Search

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.

BackgroundCetuximab is an effective antibody to treat colorectal cancer (CRC) by targeting the epidermal growth factor receptor (EGFR). However, the mechanisms of acquired resistance to cetuximab therapy, especially in patients without identifiable gene mutations, are not fully understood.MethodsOur study investigated the role of pumilio RNA-binding family member 1 (PUM1) in cetuximab resistance. We established cetuximab-resistant colon cancer cell lines SW480R and Caco-2R and knocked out PUM1 and DEAD-box helicase 5 (DDX5) with the clustered regularly interspaced short palindromic repeats (CRISPR)-caspase 9 (Cas9) system. To check cell proliferation, we used Cell Counting Kit-8. We performed qPCR and immunoblot to examine the levels of mRNAs and proteins for each cell line.ResultsOur data showed that PUM1 was upregulated in SW480R and Caco-2R cells with increased protein levels and cell proliferation, and PUM1 knockout reduced cell viability in the presence of cetuximab. We also found that PUM1 interacted with DDX5 in 3′ untranslated region (UTR) and positively regulated its mRNA expression. Furthermore, suppression of DDX5 also decreased the proliferation of SW480R and Caco-2R cells.ConclusionOur study suggests that PUM1 positively regulates DDX5 and acts as a promoter in cetuximab-resistant colon cancer cells.

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.

In this paper, we study the problem of GPS trajectory data cleaning, aiming to clean the noises in trajectory data. The noises can be generated due to many factors, such as GPS devices failure, sensor error, transmission error and storage error. Existing cleaning algorithms usually focus on certain types of noises and have many limitations in applications. In this paper, we propose a data-driven approach to clean the noises by exploiting historical trajectory point cloud. We extract road information from the historical trajectories and use such information to detect and correct the noises. As compared to map matching techniques, our method does not have many requirements such as high sampling rates, and it is robust to noises and nonuniform distribution in the historical trajectory point cloud. Extensive experiments are conducted on real datasets to demonstrate that the proposed approach can effectively clean the noises while not utilizing any map information.

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.

Herpesviruses constitute a large family of disease-causing DNA viruses. Each herpesvirus strain is capable of infecting particular organisms with a specific cell tropism. Upon infection, pattern recognition receptors (PRRs) recognize conserved viral features to trigger signaling cascades that culminate in the production of interferons and pro-inflammatory cytokines. To invoke a proper immune response while avoiding collateral tissue damage, signaling proteins involved in these cascades are tightly regulated by post-translational modifications (PTMs). Herpesviruses have developed strategies to subvert innate immune signaling pathways in order to ensure efficient viral replication and achieve persistent infection. The ability of these viruses to control the proteins involved in these signaling cascades post-translationally, either directly via virus-encoded enzymes or indirectly through the deregulation of cellular enzymes, has been widely reported. This ability provides herpesviruses with a powerful tool to shut off or restrict host antiviral and inflammatory responses. In this review, we highlight recent findings on the herpesvirus-mediated post-translational control along PRR-mediated signaling pathways.

Herpesviruses can be detected by pattern recognition receptors (PRRs), which then activate downstream adaptors, kinases and transcription factors (TFs) to induce the expression of interferons (IFNs) and inflammatory cytokines. IFNs further activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, inducing the expression of interferon-stimulated genes (ISGs). These signaling events constitute host innate immunity to defeat herpesvirus infection and replication. A hallmark of all herpesviruses is their ability to establish persistent infection in the presence of active immune response. To achieve this, herpesviruses have evolved multiple strategies to suppress or exploit host innate immune signaling pathways to facilitate their infection. This review summarizes the key host innate immune components and their regulation by herpesviruses during infection. Also we highlight unanswered questions and research gaps for future perspectives.

To solve the problems encountered in practical processes of magneto-optical sensing, the infinitesimal distributed-parameter model and finite-element accumulation of different dielectric properties of micromaterials were used to describe the evolution of light polarization states, instead of the previously commonly used method of lumped-parameter simulation, thus essentially explaining the mechanism of sensing, magneto-optical effects, and related factors, and achieving multiphysics coupling using the COMSOL finite-element analysis method. Considering the cases of the Faraday effect without and with line birefringence, the magneto-optical effect and output characteristics of an infinitesimal magneto-optical sensor were simulated and studied. The results verified the effectiveness of the infinitesimal sensor model. Because the magnetic field, stress, and temperature changes alter the dielectric properties of magneto-optical materials, the finite-element accumulation method lays a good foundation for research on theoretical analysis and performance of magneto-optical sensors affected by factors such as the magnetic field, temperature, and stress.

