9, Caldicellulosiruptor obsidiansis, and Enterococcus faecium were the species of bacteria that significantly altered among patients with normal lymphocytes and neutrophils and patients with decreased lymphocytes and/or increased neutrophils, respectively. Fecal abundances of Enterococcus sp. DA9, Prevotella intermedia, and Bifidobacterium dentium were correlated with COVID-19 disease severity. Decreased lymphocytes and increased neutrophils, combined with decreased Bifidobacterium dentium and Prevotella intermedia, and increased Enterococcus sp. DA9 have the highest power to predict severe cases of COVID-19 patients (area under receiver operating characteristic curve: 0.79). In conclusion, changes in the abundance of intestinal bacteria can reflect the severity of COVID-19 disease, and the combination with lymphocytes and neutrophils might be prognostic factors of COVID-19. IMPORTANCE The 2019 coronavirus disease (COVID-19) patients had a unique profile of gut bacteria. In this study, we characterized the intestinal bacteria in our COVID-19 cohorts and found that there was an increased incidence of severe cases in COVID-19 patients with decreased lymphocytes and increased neutrophils. Levels of lymphocytes and neutrophils and abundances of intestinal bacteria correlated with the severity of COVID-19.

Abstract Spinal cord injury (SCI) animal models have been widely created and utilized for repair therapy research, but more suitable experimental animals and accurate modeling methodologies are required to achieve the desired results. In this experiment, we constructed an innovative dorsal 1/4 spinal cord transection macaque model that had fewer severe problems, facilitating postoperative care and recovery. In essence, given that monkeys and humans share similar genetics and physiology, the efficacy of this strategy in a nonhuman primate SCI model basically serves as a good basis for its prospective therapeutic use in human SCI.

Abstract Decubitus ulcers are a common spinal cord injury (SCI) complication that puts patients' lives in danger and has emerged as a more prevalent issue in modern clinical rehabilitation and care. Decubitus ulcers in humans can currently be treated in a number of different ways, but there are fewer studies on how to treat and care for decubitus ulcers in macaques. To treat a 20‐year‐old adult male macaque monkey with SCI and decubitus ulcers after a quarter transection of the thoracic spinal cord, a number of scientific care procedures and pharmaceutical treatments, such as dietary changes and topical or intravenous administration of medication, were carried out and continuously monitored in real‐time. In comparison to the untreated group, we observed a significant improvement in decubitus wound healing in the macaques. In this article, we provide a good protocol for decubitus ulcer care after SCI and suggest that future experimental animal modeling needs to focus on issues such as care for postoperative complications.

Abstract Background Diabetes-related limb ischemia is a challenge for lower extremity amputation. Aurora Kinase A (AURKA) is an essential serine/threonine kinase for mitosis, while its role in limb ischemia remains unclear. Method Human microvascular endothelial cells (HMEC-1) were cultured in high glucose (HG, 25 mmol/L d-glucose) and no additional growth factors (ND) medium to mimic diabetes and low growth factors deprivation as in vitro model. Diabetic C57BL/6 mice were induced by streptozotocin (STZ) administration. After seven days, ischemia was surgically performed by left unilateral femoral artery ligation on diabetic mice. The vector of adenovirus was utilized to overexpress AURKA in vitro and in vivo. Results In our study, HG and ND-mediated downregulation of AURKA impaired the cell cycle progression, proliferation, migration, and tube formation ability of HMEC-1, which were rescued by overexpressed AURKA. Increased expression of vascular endothelial growth factor A (VEGFA) induced by overexpressed AURKA were likely regulatory molecules that coordinate these events. Mice with AURKA overexpression exhibited improved angiogenesis in response to VEGF in Matrigel plug assay, with increased capillary density and hemoglobin content. In diabetic limb ischemia mice, AURKA overexpression rescued blood perfusion and motor deficits, accompanied by the recovery of gastrocnemius muscles observed by H&E staining and positive Desmin staining. Moreover, AURKA overexpression rescued diabetes-related impairment of angiogenesis, arteriogenesis, and functional recovery in the ischemic limb. Signal pathway results revealed that VEGFR2/PI3K/AKT pathway might be involved in AURKA triggered angiogenesis procedure. In addition, AURKA overexpression impeded oxidative stress and subsequent following lipid peroxidation both in vitro and in vivo, indicating another protective mechanism of AURKA function in diabetic limb ischemia. The changes in lipid peroxidation biomarkers (lipid ROS, GPX4, SLC7A11, ALOX5, and ASLC4) in in vitro and in vivo were suggestive of the possible involvement of ferroptosis and interaction between AUKRA and ferroptosis in diabetic limb ischemia, which need further investigation. Conclusions These results implicated a potent role of AURKA in diabetes-related impairment of ischemia-mediated angiogenesis and implied a potential therapeutic target for ischemic diseases of diabetes.

Abstract Background Our recent studies found that intestinal mechanical signals can regulate mucus synthesis and secretion of intestinal goblet cells through piezo type mechanosensitive ion channel component 1 (Piezo1), but the detailed molecular mechanisms remain to be investigated. Previous studies using a water avoidance stress (WAS) model reported decreased intestinal mucus accompanied by abnormal intestinal motility. It has also been reported that the expression of mucin2 was negatively correlated with histone H3 lysine 9 trimethylation (H3K9me3), a key regulator of histone methylation, and that mechanical stimulation can affect methylation. In this study, we aimed to determine whether and how Piezo1 expressed on goblet cells regulates mucus barrier function through methylation modification. Methods A murine WAS model was established and treated with Yoda1 (Piezo1 agonist), and specific Piezo1 flox-mucin2 Cre mice were also tested. The mucus layer thickness and mucus secretion rate of mouse colonic mucosa were detected by a homemade horizontal Ussing chamber, intestinal peristaltic contraction was detected by the ink propulsion test and organ bath, goblet cells and mucus layer morphology were assessed by HE and Alcian blue staining, mucus permeability was detected by FISH, and the expression levels of Piezo1, H3K9me3 and related molecules were measured by Western blots and immunofluorescence. LS174T cells were cultured on a shaker board in vitro to simulate mechanical stimulation. Piezo1 and H3K9me3 were inhibited, and changes in mucin2 and methylation-related pathways were detected by ELISAs and Western blots. ChIP-PCR assays were used to detect the binding of H3K9me3 and mucin2 promoters under mechanical stimulation. Results Compared with those of the controls, the mucus layer thickness and mucus secretion rate of the mice exposed to WAS were significantly decreased, the mucus permeability increased, the number of goblet cells decreased, and the intestinal contraction and peristalsis were also downregulated and disordered. Intraperitoneal injection of Yoda1 improved mucus barrier function and intestinal contraction. In the colonic mucosa of mice exposed to WAS, Piezo1 was decreased, and histone H3 lysine 9 trimethylation (H3K9me3) and methyltransferase suppressor of variegation 3–9 homolog 1 (SUV39h1) were increased, but activating Piezo1 alleviated these effects of WAS. Piezo1 flox-mucin2 Cre mice showed decreased mucus expression and increased methylation compared to wild-type mice. Cell experiments showed that mechanical stimulation induced the activation of Piezo1, decreased H3K9me3 and SUV39h1, and upregulated mucin2 expression. Inhibition of Piezo1 or H3K9me3 blocked the promoting effect of mechanical stimulation on LS174T mucin2 expression. The binding of H3K9me3 to the mucin2 promoter decreased significantly under mechanical stimulation, but this could be blocked by the Piezo1 inhibitor GsMTx4. Conclusion Piezo1 mediates mechanical stimulation to inhibit SUV39h1, thereby reducing H3K9me3 production and its binding to the mucin2 promoter, ultimately promoting mucin2 expression in goblet cells. This study further confirmed that piezo1 on goblet cells could regulate mucus barrier function through methylation.

