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CX3CR1high myeloid cells in the small intestine mediate the induction of oral tolerance by driving regulatory T (Treg) cells. Bacterial metabolites, e.g. pyruvate and lactate, induce a dendrite extension of CX3CR1high myeloid cells into the intestinal lumen via GPR31. However, it remains unclear whether the pyruvate–GPR31 axis is involved in the induction of oral tolerance. Here, we show that pyruvate enhances oral tolerance in a GPR31-dependent manner. In ovalbumin (OVA)-fed Gpr31-deficient mice, an OVA-induced delayed-type hypersensitivity response was substantially induced, demonstrating the defective induction of oral tolerance in Gpr31-deficient mice. The percentage of RORγt+ Treg cells in the small intestine was reduced in Gpr31-deficient mice. In pyruvate-treated wild-type mice, a low dose of OVA efficiently induced oral tolerance. IL-10 production from intestinal CX3CR1high myeloid cells was increased by OVA ingestion in wild-type mice, but not in Gpr31-deficient mice. CX3CR1high myeloid cell-specific IL-10-deficient mice showed a defective induction of oral tolerance to OVA and a decreased accumulation of OVA-specific Treg cells in the small intestine. These findings demonstrate that pyruvate enhances oral tolerance through a GPR31-dependent effect on intestinal CX3CR1high myeloid cells.

Background Anastomotic leakage (AL) is one of the commonest and most serious complications after rectal cancer surgery. The previous analyses on predictors for AL included small-scale patients, and their prediction models performed unsatisfactorily. Methods Clinical data of 5,220 patients who underwent anterior resection for rectal cancer were scrutinized to create a prediction model via random forest classifier. Additionally, data of 836 patients served as the test dataset. Patients diagnosed with AL within 6 months' follow-up were recorded. A total of 20 candidate factors were included. Receiver operating characteristic (ROC) curve was conducted to determine the clinical efficacy of our model, and compare the predictive performance of different models. Results The incidence of AL was 6.2% (326/5,220). A multivariate logistic regression analysis and the random forest classifier indicated that sex, distance of tumor from the anal verge, bowel stenosis or obstruction, preoperative hemoglobin, surgeon volume, diabetes, neoadjuvant chemoradiotherapy, and surgical approach were significantly associated with AL. After propensity score matching, the temporary stoma was not identified as a protective factor for AL (P=0.58). Contrastingly, the first year of performing laparoscopic surgery was a predictor (P=0.009). We created a predictive random forest classifier based on the above predictors that demonstrated satisfactory prediction efficacy. The area under the curve (AUC) showed that the random forest had higher efficiency (AUC =0.87) than the nomogram (AUC =0.724). Conclusions Our findings suggest that eight factors may affect the incidence of AL. Our random forest classifier is an innovative and practical model to effectively predict AL, and could provide rational advice on whether to perform a temporary stoma, which might reduce the rate of stoma and avoid the ensuing complications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.

Correlation between blood inflammatory parameters and acute appendicitis (AA) remains controversial. This meta-analysis aims to evaluate whether platelet (PLT) indices including mean platelet volume (MPV), PLT count, and platelet distribution width (PDW) are associated with AA. Pubmed, Embase, and Cochrane Library databases were searched for observational studies published from inception through April 2020 by two independent investigators. Studies reporting associations between platelet indices and AA were selected for inclusion. Standardized mean difference (SMD) and 95% confidence interval (CI) were estimated for continuous outcomes using a DerSimonian-Laird random-effects model. Of 842 records identified, 17 studies with a total of 6793 subjects met our inclusion criteria. Meta-analysis indicated that compared with those in healthy controls, significant decrease in MPV levels was observed in subjects with AA (SMD - 0.34; 95% CI - 0.56 to - 0.12; P = 0.003). Subgroup analyses represented a significant reduction of MPV levels in patients aged ≥ 30 years and non-complicated/non-perforated AA. Due to the small number of studies and patients included in each subgroup, these subgroup analyses need to be interpreted with caution. However, none of the levels of PLT (SMD - 0.13; 95% CI - 0.28-0.012; P = 0.071) or PDW (SMD 0.30; 95% CI - 0.22-0.83; P = 0.257) was seen decrease or increase in subjects with AA. This meta-analysis indicates a significant decrease in MPV levels in patients with AA, which makes MPV have the potential of serving as a biomarker for AA. The associations of other PLT indices with AA need to be further examined.