Advanced BiCMOS technology is a cost-effective candidate for wide-range of applications, including Radar (automotive radars, high-speed industrial sensors), high-speed wireless and wireline communication, high-speed instrumentation, and mmWave THz imaging and sensing that require high performance SiGe HBTs with high cut-off frequencies fT and high maximum frequencies fMAX. Development of SiGe HBTs in BiCMOS technology with both high fT and fMAX faces significant challenges. Vertical scaling is employed to increase fT in advanced SiGe HBTs including reduction in base and collector thickness or by increasing the collector doping. All these approaches reduce the carrier transit times, but result in an increase in the base resistance and the collector-base capacitance, which degrade fMAX. To overcome these limits, lateral scaling is necessary to reduce the base resistance and the collector-base capacitance. Reduction in emitter width reduces the intrinsic base resistance and Ccb, self-aligned emitter-base integration schemes reduce the extrinsic base link resistance, and raised extrinsic base helps with lower Rb and Ccb. In short, these scaling rules and approaches would need to reduce both base resistance and collector-base capacitance simultaneously for improved fMAX and fT In this paper, results from two experimental studies are presented in a 90nm SiGe BiCMOS technology. Compared with the baseline, one experiment shows more reduction in collector-base capacitance, while the other shows more reduction in base resistance. Both experiments achieved 300GHz fT and met or exceeded the 360GHz fMAX goal of the technology. In addition to straight vertical and lateral scaling, a series of experiments employing other process techniques and structure innovation have also been studied and are reviewed in this paper, including millisecond anneal techniques, low temperature silicide and low temperature contact processes, and secondary trench isolation, achieving fT around 300GHz and fMAX toward half THz.

Welcome to G03: SiGe, Ge, and Related Compounds: Materials, Processing, and Devices 9! Take a moment to listen to welcome remarks from the lead organizer, Qizhi Liu.

Gene editing with CRISPR/Cas9 is a powerful tool to study the function of target genes. Although this technology has demonstrated wide efficiency in many species, including fertilized zebrafish and medaka fish embryos when microinjected, its application to achieve efficient gene editing in cultured fish cells have met some difficulty. Here, we report an efficient and reliable approach to edit genes in cultured medaka (Oryzias latipes) fish cells using pre-formed gRNA-Cas9 ribonucleoprotein (RNP) complex. Both medaka fish haploid and diploid cells were transfected with the RNP complex by electroporation. Efficient gene editing was demonstrated by polymerase chain reaction (PCR) amplification of the target gene from genomic DNA and heteroduplex mobility assay carried out with polyacrylamide gel electrophoresis (PAGE). The heteroduplex bands caused by RNP cleavage and non-homologous end joining could be readily detected by PAGE. DNA sequencing confirmed that these heteroduplex bands contains the mutated target gene sequence. The average gene editing efficiency in haploid cells reached 50%, enabling us to generate a clonal cell line with ntrk3b gene mutation for further study. This RNP transfection method also works efficiently in diploid medaka cells, with the highest mutation efficiency of 61.5%. The specificity of this synthetic RNP CRISPR/Cas9 approach was verified by candidate off-target gene sequencing. Our result indicated that transfection of pre-formed gRNA-Cas9 RNP into fish cells is efficient and reliable to edit target genes in cultured medaka fish cells. This method will be very useful for gene function studies using cultured fish cells., Summary: In this paper, we report an efficient genome editing method for cultured medaka fish cells using pre-formed CRISPR/Cas9 RNP. This method will be very useful for gene function studies using cultured fish cells.

This paper presents a new trajectory search engine called Torch for querying road network trajectory data. Torch is able to efficiently process two types of typical queries (similarity search and Boolean search), and support a wide variety of trajectory similarity functions. Additionally, we propose a new similarity function LORS in Torch to measure the similarity in a more effective and efficient manner. Indexing and search in Torch works as follows. First, each raw vehicle trajectory is transformed to a set of road segments (edges) and a set of crossings (vertices) on the road network. Then a lightweight edge and vertex index called LEVI is built. Given a query, a filtering framework over LEVI is used to dynamically prune the trajectory search space based on the similarity measure imposed. Finally, the result set (ranked or Boolean) is returned. Extensive experiments on real trajectory datasets verify the effectiveness and efficiency of Torch.