Trilobatin (TBL) is a key sweet compound from the traditional Chinese sweet tea plant (Rubus suavissimus S. Lee). Because of its intense sweetness, superior taste profile, and minimal caloric value, it serves as an exemplary natural dihydrochalcone sweetener. It also has various health benefits, including anti-inflammatory and glucose-lowering effects. It is primarily produced through botanical extraction, which impedes its scalability and cost-effectiveness. In a novel biotechnological approach, phloretin is used as a precursor that is transformed into TBL by the glycosyltransferase enzyme ph-4′-OGT. However, this enzyme’s low catalytic efficiency and by-product formation limit the large-scale synthesis of TBL. In our study, the enzyme Mdph-4′-OGT was used to screen 17 sequences across species for TBL synthesis, of which seven exhibited catalytic activity. Notably, PT577 exhibited an unparalleled 97.3% conversion yield within 3 h. We then optimized the reaction conditions of PT577, attaining a peak TBL bioproduction of 163.3 mg/L. By employing virtual screening, we identified 25 mutation sites for PT577, thereby creating mutant strains that reduced by-products by up to 50%. This research enhances the enzymatic precision for TBL biosynthesis and offers a robust foundation for its industrial-scale production, with broader implications for the engineering and in silico analysis of glycosyltransferases.

Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Adopting banana peel as a raw material, the adsorption properties of banana peel hydrothermal carbon modified with a KOH solution for lead ions in aqueous solution were studied. The surface structure and functional groups of the modified hydrothermal carbon were analyzed by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared (FT-IR) spectroscopy, the Brunner–Emmet–Teller (BET) method, element analysis, and Raman spectroscopy. The results showed that an adsorption capacity of 42.92 mg/g and a removal rate of 86.84% were achieved when the banana peel hydrothermal carbon was modified with a KOH solution of 0.5 mol/L, with a pH of 6 and a solid–liquid ratio of 1 g/L. The equilibrium adsorption time for lead ions in solution being adsorbed using KOH-modified hydrothermal carbon was 240 min, the adsorption process satisfied the quasi-second-order kinetic model and the Redlich–Peterson isotherm equation, and the equilibrium removal efficiency was 88.62%. The adsorption of lead ions using KOH-modified hydrothermal carbon is mainly chemical–physical adsorption.

This study investigated the adsorption performance of hydrothermal carbon derived from banana peel and modified with different concentrations of phosphoric acid solution, then used to adsorb lead ions in an aqueous solution. The surface structure and functional groups of the modified hydrothermal carbon were analyzed using XRD, SEM, FT-IR, elemental analysis, and BET. The results showed that the adsorption capacity of modified hydrothermal carbon derived from banana peel reached 40.64 mg/g at a hydrothermal temperature of 240 °C, a phosphoric acid solution of 2 mol/L, and a solid–liquid ratio of 2 g/L, with a removal efficiency of 82.74%. The adsorption process conformed to the pseudo-second-order kinetic model and the Langmuir isotherm equation. The correlation coefficient of 0.99 for fitting the adsorption process using an artificial neural network, indicating that the artificial neural network could be used to predict adsorption. The adsorption of Pb(II) from an aqueous solution by phosphoric acid-modified hydrothermal carbon was dominated by monolayer chemical adsorption, and the adsorption mechanisms included electrostatic attraction, ion exchange, surface complexation, and physical adsorption.

BackgroundNecroptosis is an immune-related cell death pathway involved in the regulation of the tumor microenvironment (TME). Here, we aimed to explore the role of necroptosis in clear cell renal cell carcinoma (ccRCC) and construct a necroptosis-related lncRNA (NRL) model to assess its potential association with clinical characteristics and immune status.MethodsGene expression profiles and clinical data for ccRCC patients were obtained from the Cancer Genome Atlas (TCGA). Pearson’s correlation, univariate Cox, and least absolute shrinkage and selection operator analyses were used to develop an NRL model. Kaplan–Meier (K-M) and receiver operating characteristic (ROC) curve analyses were used to determine the prognostic value of the NRL model. The clinical information was used to assess the diagnostic value of the NRL model. The TME, immune function, immune cell infiltration, and immune checkpoints associated with the NRL model risk score were studied using the ESTIMATE, GSEA, ssGSEA, and CIBERSORT algorithms. The immunophenoscore (IPS) and half-maximal inhibitory concentration (IC50) were used to compare the efficacies of immunotherapy and chemotherapy based on the NRL model. Finally, in vitro assays were performed to confirm the biological roles of NRLs.ResultsA total of 18 necroptosis-related genes and 285 NRLs in ccRCC were identified. A four-NRL model was constructed and showed good performance in the diagnosis and prognosis of ccRCC patients. The ESTIMATE scores, tumor mutation burden, and tumor stemness indices were significantly correlated with NRL model risk score. Immune functions such as chemokine receptors and immune receptor activity showed differences between different risk groups. The infiltration of immunosuppressive cells such as Tregs was higher in high-risk patients than in low-risk patients. High-risk patients were more sensitive to immunotherapy and some chemotherapy drugs, such as sunitinib and temsirolimus. Finally, the expression of NRLs included in the model was verified, and knocking down these NRLs in tumor cells affected cell proliferation, migration, and invasion.ConclusionNecroptosis plays an important role in the progression of ccRCC. The NRL model we constructed can be used to predict the clinical characteristics and immune features of ccRCC patients.