Background MicroRNAs (miRNAs) play an important regulatory role in carcinogenesis and cancer progression. MiR-95-3p has been reported to be an oncogene in hepatocellular carcinoma. However, the role of miR-95-3p in colorectal carcinoma (CRC) remains unclear. Methods miR-95-3p was validated in an independent validation sample cohort of 215 CRC tissues. Functional assays, Cell proliferation (MTT) assay colony formation, wound healing, transwell and animal xenograft assays were used to determine the oppressor role of miR-95-3p in human CRC progression. Furthermore, Bioinformatics analysis, western blotting and dual-luciferase reporter assay were used to determine the mechanism by which miR-95-3p suppresses progression of CRC cells. Results In this study, we found that miR-95-3p was downregulated in CRC tissues. The low level of miR-95-3p in CRC tumors was correlated with aggressive clinicopathological characteristics, and it predicted poor prognosis in CRC patients. The overexpression of miR-95-3p significantly inhibited CRC cell proliferation, colony formation and metastasis in vitro and in vivo. Bioinformatic analysis further identified hepatoma-derived growth factor (HDGF) as a novel target of miR-95-3p in CRC cells. These findings suggest that miR-95-3p regulates CRC cell survival, partially through the downregulation of HDGF. Conclusions Therefore, the miR-95-3p/HDGF axis might serve as a novel therapeutic target in patients with CRC.

Purpose: MicroRNAs (miRNAs) are key regulators of the growth and development of a wide range of cancer types such as colorectal cancer (CRC). A number of previously studies have observed that the levels of miR-365a-3p expression are dysregulated in many cancers, but the specific role of this miRNA in CRC and its association with patient prognosis remains unclear. Methods: The expression of miR-365a-3p in CRC tissues and cell lines was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between miR-365a-3p expression and clinicopathological characteristics was further analyzed. After increasing the expression of miR-365a-3p by plasmid transfection in CRC cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among miR-365a-3p, ADAM10 and JAK in CRC, was explored by luciferase reporter assay. Results: In the present study, we determined that CRC cells and clinical samples exhibited decreased miR-365a-3p expression, and this was associated with larger tumor size, lymph node metastasis, and local invasion. Patients with lower expression of miR-365a-3p had significantly decreased recurrence-free survival (RFS) and overall survival (OS) relative to those with higher levels of this miRNA. In a multivariate analysis, we confirmed that reduced miR-365a-3p levels were independently predictive of poorer CRC patient outcomes. In a functional study, we determined that elevated miR-365a-3p expression inhibited the ability of CRC cells to proliferate and metastasize in vitro and in vivo. We further identified ADAM10 as a direct miR-365a-3p target, resulting in the suppression of ADAM10 expression in cells expressing this miRNA and ADAM10 levels were in turn closely linked to JAK/STAT signaling. Conclusion: Our study suggested the ability of miR-365a-3p to inhibit the progression of CRC at least in part via suppressing ADAM10 expression and associated JAK/STAT signaling, thus identifying this signaling axis as a possible prognostic and therapeutic target in CRC.

The molecular mechanisms governing the metastasis of colorectal cancer (CRC) are incompletely understood. In the present study, we found NOVA1 to be expressed at higher levels in CRC cell lines and tissue samples, and this upregulation was positively correlated with TNM stage (p = 0.034), poor differentiation (p = 0.001), and lymph node metastasis (p = 0.008). Both overall survival (OS) and relapse-free survival (RFS) were both significantly decreased in patients with high NOVA1 expression relative to those with low expression. Through a multivariate analysis, we determined that NOVA1 independently predicted poor outcomes in those with CRC. In further functional studies, we found that NOVA1 expression controlled the proliferation and invasive characteristics of CRC cells via a mechanism wherein NOVA1 bound and stabilized the IL6 mRNA, enhancing IL-6/JAK2/STAT3 signaling to in turn upregulate matrix metalloproteinases (MMPs) 2, 7, and 9. NOVA1 therefore plays key functional roles in regulating CRC progression, and our results further indicate that it serve as a valuable prognostic biomarker and potentially a target for therapeutic treatment in individuals with CRC.