C-type lectins (CTLs) are a large family of calcium-dependent carbohydrate-binding proteins. They function primarily in cell adhesion and immunity by recognizing various glycoconjugates. We identified 14 transcripts encoding proteins with one or two CTL domains from the transcriptome from Asian corn borer, Ostrinia furnacalis (Guenée; Lepidoptera: Pyralidae). Among them, five (OfCTL-S1 through S5) only contain one CTL domain, the remaining nine (OfIML-1 through 9) have two tandem CTL domains. Five CTL-Ss and six OfIMLs have a signal peptide are likely extracellular while another two OfIMLs might be cytoplasmic. Phylogenetic analysis indicated that OfCTL-Ss had 1:1 orthologs in Lepidoptera, Diptera, Coleoptera and Hymenoptera species, but OfIMLs only clustered with immulectins (IMLs) from Lepidopteran. Structural modeling revealed that the 22 CTL domains adopt a similar double-loop fold consisting of β-sheets and α-helices. The key residues for calcium-dependent or independent binding of specific carbohydrates by CTL domains were predicted with homology modeling. Expression profiles assay showed distinct expression pattern of 14 CTLs: the expression and induction were related to the developmental stages and infected microorganisms. Overall, our work including the gene identification, sequence alignment, phylogenetic analysis, structural modeling, and expression profile assay would provide a valuable basis for the further functional studies of O. furnacalis CTLs.

The true survival benefit of different curative strategies involving type of operative procedure and timing for patients with initial noncurative colorectal liver metastases remains uncertain. The goal of this study was to examine the effect of primary tumor resection on patients’ survival and to clarify the predictive factors related to overall survival (OS). This was a retrospective study that included 219 patients with initial noncurative colorectal liver metastases without extrahepatic disease. The clinicopathological characteristics of patients and their survival were examined. Survival analysis was performed using the Kaplan–Meier method. All variables associated with P

Insertional mutagenesis (IM) by retrovirus (RV) is a high-throughput approach for interrogating gene functions in model species. Haploid cell provides a unique system for genetic screening by IM and prosperous progress has been achieved in mammal cells. However, little was known in lower vertebrate cells. Here, we report development of retroviral vectors (rvSAchCVgfp, rvSAchCVpf and rvSAchSTpf) and establishment of IM library in medaka haploid cells. Each vector contains a modified gene trapping (GT) cassette, which could extend the mutated cell population including GT insertions not in-frame or in weakly expressed genes. Virus titration determined by flow cytometry showed that rvSAchSTpf possessed the highest supernatant virus titer (1.5×10(5)TU/ml) in medaka haploid cell, while rvSAchCVpf produced the lowest titer (2.8×10(4)TU/ml). However, quantification of proviral DNAs in transduced cells by droplet digital PCR (ddPCR) demonstrated that the "real titer" may be similar among the three vectors. Furthermore, an IM library was established by FACS of haploid cells transduced with rvSAchCVgfp at a MOI of 0.1. A single copy RV integration in the majority of cells was confirmed by ddPCR in the library. Notably, there was a significant decrease of haploid cell percentage after FACS, suggesting potential trapping for survival/growth essential genes. Our results demonstrated successful development of retroviral vectors for IM in medaka haploid cells, serving for haploid genetic screening of host factors for virus infection and genes underlying certain cellular processes in fish model.

Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues (P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/β-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC.

Conventional recommendation systems often use binary relations matrices, which could not represent raw data sets efficiently and uniformly. The graph model can represent multiple relationships and form a unified standard of the feature space to recommend the candidate items. Existing graph-based work is generally based on the path to establish the feature space of the data, only concerned about the impact of an item on the description of the user. Utilizing combination features to construct user profiles, this paper concentrates on the contribution maked by combination of items and designs a user-based collaborative filtering algorithm (CFC), and validates the validity of the algorithm in the prototype of the proposed system. The experimental results show that the recommendation algorithms can significantly improve accuracy of the recommendation.