Summary: Temporal associative learning binds discontiguous conditional stimuli (CSs) and unconditional stimuli (USs), possibly by maintaining CS information in the hippocampus after its offset. Yet, how learning regulates such maintenance of CS information in hippocampal circuits remains largely unclear. Using the auditory trace fear conditioning (TFC) paradigm, we identify a projection from the CA1 to the subiculum critical for TFC. Deep-brain calcium imaging shows that the peak of trace activity in the CA1 and subiculum is extended toward the US and that the CS representation during the trace period is enhanced during learning. Interestingly, such plasticity is consolidated only in the CA1, not the subiculum, after training. Moreover, CA1 neurons, but not subiculum neurons, increasingly become active during CS-and-trace and shock periods, respectively, and correlate with CS-evoked fear retrieval afterward. These results indicate that learning dynamically enhances stimulus information maintenance in the CA1-subiculum circuit during learning while storing CS and US memories primarily in the CA1 area.

Abstract. Background:. Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with an extremely poor prognosis. There is an urgent demand to explore novel therapeutic strategies. L-fucose has been confirmed to participate in anti-inflammation and antitumor activities. However, the effect of L-fucose on the progression of CCA has not been well investigated. This study aimed to determine whether L-fucose induced the inhibition of CCA and its possible mechanism. Methods:. The anti-growth activity was determined using Cell Counting Kit-8 assay, colony formation assays, Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assay, and cell cycle analysis. The anti-metastasis activity was determined by wound healing, transwell, and invasion assays. The anti-angiogenesis activity was determined by tube formation and transwell assays. MicroRNAs that may be involved in the L-fucose-induced CCA inhibition was analyzed using bioinformatics methods. The preclinical therapeutic efficacy was mainly estimated by ultrasound in xenograft nude mouse models. Differences were analyzed via Student's t test or one-way analysis of variance. Results:. L-Fucose induced apoptosis and G0/G1 cell cycle arrest, inhibited cell epithelial-mesenchymal transition of CCA cells, and additionally inhibited tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, leading to a decrease in cell proliferation, metastasis, and angiogenesis. Mechanistically, L-fucose induced microRNA-200b (miR-200b) upregulation, and mitogen-activated protein kinase 7 (MAPK7) downregulation was found to be targeted by miR-200b, with decreased cell proliferation and metastasis. Additionally, phosphorylated signal transducer and activator of transcription 3 was found to be downregulated after L-fucose treatment. Finally, in vivo experiments in CCA xenograft models also confirmed the antitumor properties of L-fucose. Conclusion:. L-Fucose inhibited the progression of CCA via the miR-200b/MAPK7 and signal transducer and activator of transcription 3 signaling pathways.

Abstract Background Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. Method To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). Results Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. Conclusion These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Abstract The coronavirus disease 2019 (COVID‐19) has presented unprecedented challenges to the generic drug development, including interruptions in bioequivalence (BE) studies. Per guidance published by the US Food and Drug Administration (FDA) during the COVID‐19 public health emergency, any protocol changes or alternative statistical analysis plan for COVID‐19‐interrupted BE study should be accompanied with adequate justifications and not lead to biased equivalence determination. In this study, we used a modeling and simulation approach to assess the potential impact of study outcomes when two different batches of a Reference Standard (RS) were to be used in an in vivo pharmacokinetic BE study due to the RS expiration during the COVID‐19 pandemic. Simulations were performed with hypothetical drugs under two scenarios: (1) uninterrupted study using a single batch of an RS, and (2) interrupted study using two batches of an RS. The acceptability of BE outcomes was evaluated by comparing the results obtained from interrupted studies with those from uninterrupted studies. The simulation results demonstrated that using a conventional statistical approach to evaluate BE for COVID‐19‐interrupted studies may be acceptable based on the pooled data from two batches. An alternative statistical method which includes a “batch” effect to the mixed effects model may be used when a significant “batch” effect was found in interrupted four‐way crossover studies. However, such alternative method is not applicable for interrupted two‐way crossover studies. Overall, the simulated scenarios are only for demonstration purpose, the acceptability of BE outcomes for the COVID19‐interrupted studies could be case‐specific.

Substantial mucosa defects in gastrointestinal tracts are difficult to repair, causing high mortality. Existing artificial mucosa studies overlooked the natural surface texture and the paracrine action between epithelial cells and fibroblasts, leading to an incomplete repair of the mucosa. Here, a Janus film with an exterior surface having a ridge-like texture and an interior flat surface to mimic the anatomical pattern of natural mucosa in digestive tracts is obtained through cryogenic electrospinning (e-spinning). Inspired by the natural mucosa surface textures, biopolymer nanofiber assemblies are employed to replicate the micro-ridges of the exterior layer of mucosa, while the flat surface mimics the morphology of the inferior layer. Hence, the exterior surface of Janus film bolsters epithelial cells' proliferation through the macro pores between fiber assemblies and the nanopores on fibers. In addition, the Janus film realizes a bilayer epithelium/lamina propria reconstruction by culturing epithelial cells and fibroblasts on different sides of the Janus film. Moreover, the Janus film assists the paracrine action between epithelial cells and fibroblasts while insulating their direct contact, an essential mimicry of the natural counterpart. In summary, it is proved that the Janus film will be a promising repair solution for mucosa defects in digestive tracts.

Summary: Asphalt binder is inevitably aged by ultraviolet (UV) light during its service period. UV ageing can significantly decrease the technical properties of asphalt binder. The sensitivity of asphalt to UV ageing and thermal-oxidative ageing differs, such that the UV ageing performance cannot be determined based on the thermal-oxidative ageing performance. Previous researches mainly focused on the chemical composite and technical performance changes of asphalt binder during UV ageing, and the UV light parameters effect on the ageing rate of asphalt binder. However, the theory for characterizing and explaining the development of UV ageing depth does not get too much attentions, and the UV ageing mechanism of asphalt binder is not very clear. Therefore, it cannot guide to develop or select the good methods or anti-UV ageing additives for asphalt binders. This paper focuses on the latest researches of the mechanisms and anti-ageing methods of asphalt binders. With the increase of UV ageing time, the UV ageing of asphalt binder develops gradually from the surface to inner part. There are various methods, such as low-penetration grade asphalt, less air void ratio, UV stabilizers and UV light absorbers, that can improve the UV ageing resistance of asphalt binders. A new theory of sensitive wavelengths of asphalt UV ageing is proposed, which can enrich the basic theory of asphalt UV ageing. Depending on this theory, different wavelengths of UV light have different ageing effects on asphalt binder. The composite anti-UV ageing additives with barrier and specific absorption effects on UV light is proposed, and may have better improvement effect on the anti-UV ageing performance of asphalt binder.