The advent of the era of cloud computing and big data has brought opportunities for mental health education in colleges and universities, but it has also brought challenges. How can we use the advantages of cloud computing and big data to eliminate cloud computing and big data? The impact of the data age on us has become a problem that college mental health educators must face. Mental health educators in colleges and universities should emancipate their minds, update their concepts, and further improve their own data literacy; help college students establish a big data awareness of mental health education; realize personalized education; establish a mental health protection mechanism for college students to further develop college mental health education Lay a solid and firm foundation. Based on this research background, the paper uses computers to design a university mental health education platform, and uses big data analysis methods to analyze the current mental health status of college students.

BackgroundAltered expression profile of microRNAs (miRNAs) was reported to be associated with colorectal cancer (CRC). The aims of this study are to identify the changed miRNAs in the plasma of CRC patients and explore the underlying mechanism of these miRNAs during tumorigenesis.MethodsPlasma miRNA expression profiles were compared between healthy people and CRC patients. MiRNA expression was measured using quantitative real-time PCR. Colony formation and MTT assays were used to test cell proliferation. Luciferase assay, immunohistochemistry and Western blotting were employed to explore the molecular mechanism.ResultsMiR-142-3p level was found as the most significantly repressed miRNA in CRC patients. Overexpression of miR-142-3p dramatically repressed colony formation and cell proliferation of both HT29 and HCT116 cells while inhibition of miR-142-3p promoted those of the cells. Interestingly, overexpression of miR-142-3p reduced the level and nuclear accumulation of β-catenin. We further observed that miR-142-3p remarkably inhibited the transcriptional activity of β-catenin gene (CTNNB1). However, mutations in the predicted binding sites blocked this inhibition, suggesting that miR-142-3p may directly bind to the mRNA of β-catenin.ConclusionIn conclusion, we identified miR-142-3p exerts its function as a tumor suppressor through blocking the activation of Wnt signaling by directly targeting to CTNNB1.

A protective loop ileostomy is recommended in ultra-low rectal cancer to reduce the complications associated with anastomotic leakage (AL), but there are few studies on the complications after AL. The purpose of this study was to outline our experience in the successful treatment of severe abdominal infection after AL in rectal cancer patients with the protective loop ileostomy.In this report, we describe three cases of AL after standard total mesorectal excision with the protective loop ileostomy. Severe abdominal infection occurred postoperatively. The patients were successfully treated by surgical reintervention and had an uneventful recovery. No recurrence was observed after 2 years.We consider that pelvic floor reconstruction and extending the extubation time should be performed in patients with a high risk of AL. Moreover, when severe abdominal infection and early infectious shock occur after AL, immediate reoperation should be performed to minimize the complication.Protective loop ileostomy can't decrease the re-operation rate for patients with AL. We should take preventive measures during and after the operation, as well as early detection and early treatment.

Highlights • The hemoclip device is effective and safe for endoscopic closure of the anastomotic leakage after low anterior resection. • Hemoclip device reduce costs as well as avoid an additional operation for the patient. • Strict criteria should be applied when identifying suitable patients., Introduction and importance Hemoclips have been used to protect leakage after endoscopic resection of large colorectal polyps or early-staged rectal cancer, or for perforation of the sigmoid colon during colonoscopy. However, endoscopic clips were seldom used to manage anastomotic leakage after low anterior resection of rectal cancer. Case presentation A patient with postoperative anastomotic leakage after low anterior resection for rectal cancer was successfully treated by endoscopic hemoclips under colonoscopic vision after failure of conservative treatment. Postoperative course was uncomplicated and the patient was discharged from the hospital seven days later. Clinical discussion and conclusion Endoscopic hemoclips should be considered as an alternative option for the treatment of an anastomotic leakage in cases where conservative treatment has failed. As they are safe and effective for closure, however good bowel preparation and strict inclusion criteria are required.

SQUAMOSA promoter-binding protein-like (SPL) transcription factors are very important for the plant growth and development. Here 15 RoSPLs were identified in Rubus occidentalis. The conserved domains and motifs, phylogenetic relationships, posttranscriptional regulation, and physiological function of the 92 SPL family genes in Fragaria vesca, Malus domestica, Prunus persica, R. occidentalis, and Pyrus pyrifolia were analyzed. Sequence alignment and phylogenetic analysis showed the SPL proteins had sequence conservation, some FvSPLs could be lost or developed, and there was a closer relationship between M. domestica and P. pyrifolia, F. vesca and R. occidentalis, respectively. Genes with similar motifs clustering together in the same group had their functional redundancy. Based on the function of SPLs in Arabidopsis thaliana, these SPLs could be involved in vegetative transition from juvenile to adult, morphological change in the reproductive phase, anthocyanin biosynthesis, and defense stress. Forty-eight SPLs had complementary sequences of miR156, of which nine PrpSPLs in P. persica and eight RoSPLs in R. occidentalis as the potential targets of miR156 were reported for the first time, suggesting the conservative regulatory effects of miR156 and indicating the roles of miR156-SPL modules in plant growth, development, and defense response. It provides a basic understanding of SPLs in Rosaceae plants.

Hyperuricemia contributes to vascular injury and dysfunction, yet the potential mechanisms are not well understood. Uric acid (UA) has been found to stimulate macrophage migration inhibitory factor (MIF) up-regulation in renal tubules from rats subjected to UA-induced nephropathy. Given that MIF is able to induce vascular smooth muscle cell (VSMC) de-differentiation (from contractile state to a secretory state), we thus hypothesized that UA-induced vascular injury is via up-regulating of MIF in VSMCs, which enhancing vascular inflammation and VSMC transition. Within a mouse model of UA injection (500 mg/kg, twice/day, 14 days), we measured circulating and vascular MIF levels under UA stimulation at 6 h, day 1, and 14. We tested the efficacy of MIF inhibitor (10 mg/kg, twice/day, 14 days) on UA-induced vascular inflammation and remodeling. High plasma level of UA induced vascular MIF release into the plasma at acute phase. In the chronic phase, the protein level of MIF is up-regulated in the vessels. MIF inhibitor suppressed vascular inflammatory responses, repressed VSMC de-differentiation, and attenuated vascular remodeling and dysfunction following UA stimulation. Knockdown of MIF in cultured VSMCs repressed UA-induced de-differentiation. Our results provided a novel mechanism for MIF-mediated vascular injury in response to UA stimulation, and suggested that anti-MIF interventions may be of therapeutic value in hyperuricemic patients.

BACKGROUND: Improved patient satisfaction in endoscopy is worthy of study as it is an invasive and potentially uncomfortable procedure. There is growing literature on patient satisfaction assessment in endoscopy as part of improving quality assurance. This study aimed to determine whether virtual reality (VR) technology can decrease patients' pain and nervousness during colonoscopies. METHODS: Patients enrolled without sedation were randomly categorised into groups that watched VR (VR group; n=58) and those that did not watch VR (control group; n=59). The primary outcomes were pain score and skin conductance. Secondary endpoints included heart rate, systolic and diastolic arterial pressures, overall patient satisfaction, willingness to repeat the procedure, the difficulty of the procedure, the procedure duration, and bowel preparation. RESULTS: The median (interquartile range (IQR)) pain scores were 7 (6–8) and 5 (4–6) in the control and VR groups, respectively (p

Lithium-sulfur batteries (LSBs) have been considered as the future potential energy storage system with advantages of high energy density (2600 Wh kg-1), eco-friendliness and low cost. However, the poor conductivity and serious shuttle effects of polysulfides block their application. Herein, g-C3N4/carbon heterostructure on graphene nanosheet (PCNG) is constructed via phenyl-modified strategy and in-situ thermal polycondensation, which has a unique electron cloud distribution with excellent sulfur immobilization ability as well as good electroconductivity. As a result, Li-S cells with simple S/C cathodes and PCNG interlayers show a high initial capacity of 1192 mAh g-1 at 0.1 C, and an ultra-long lifespan with a slow capacity attenuation of 0.050% per cycle after 800 cycles. The cell with PCNG/PP separator also has a stable cycle performance at high area sulfur loading of 7 mg cm-2. These findings provide a new sight on functionalizing g-C3N4 for application in Li-S electrochemistry.