Abstract Background Systemic inflammatory response (SIR) plays a crucial role in every step of tumorigenesis and development. More recently, the fibrinogen-to-albumin ratio (FAR), an inflammation-based model, was suggested as a prognostic maker for various cancer patients. This research aimed to estimate the prognostic abilities of FAR, neutrophil–lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet– lymphocyte ratio (PLR), and systemic immune–inflammation index (SII) in patients with hepatocellular carcinoma (HCC) subjected to curative hepatectomy. Methods A total of 1,502 cases who underwent hepatectomy for HCC were included. The predictive performances of FAR, NLR, MLR, PLR and SII were assessed with regards to overall survival (OS) and disease-free survival (DFS). The area under the time-dependent receiver operating characteristic curve was used to compare prognostic performances. Results Data revealed that FAR had higher predictive accuracy than other inflammation-based models and alpha-fetoprotein (AFP) in assessing OS and DFS. Indeed, the OS and DFS of patients with high FAR (> 8.9), differentiated by the optimal cut-off value of FAR, were remarkably reduced (p

AimsThis study aimed to evaluate the safety, efficacy, and long-term outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) for treating colorectal adenomas and tumors.MethodsA systematic literature review was conducted using databases including PubMed, Web of Science, and Embase. Parameters such as number of patients or lesions, histological diagnosis, lesion size, surgery time, en-bloc resection, R0 resection, severe postoperative complications, and local recurrence were extracted and pooled for analysis.ResultsA total of 12 retrospective studies involving 1289 patients and 1850 lesions were included in the analysis. EMR was found to have a shorter operation time by 53.6 minutes (95% CI: 51.3, 55.9, PConclusionsThe study suggests that the choice of surgical method may have a greater impact on recurrence compared to the pathological type, and that ESD may be more suitable for the treatment of malignant lesions despite its higher rates of severe postoperative complications and longer operation time.

PurposeTo evaluate the outcomes and prognostic factors for patients using conversion therapy with lenvatinib combined with transcatheter arterial chemoembolization (TACE) plus programmed cell death protein-1 (PD-1) inhibitors (LTP) for initially unresectable hepatocellular carcinoma (iuHCC).MethodsData on 94 consecutive patients with iuHCC who received LTP conversion therapy from November 2019 to September 2022 were retrospectively analyzed. Early tumor response was reported when patients showed complete or partial response at the time of their first follow-up (4–6 weeks) after initial treatment, in accordance with mRECIST. The endpoints consisted of conversion surgery rate, overall survival (OS), and progression-free survival (PFS).ResultsEarly tumor response was found in 68 patients (72.3%) and not in the remaining 26 patients (27.7%) in the entire cohort. Early responders had a significantly higher conversion surgery rate than non-early responders (44.1% vs. 7.7%, p=0.001). Early tumor response was the only factor independently associated with successful conversion resection, as indicated by multivariate analysis (OR=10.296; 95% CI: 2.076–51.063; p=0.004). Survival analysis showed that early responders had longer PFS (15.4 vs. 7.8 months, p=0.005) and OS (23.1 vs. 12.5 months, p=0.004) than non-early responders. Early responders who underwent conversion surgery also had significantly longer median PFS and OS (not reached, not reached) than those who did not (11.2 months, p=0.004; 19.4 months, p

ObjectiveThis study aimed to analyze the association between the activity of daily living (ADL), coronavirus disease (COVID-19), and the value of the Barthel Index in predicting the prognosis of patients.MethodsThis study included 398 patients with COVID-19, whose ADL at admission to hospital were assessed with the Barthel Index. The relationship between the index and the mortality risk of the patients was analyzed. Several regression models and a decision tree were established to evaluate the prognostic value of the index in COVID-19 patients.ResultsThe Barthel Index scores of deceased patients were significantly lower than that of discharged patients (median: 65 vs. 90, P < 0.001), and its decrease indicated an increased risk of mortality in patients (P < 0.001). After adjusting models for age, gender, temperature, pulse, respiratory rate, mean arterial pressure, oxygen saturation, etc., the Barthel Index could still independently predict prognosis (OR = 0.809; 95% CI: 0.750–0.872). The decision tree showed that patients with a Barthel Index of below 70 had a higher mortality rate (33.3–40.0%), while those above 90 were usually discharged (mortality: 2.7–7.2%).ConclusionThe Barthel Index is of prognostic value for mortality in COVID-19 patients. According to their Barthel Index, COVID-19 patients can be divided into emergency, observation, and normal groups (0–70; 70–90; 90–100), with different treatment strategies.

In the theoretical controller design of the high-speed supercavitating vehicle (HSSV), there will always be the problem that the physical saturation limit has to be exceeded by the motion range of the actuator to satisfy the requirements of stable motion of the supercavitating vehicle. This paper proposes a solution which could satisfy the requirements of stable motion of the vehicle without saturation of the actuator. First of all, the rotation range of the actuator and the motion performance of the vehicle with robust controller are analyzed under the condition where saturation is neglected. Then, according to the analysis conclusion, the controller is improved by using linear active disturbance rejection control (LADRC) method, which provides the additional control component to reduce the rotation angle and rotation speed of the actuator. Finally, the simulation proves that the solution could realize the stable motion of vehicle without saturation of actuator.

Aiming at the problems of complex equations, low accuracy, and the strict measurement point layout requirements of the existing electric field integration method, a non-contact measurement method based on the inversion voltage of the near electric field is proposed. Firstly, the field source relationship is clarified, the connection between the spatial electric field and the voltage is derived, and a near-end electric field inversion method is proposed. Secondly, a three-dimensional simulation model of an overhead line is established using COMSOL finite element software, the three-dimensional spatial potential distribution of the overhead line is obtained, and the voltage is inverted and calculated. Finally, an overhead line simulation test platform was built, and MEMS electric field sensors were used for testing and verification. The results show that the maximum error of the three-phase voltage inversion of the proximal electric field measurement is 6.8%, and the error between the voltage obtained by the experimental inversion measurement and the reference voltage is less than 7.2%. The simulation and experimental results also verify the accuracy and feasibility of the inversion voltage of the proximal electric field. The results of this paper can lay a foundation for the practical application of small and miniaturized electric field sensors, and help in the construction and development of smart grids.

Drug–drug interaction (DDI) prediction is one of the essential tasks in drug development to ensure public health and patient safety. Drug combinations with potentially severe DDIs have been verified to threaten the safety of patients critically, and it is therefore of great significance to develop effective computational algorithms for identifying potential DDIs in clinical trials. By modeling DDIs with a graph structure, recent attempts have been made to solve the prediction problem of DDIs by using advanced graph representation learning techniques. Still, their representational capacity is limited by isomorphic structures that are frequently observed in DDI networks. To address this problem, we propose a novel algorithm called DDIGIN to predict DDIs by incorporating a graph isomorphism network (GIN) such that more discriminative representations of drugs can thus be learned for improved performance. Given a DDI network, DDIGIN first initializes the representations of drugs with Node2Vec according to the topological structure and then optimizes these representations by propagating and aggregating the first-order neighboring information in an injective way. By doing so, more powerful representations can thus be learned for drugs with isomorphic structures. Last, DDIGIN estimates the interaction probability for pairwise drugs by multiplying their representations in an end-to-end manner. Experimental results demonstrate that DDIGIN outperforms several state-of-the-art algorithms on the ogbl-ddi (Acc = 0.8518, AUC = 0.8594, and AUPR = 0.9402) and DDInter datasets (Acc = 0.9763, AUC = 0.9772, and AUPR = 0.9868). In addition, our case study indicates that incorporating GIN enhances the expressive power of drug representations for improved performance of DDI prediction.