The State Council of China requires that all urban public hospitals must eliminate drug markups by September 2017, and that hospital drugs must be sold at the purchase price. Nanjing-one of the first provincial capital cities to implement the reform-is studied to evaluate the effects of the comprehensive reform on drug prices in public hospitals, and to explore differential compensation plans.Sixteen hospitals were selected, and financial data were collected over the 48-month period before the reform and for 12 months after the reform. An analysis was carried out using a simple linear interrupted time series model.The average difference ratio of drug surplus fell 13.39% after the reform, and the drug markups were basically eliminated. Revenue from medical services showed a net growth of 28.25%. The overall compensation received from government financial budget and medical service revenue growth was 103.69% for the loss from policy-permitted 15% markup sales, and 116.48% for the net loss. However, there were large differences in compensation levels at different hospitals, ranging from -21.92% to 413.74% by medical services revenue growth, causing the combined rate of both financial and service compensation to vary from 28.87-413.74%, There was a significant positive correlation between the services compensation rate and the proportion of medical service revenue (p .001), and the compensation rate increased by 8% for every 1% increase in the proportion of services revenue.Nanjing's pricing and compensation reform has basically achieved the policy targets of eliminating the drug markups, promoting the growth of medical services revenue, and adjusting the structure of medical revenue. However, the growth rate of service revenue of hospitals varied significantly from one another.Nanjing's reform represents successful pricing and compensation reform in Chinese urban public hospitals. It is recommended that a differentiated and dynamic compensation plan should be established in accordance with the revenue structure of different hospitals.

The purpose of this study was to evaluate the risk factors for anastomotic leakage (AL) after anterior resection for middle and low rectal cancer in order to help surgeons to decide which patients could benefit from a diverting stoma. Data on 319 patients having a middle and low rectal cancer resection with anastomosis between May 2011 and October 2015 from two hospitals were included in the study. The analysis included the following variables: patient-related variables (gender, age, diabetes mellitus, ASA score, preoperative radiochemotherapy, body mass index, blood hemoglobin, and serum albumin level), tumor-related variables (K-ras status, distance of tumor from the anal verge, histopathologic grade, pathological T stage, pathological N stage, pathological M stage, TNM stage, and tumor size), and surgery-related variables (laparoscopic or open surgery, blood loss, and operative time). Univariate and multivariate regression analysis were carried out to identify risk factors for AL. The AL rate was 11.91% (38/319). Male (OR 2.898, 95% CI 1.265–6.637, p = 0.012), diabetes mellitus (OR 2.482, 95% CI 1.004–6.134, p = 0.049), K-ras mutation (OR 2.544, 95% CI 1.210–5.348, p = 0.014), distance of tumor from the anal verge (OR 3.445, 95% CI 1.631–7.279, p = 0.001), and preoperative radiochemotherapy (OR 2.790, 95% CI 1.056–7.372, p = 0.039) were independent risk factors of AL. One (2.63%) in 38 patients with AL presented with no risk factor of AL, 6 (15.8%) in 38 patients with 1 risk factor, 16 (42.1%) in 38 patients with 2 risk factors, 9 (23.7%) in 38 patients with 3 risk factors, and 6 (15.7%) in 38 patients with 4 risk factors. No patient with 5 risk factors in our study. AL rate increased with the elevated number of risk factors clustering in individuals. K-ras mutation is first reported to be an independent risk factor for AL after sphincter-preserving surgery without diverting stoma. A diverting stoma should be performed in sphincter-preserving surgery for middle and low rectal cancer patients with 2 or more risk factors identified in this analysis.

Recent years have seen the rapid development of Location Based Services (LBSs). Many users of these services are making use of them to, for example, plan trips, find houses or explore their surroundings. In this paper we introduce a novel problem called the diversity and distribution-aware region search (DARS) problem. In particular, DARS aims to find regions of size \(a \times b\) where the number of different categories is maximized such that objects of different categories are not too scattered from each other and objects of the same category are within reasonable distance (which is a tunable parameter to cater for different users’ needs). We propose several methods to tackle the problem. We first design a sweepline based method, and then design various techniques to further improve the efficiency. We have conducted extensive experiments over real datasets and demonstrate both the usefulness and the efficiency of our methods.

Trajectory data contains abundant temporal and spatial information of moving objects. By calculating and analyzing trajectory data, behavior patterns of mobile objects can be found. Among these behavior patterns the discovery of chasing patterns is interesting which will provide effective services for intelligent urban traffic management, criminal investigation, environmental monitoring and other application fields. However, existing chasing pattern discovery methods only compare the local similarity of trajectories, and do not consider the potential significance of stay points or change in speed. This article proposes a new algorithm for chasing pattern discovery based on the stay point detection technology. An optimized stay point detection algorithm is also designed to improve the distance calculation method. The algorithms were evaluated with real and simulation trajectory data and achieved very good results which have higher accuracy and recall rate compared with the existing chasing pattern discovery algorithms.