Abstract Objective This study aims to evaluate the diagnostic value of D-dimer for acute aortic dissection (AAD) by the method of meta-analysis. Methods PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases from the establishment of the databases to December 2020 were systematically searched, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) system was used to evaluate the quality of the literature. STATA 15.0 software was applied to calculate the pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (+LR), negative likelihood ratio (−LR) to draw summary receiver operating characteristics (SROC) curve and calculate the area under the curve (AUC). Meta-regression and subgroup analyses were used to explore the source of heterogeneity. Results A total of 16 clinical studies were enrolled in this study, including 1135 patients. The results of the meta-analysis showed that the pooled sensitivity was 0.96 (95% CI 0.91–0.98), the pooled specificity was 0.70 (95% CI 0.57–0.81), and the pooled DOR was 56.57 (95% CI 25.11–127.44), the pooled +LR was 3.25 (95% CI 2.18–4.85), the pooled −LR was 0.06 (95% CI 0.03–0.12), and the AUC was 0.94 (95% CI 0.91–0.95). Meta-regression and subgroup analysis results showed that publication year, sample size and cutoff value might be sources of heterogeneity. When the concentration of D-dimer was less than or equal to 500 ng/ml, the sensitivity significantly increased. Conclusion D-dimer has an excellent diagnostic value for AAD. It is a useful tool for detecting suspected AAD because of the excellent pooled sensitivity. D-dimer ≤ 500 ng/ml increases the potential to identify the suspected patients with AAD.

ObjectiveTo estimate the magnitude of the nocebo response and explore its influencing factors in irritable bowel syndrome (IBS).MethodsThe PubMed, Embase, and Cochrane Library databases were searched up to March 2021. We performed a random effects meta-analysis of the proportion of adverse events (AEs) in placebo-treated patients with IBS who are involved in parallel-designed, randomized, placebo-controlled trials investigating pharmacological interventions and evaluated the effect of trial characteristics on the magnitude of the nocebo response rate.ResultsA total of 6,107 studies were identified from the databases. After evaluation, 53 met the eligibility criteria and were included. The overall pooled nocebo response rate was 32% (95% CI: 26–38%). The most commonly reported AEs were headache (9%), nasopharyngitis (7%), abdominal pain (4%), and nausea (4%). The nocebo response rate was low compared with that in the treatment group applying probiotics, antispasmodics, and Traditional Chinese medicine, but high compared with that in antibiotic treatment group. The nocebo rate in patients using diaries to record AEs was lower than the average, and was higher in patients recording through checkup.DiscussionPatients with IBS have significant nocebo response intensity in clinical trials. Based on findings in this study, we recommend the researchers pay attention to the common AEs and carefully analyze the relation to the intervention.

The UV aging of bitumen has a significant influence on the pavement service life, therefore, the research on UV aging has attracted increasing attention recently. It is known that the aging of bituminous pavements does not occur instantly through the full depth, instead, the aging depth of the bitumen increases gradually with the increasing aging time. The limitation of the research is that the development mechanism of the aging depth of bitumen is not clearly known. Various thicknesses of bituminous membranes were prepared and the UV light transmission and absorption properties of bituminous membranes were investigated by UV–visible spectrophotometric, aiming to determine the penetration depth of UV light in bitumen after UV aging. It is concluded that, for the same bituminous membrane, the transmittance of UV light increases with the increase of the light wavelength; while the transmittance of UV light decreases significantly with the increase of bituminous membrane thickness. The penetration depth of UV light in bitumen increases gradually with increasing UV aging time. The relationship between UV light penetration depth in bitumen and aging depth of bitumen was analyzed, and UV aging models of three parts of bitumen were established to reveal the development mechanism of the UV aging depth of bitumen during UV aging. The increasing aging depth of bitumen is due to the increase of UV light penetration depth in bitumen, and the diffusion action of aging products from surface bitumen to deeper bitumen. During the UV aging, the bitumen actually comprises three parts, namely, the surface direct aging part (UV light can reach), the deeper diffusion aging part (aged by the diffusion action) and the internal unaged part (UV light and diffusion action can not affect).

Ethnopharmacological relevance: Zhizhu Kuanzhong (ZZKZ) is a traditional Chinese medicine modified from classic formula Zhizhu decoction in “Synopsis of Golden Chamber” (Han Dynasty in the 3rd century) and the Zhizhu pill in “Differentiation on Endogenous” in Jin Dynasty (1,115–1,234). ZZKZ contains four botanical drugs, including Citrus × Aurantium L [Rutaceae; Aurantii Fructus Immaturus], Atractylodes Macrocephala Koidz. [Compositae; Rhizoma Atractylodis Macrocephalae], Bupleurum Chinense DC [Apiaceae; Radix Bupleuri Chinensis], and Crataegus Pinnatifida Bunge [Rosaceae; Fructus Crataegi Pinnatifidae], which have been widely used in clinical therapy for functional dyspepsia (FD).Aim of the study: This study aimed to evaluate the pharmacological effects and mechanisms of action of ZZKZ on gastric hypersensitivity and motor dysfunction in a rat model of FD.Materials and methods: FD was induced in Sprague-Dawley rats by neonatal gastric irritation with 0.1% iodoacetamide. The FD rats were treated with ZZKZ (0.5 g/kg, 1.0 g/kg, or 1.5 g/kg respectively) by gavage for 7 days, while domperidone (3 mg/kg) acted as treatment control. Body weight gain, food intake, gastric emptying, and intestinal propulsion were also measured. Ex vivo gastric smooth muscle activity recordings and greater splanchnic afferent (GSN) firing recordings were employed to evaluate gastric motility and sensation. Particularly, the role of 5-HT in the action of ZZKZ in improving gastric dysmotility and hypersensitivity was explored.Results: ZZKZ promoted weight gain, food intake, gastric emptying, and intestinal propulsion in FD rats. ZZKZ promoted spontaneous and ACh-induced contractions of gastric smooth muscle strips in FD rats, alleviated spontaneous activity, and chemical (acid perfusion) and mechanical (intragastric distension) stimulated GSN firing in FD rats. ZZKZ ameliorated gastric smooth muscle contraction and GSN firing induced by 5-HT in FD rats. ZZKZ stimulated the release of serum 5-HT, with reduced 5-HT3 receptor and increased 5-HT4 receptor mRNA expression in the guts of FD rats.Conclusion: This study demonstrated that ZZKZ improves FD-related gastric hypersensitivity and motor dysfunction and should be an effective compound for relieving FD symptoms. The gastric 5-HT system with lower 5-HT3 activity and increased 5-HT4 distribution is involved in the mechanisms of ZZKZ underlying the treatment of FD.

Dysfunction of the mucus layer allows commensal and pathogenic microorganisms to reach the intestinal epithelium, thereby leading to infection and inflammation. This barrier is synthesized and secreted by host goblet cells. Many factors that influence the function of goblet cells (GCs) have been studied. However, how the microenvironment surrounding GCs influences the mucus layer and microbiota of the colon is unclear. To explore the effect of GC Piezo1 on the mucus layer and microbiota in the colon, we generated an intestinal epithelial Piezo1 conditional knockout mouse model. The fecal-associated microbiota (FAM) and mucosa-associated microbiota (MAM) of the two groups were characterized based on amplicon sequencing of the 16S rRNA gene. Our results showed that GC Piezo1-/- mice developed decreased GC numbers, thinner mucus layer, and increased inflammatory cytokines (e.g., CXCL1, CXCL2, IL-6) on the 7th day. In addition, decreased Spdef and increased DOCK4 were discovered in KO mice. Meanwhile, the diversity and richness were increased in MAM and decreased in FAM in the GC Piezo1-/- group compared with the GC Piezo1+/+ group. We also observed increased abundances of Firmicutes and decreased abundances of Verrucomicrobiota and Actinobacteriota in the MAM of the GC Piezo1-/- group. Additionally, BugBase predicts that potentially pathogenic bacteria may have increased in the inner mucus layer, which is consistent with the higher abundance of Helicobacter hepaticus, Lactobacillus johnsonii, Escherichia-Shigella and Oscillospiraceae in MAM. These results further support the hypothesis that the role of Piezo1 in GCs is important for maintaining the function of the mucus layer and intestinal microbiota balance in the mouse colon.

BackgroundFecal microbiota transplantation (FMT) is an effective treatment for intestinal and extra-intestinal disorders. Nonetheless, long-term safety and efficacy remain major challenges for FMT applications. To date, few long-term follow-up studies have been published on FMT in children.MethodsRetrospective reviewed the medical charts of 74 patients who underwent 508 FMT courses between August 2014 and July 2019 at our medical center. All the FMT procedures followed uniform standards. Baseline characteristics pre-FMT and follow-up data were collected at 1, 3, 6, 12, 36, 60, and 84 months after FMT. All potential influencing factors for adverse events (AEs) were analyzed and assessed using regression analyses.ResultsA total of 70 (13.7%) short-term AEs occurred in twenty-six patients (35.1%). Most AEs (88.5%) occurred within 2 days post-FMT. A total of 91.4% of the AEs were self-limiting. Ulcerative colitis (UC) and within four times of FMT were associated with a higher rate of AEs (p = 0.028 and p = 0.021, respectively). The primary clinical remission rate after FMT was as high as 72.9%. Twenty-five children were followed for more than 5 years after FMT. The clinical remission rates gradually decreased over time after FMT. During follow-up, none of the patients developed autoimmune, metabolic, or rheumatologic disorders or tumor-related diseases. However, nine children developed rhinitis, five developed rhinitis, were underweight, and six developed constipation.ConclusionsFMT is a safe and effective treatment for dysbiosis in children. The long-term efficacy of FMT for each disease decreased over time. Moreover, multiple FMTs are recommended 3 months post-FMT for recurrent diseases.

Abstract Background Epithelial–mesenchymal transition (EMT) promotes migration, invasion, and metastasis of hepatocellular carcinoma (HCC) cells. The molecular mechanisms behind EMT and metastasis in HCC remain unclear. Methods Microarray analysis was used to identify lncRNAs expression during polarization of U937 macrophages from M2 to M1 phenotype. The expression of the identified lncRNA was compared between clinical samples of HCC tissues or adjacent normal tissues, as well as between HCC and normal liver cell lines. lnc-Ma301 was overexpressed or knocked-down in HCC cell lines, and the effects were assessed in vitro and in vivo. Interactions among lnc-Ma301 and its potential downstream targets caprin-1 were investigated in HCC cell lines. Effects of lnc-Ma301 over- and underexpression on the Akt/Erk1 signaling pathways were examined. Results Microarray analyses identified lnc-Ma301 as one of the most overexpressed long non-coding RNAs during polarization of U937 macrophages from M2 to M1 phenotype. Lnc-Ma301 showed lower expression in HCC tissues than in adjacent normal tissues, and lower expression was associated with worse prognosis. Activation of lnc-Ma301 inhibited cell proliferation, migration and EMT in HCC cell cultures, and it inhibited lung metastasis of HCC tumors in mice. Mechanistic studies suggested that lnc-Ma301 interacts with caprin-1 to inhibit HCC metastasis and EMT through Akt/Erk1 pathway. Conclusions Lnc-Ma301 may help regulate onset and metastasis of HCC.

PANoptosis is a newly-discovered cell death pathway that involves crosstalk and co-ordination between pyroptosis, apoptosis, and necroptosis processes. However, the roles of PANoptosis-related genes (PRGs) in prognosis and immune landscape of colon cancer remain widely unknown. Here, we performed a bioinformatics analysis of expression data of nineteen PRGs identified from previous studies and clinical data of colon cancer patients obtained from TCGA and GEO databases. Colon cancer cases were divided into two PRG clusters, and prognosis-related differentially expressed genes (PRDEGs) were identified. The patient data were then separated into two corresponding distinct gene clusters, and the relationship between the risk score, patient prognosis, and immune landscape was analyzed. The identified PRGs and gene clusters correlated with patient survival and immune system and cancer-related biological processes and pathways. A prognosis signature based on seven genes was identified, and patients were divided into high-risk and low-risk groups based on the calculated risk score. A nomogram model for prediction of patient survival was also developed based on the risk score and other clinical features. Accordingly, the high-risk group showed worse prognosis, and the risk score was related to immune cell abundance, cancer stem cell (CSC) index, checkpoint expression, and response to immunotherapy and chemotherapeutic drugs. Results of quantitative real-time polymerase chain reaction (qRT-PCR) showed that LGR5 and VSIG4 were differentially expressed between normal and colon cancer samples. In conclusion, we demonstrated the potential of PANoptosis-based molecular clustering and prognostic signatures for prediction of patient survival and tumor microenvironment (TME) in colon cancer. Our findings may improve our understanding of the role of PANoptosis in colon cancer, and enable the development of more effective treatment strategies.

The study was conducted to construct a cellular senescence-related risk score signature to predict prognosis and immunotherapy response in colon cancer. Colon cancer data were acquired from the Gene Expression Omnibus and The Cancer Genome Atlas databases. And cellular senescence-related genes were obtained from the CellAge database. The colon cancer data were classified into different clusters based on cellular senescence-related gene expression. Next, prognostic differential genes among clusters were identified with survival analysis. A cellular senescence-related risk score signature was developed by performing the LASSO regression analysis. Finally, PCA analysis, t-SNE analysis, Kaplan-Meier survival analysis, ROC analysis, univariate Cox regression analysis, multivariate Cox regression analysis, C-index analysis, meta-analysis, immune infiltration analysis, and IPS score analysis were used to evaluate the significance of the risk signature for predicting prognosis and immunotherapy response in colon cancer. The colon cancer data were classified into three clusters. The patients in cluster A and cluster B had longer survival. A cellular senescence-related risk score signature was developed. Patients in the low-risk score group showed a better prognosis. The risk score signature could predict colon cancer patients’ prognosis independently of other clinical characteristics. The risk score signature predicted the prognosis of colon cancer patients more accurately than other signatures. Patients in the low-risk score group showed a better response to immunotherapy. The opposite was true for the high-risk score group. In conclusion, the cellular senescence-related risk score signature could be used for the prediction of prognosis and immunotherapy response in colon cancer.

Step counting is an effective method to assess the activity level of grazing sheep. However, existing step-counting algorithms have limited adaptability to sheep walking patterns and fail to eliminate false step counts caused by abnormal behaviors. Therefore, this study proposed a step-counting algorithm based on behavior classification designed explicitly for grazing sheep. The algorithm utilized regional peak detection and peak-to-valley difference detection to identify running and leg-shaking behaviors in sheep. It distinguished leg shaking from brisk walking behaviors through variance feature analysis. Based on the recognition results, different step-counting strategies were employed. When running behavior was detected, the algorithm divided the sampling window by the baseline step frequency and multiplied it by a scaling factor to accurately calculate the number of steps for running. No step counting was performed for leg-shaking behavior. For other behaviors, such as slow and brisk walking, a window peak detection algorithm was used for step counting. Experimental results demonstrate a significant improvement in the accuracy of the proposed algorithm compared to the peak detection-based method. In addition, the experimental results demonstrated that the average calculation error of the proposed algorithm in this study was 6.244%, while the average error of the peak detection-based step-counting algorithm was 17.556%. This indicates a significant improvement in the accuracy of the proposed algorithm compared to the peak detection method.

Concrete structures are subjected to various forms of damage in cold regions. However, the interfacial bonding properties of traditional concrete (NC) reinforced with textile-reinforced cementitious composite (TRECC) under freeze–thaw cycle damage have not been fully studied. In this paper, different control groups were obtained by adjusting the types and layers of Fiber Reinforced Plastics (FRP) in TRECC and the interfacial roughness level between TRECC and NC. After experiencing 0–300 freeze–thaw cycles, each group underwent the uniaxial tensile test, three-point bending test, and scanning electron microscope observation. The results show that FRP type in TRECC can determine the strength of specimens. After 100 freeze–thaw cycles, the ultimate tensile strength of TRECC with two different FRP types increased by 38.4% and 55.3%, respectively, compared with TRECC. Furthermore, the bond strength and resistance to freeze–thaw damage of TRECC-NC interface increased with the increase of roughness under the action of freeze–thaw cycles. After 100 freeze–thaw cycles, the bonding strength of the repair system reached the highest. Compared with 0 freeze–thaw cycles, the ultimate tensile strength of the TRECC-NC reinforcement system under low roughness and high roughness increased by 50.05% and 61.25%, respectively. Meanwhile, the internal cracks of TRECC gradually developed and penetrated, reducing the cooperative working ability between TRECC-NC.

Fundamental sheep behaviours, for instance, walking, standing, and lying, can be closely associated with their physiological health. However, monitoring sheep in grazing land is complex as limited range, varied weather, and diverse outdoor lighting conditions, with the need to accurately recognise sheep behaviour in free range situations, are critical problems that must be addressed. This study proposes an enhanced sheep behaviour recognition algorithm based on the You Only Look Once Version 5 (YOLOV5) model. The algorithm investigates the effect of different shooting methodologies on sheep behaviour recognition and the model’s generalisation ability under different environmental conditions and, at the same time, provides an overview of the design for the real-time recognition system. The initial stage of the research involves the construction of sheep behaviour datasets using two shooting methods. Subsequently, the YOLOV5 model was executed, resulting in better performance on the corresponding datasets, with an average accuracy of over 90% for the three classifications. Next, cross-validation was employed to verify the model’s generalisation ability, and the results indicated the handheld camera-trained model had better generalisation ability. Furthermore, the enhanced YOLOV5 model with the addition of an attention mechanism module before feature extraction results displayed a mAP@0.5 of 91.8% which represented an increase of 1.7%. Lastly, a cloud-based structure was proposed with the Real-Time Messaging Protocol (RTMP) to push the video stream for real-time behaviour recognition to apply the model in a practical situation. Conclusively, this study proposes an improved YOLOV5 algorithm for sheep behaviour recognition in pasture scenarios. The model can effectively detect sheep’s daily behaviour for precision livestock management, promoting modern husbandry development.

This Special Issue is devoted to research on asphalt pavement materials, including asphalt binders, asphalt mixtures and recycled asphalt pavement (RAP) [...]

Tumor metastasis is one of the major factors for the high mortality in cholangiocarcinoma (CCA), but its underlying mechanisms are not fully understood. Here, we report that Piezo-type mechanosensitive ion channel component 1 (Piezo 1) is detected to be significantly upregulated in CCA tissues, which is linked to a poor prognosis in patients, suggesting that Piezo 1 may act in a pro-metastatic role in CCA development. Piezo 1 is activated through 20% simulated physiological stretch, and deleting Piezo 1 impedes epithelial-to-mesenchymal transition (EMT) of CCA cells, as well as impairing their metastatic capacity in vitro and in vivo. Mechanistically, the activation of Piezo 1 results in large amounts of Yes-associated protein 1 (YAP) translocated into the nucleus from the cytoplasm, and thus the motility of CCA cells is significantly increased. These findings indicate that mechanical stimulation induces Piezo 1 activation, which might be involved in CCA metastasis via the Hippo/YAP signaling axis. Therefore, Piezo 1 and its downstream effectors may be a novel therapeutic target for CCA treatment.

Our study aimed to explore the effect of cellular senescence and to find potential therapeutic strategies for gastric cancer. Cellular senescence-related genes were acquired from the CellAge database, while gastric cancer data were obtained from GEO and TCGA databases. SMARCA4 had the highest mutation frequency (6%), and it was linked to higher overall survival (OS) and progression-free survival (PFS). The gastric cancer data in TCGA database served as a training set to construct a prognostic risk score signature, and GEO data were used as a testing set to validate the accuracy of the signature. Patients with the low-risk score group had a longer survival time, while the high-risk score group is the opposite. Patients with low-risk scores had higher immune infiltration and active immune-related pathways. The results of drug sensitivity analysis and the TIDE algorithm showed that the low-risk score group was more susceptible to chemotherapy and immunotherapy. Most patients with mutation genes had a lower risk score than the wild type. Therefore, the risk score signature with cellular senescence-related genes can predict gastric cancer prognosis and identify gastric cancer patients who are sensitive to chemotherapy and immunotherapy.

Heavy metal (HM) contamination resulting from industrialization and urbanization during the Anthropocene along with plant invasion can severely threaten the growth and adaptation of local flora. Invasive alien plant species generally exhibit a growth pattern consistent with their functional traits in non-contaminated environments in the introduced range. However, it remains unclear whether invasive alien plants have an advantage over native plants in contaminated environments and whether this growth pattern is dependent on the adaptation of their leaf functional traits. Here, we selected two congeneric pairs of invasive alien and native grasses that naturally co-exist in China and are commonly found growing in contaminated soil. To evaluate the effect of cadmium (Cd) on the structural and physiological leaf traits, we grew all four species in soil contaminated without or with 80 mg/kg Cd. Invasive plants contained significantly higher concentrations of Cd in all three organs (leaf, stem, and root). They displayed a higher transfer factor and bioconcentration factor (BCF) of shoot and root than natives, indicating that invasive species are potential Cd hyperaccumulators. Invasive plants accumulated polyphenol oxidase (PPO) to higher levels than natives and showed similar patterns of leaf structural and physiological traits in response to changes in Cd bioconcentration. The quantifiable leaf structural traits of invasive plants were significantly greater (except for stomatal density and number of dead leaves) than native plants. Leaf physiological traits, chlorophyll content, and flavonoid content were also significantly higher in invasive plants than in natives under Cd stress conditions after 4 weeks, although nitrogen balance index (NBI) showed no significant difference between the two species. Chlorophyll fluorescence parameters decreased, except for the quantum yield of photosystem II (ΦPSII) and the proportion of open photosystem II (qP), which increased under Cd stress conditions in both species. However, invasive plants exhibited higher fluorescence parameters than natives under Cd stress, and the decrement observed in invasive plants under Cd stress was greater than that in natives. High Cd adaptation of invasive grasses over natives suggests that invasive plants possess optimal leaf structural and physiological traits, which enable them to adapt to stressful conditions and capture resources more quickly than natives. This study further emphasizes the potential invasion of alien plants in contaminated soil environments within the introduced range. To a certain extent, some non-invasive alien plants might adapt to metalliferous environments and serve as hyperaccumulator candidates in phytoremediation projects in contaminated environments.

Abstract. Background:. The possible association between shift work with irritable bowel syndrome (IBS) and functional dyspepsia (FD) remains controversial. The purpose of the study is to conduct a meta-analysis to explore the potential association between shift work with IBS/FD. Methods:. We searched relevant observational studies on Medline (PubMed) and Embase until June 30, 2021. Two different investigators extracted data and assessed the quality of each study independently. The meta-analysis was used to evaluate the pooled odds risk (OR) between shift work and IBS/FD. Results:. Eight studies were included ultimately. Shift workers were more likely to suffer from IBS. The OR of shift work was 1.81 (95% confidence interval 1.42; 2.32) with low heterogeneity (P .05) for FD. Conclusions:. There was a positive association between shift work and IBS. The prevalence of IBS was 81% higher among shift workers than among non-shift workers. Shift work was probably a risk factor for IBS. The low heterogeneity supports the reliability of the results. However, there was no significant association between shift work and FD. The strength of the evidence was limited and further prospective cohort studies were needed.

BackgroundWith the development of the Internet, more and more patients search for disease-related information on video platforms during the treatment process, and physicians also look for learning materials through these video platforms. Bilibili is one of the most popular video platforms in China. This study evaluated information on various interesting topics, and related surgical procedures searched through Bilibili.MethodThe Bilibili platform was independently queried for 12 common vascular diseases or related surgical procedures between October and November 2021 by two independent authors using the Baidu search engine. Information about the video and uploader was collected, and descriptive analyses of the overall and first-page results were performed.ResultsA total of 3,998 search results were retrieved by searching 12 vascular-related topics, of which 2,225 actual videos (55.7%) were finally confirmed to be related to medicine. Videos for the public accounted for 84.8% of these 2,225 videos. In addition, 50.5% of the video results were uploaded by vascular surgeons, 12.4% by other specialties, 17.7% by organizations, and 19.4% by other individuals. The total number of videos searched for varicose vein and peripheral vascular diseases was the largest, and the total number of leg amputation videos was the smallest. The largest number of videos for medical professionals was about pulmonary embolism, and the smallest was about leg amputation. On the first pages, 168 results (70.0%) were actually medically relevant, and only 7.7% of the videos were uploaded by vascular surgeons.ConclusionOn the Bilibili platform, videos about vascular diseases are extensive but not comprehensive. The videos uploaded by vascular surgeons are rare, and the results searched are not precise. The online presence of vascular surgeons needs to be improved, which may partially solve the problem of low-quality videos due to the lack of strict management and censorship.

Cerebral small vessel disease (CSVD) poses a serious socio-economic burden due to its high prevalence and severe impact on the quality of life of elderly patients. Pathological changes in CSVD mainly influence small cerebral arteries, microarteries, capillaries, and small veins, which are usually caused by multiple vascular risk factors. CSVD is often identified on brain magnetic resonance imaging (MRI) by recent small subcortical infarcts, white matter hyperintensities, lacune, cerebral microbleeds (CMBs), enlarged perivascular spaces (ePVSs), and brain atrophy. Endothelial cell (EC) dysfunction is earlier than clinical symptoms. Immune activation, inflammation, and oxidative stress may be potential mechanisms of EC injury. ECs of the blood–brain–barrier (BBB) are the most important part of the neurovascular unit (NVU) that ensures constant blood flow to the brain. Impaired cerebral vascular autoregulation and disrupted BBB cause cumulative brain damage. This review will focus on the role of EC injury in CSVD. Furthermore, several specific biomarkers will be discussed, which may be useful for us to assess the endothelial dysfunction and explore new therapeutic directions.