The problem of Influence Maximization (IM) aims to find a small set of k nodes (seed nodes) in a social network G that could maximize the expected number of nodes. It has been proven to be #P-hard, and many approximation algorithms and heuristic algorithms have been proposed to solve this problem in polynomial time. Those algorithms, however, either trade effectiveness for practical efficiency or vice versa. In order to make a good balance between effectiveness and efficiency, this paper introduces a novel ranking method to identify the influential nodes without computing their exact influence. In particular, our method consists of two phases, the influence ranking and the node selection. At the first phase, we rank the node’s influence based on the centrality of the network. At the second phase, we greedily pick the nodes of high ranks as seeds by considering their marginal influence to the current seed set. Experiments on real-world datasets show that the effectiveness of our method outperforms the state-of-the-art heuristic methods by 3% to 25%; and its speed is faster than the approximate method by at least three orders of magnitude (e.g., the approximate method could not complete in 12 h even for a social network of |V| = 196,591 and |E| = 950,327, while our method completes in 100 s).

Background/Aims: Mitochondria (MT) and mitochondrial DNA (mtDNA) show maternal inheritance in most eukaryotic organisms; the sperm mtDNA is usually delivered to the egg during fertilization and then rapidly eliminated to avoid heteroplasmy, which can affect embryogenesis. In our previous study, fertilization-delivered sperm mtDNA exhibited late elimination and transcriptional quiescence in cyprinid fish embryos. However, the mechanisms underlying elimination and transcriptional quiescence of paternal mtDNA are unclear. Methods: Goldfish and zebrafish were used to investigate the fate of mtDNAs with different parental origins delivered by fertilization or microinjection in embryos. Goldfish MT from heart, liver and spermatozoa were microinjected into zebrafish zygotes, respectively. Specific PCR primers were designed so that the amplicons have different sizes to characterize goldfish and zebrafish cytb genes or their cDNAs. Results: The MT injection-delivered paternal mtDNA from sperm, as well as those from the heart and liver, was capable of persistence and transcription until birth, in contrast to the disappearance and transcriptional quiescence at the heartbeat stage of fertilization-delivered sperm mtDNA. In addition, the exogenous MT-injected zebrafish embryos have normal morphology during embryonic development. Conclusions: The fate of paternal mtDNA in fishes is dependent on the delivery strategy rather than the MT source, suggesting that the presence of sperm factor(s) is responsible for elimination and transcriptional quiescence of fertilization-delivered sperm mtDNA. These findings provide insights into the mechanisms underlying paternal mtDNA fate and heteroplasmy in cyprinid fishes.

Interspecies hybridization is widely used in aquaculture as a beneficial strategy. Diploid and triploid hybrids have been detected from the interspecies hybridization of Epinephelus coioides ♀ × Epinephelus lanceolatus ♂. This is the first report of triploidization through hybridization in grouper. Confirmation has been obtained through flow cytometry, karyotyping and erythrocyte nuclei measurement. The chromosome numbers of E. coioides, E. lanceolatus, diploid hybrid grouper are 48 and triploid hybrid grouper are 72. Measurements of erythrocyte nuclei indicate that triploid fish have a larger nuclear surface than the diploid groupers, and the average ratio of triploid to diploid surface area is 1.59. During the first 1.5 years, triploid hybrid groupers grow faster than diploid hybrid groupers or either parent species. The average growth rate of triploid hybrids is 1.61 times greater than that of diploid hybrids at 6 months of age and 1.43 times greater at 18 months of age. The triploid hybrid groupers are inferior in gonadal development, with no primary-growth-stage oocytes appearing in the gonads at 18 months of age. Morphological studies indicate that triploid hybrid groupers have distinctive differences in snout length, eye diameter, body trunk shape, and tail shape development compared with diploid hybrid groupers. Triploid hybrid groupers have an advantage in growth ability, and artificial breeding of triploid groupers might be of great potential use in the grouper aquaculture industry.

Objective Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis. Design We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided. Results Five signatures were selected to construct a subnetwork. The expression of GRB2 , PTPN11 , ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71). Conclusions Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis.

BACKGROUND It has been speculated that zinc finger protein 148 (ZNF148) is a tumor suppressor. However, to the authors' knowledge, little is known about the clinical significance of ZNF148 expression in patients with colorectal cancer (CRC). The objective of the current study was to clarify the association between ZNF148 expression and the postoperative prognosis of patients with CRC. METHODS Tissue microarrays containing 56 normal mucosa, 51 adenoma, 742 CRC (TNM stage I-IV), 16 familial adenomatous polyposis, and 21 metastatic CRC specimens were examined immunohistochemically for ZNF148 expression. RESULTS Expression of ZNF148 was found to increase consecutively from normal mucosa to stage I CRC, and then decreased consecutively from stage I to stage IV CRC. Lower expression of ZNF148 in tumors was found to be significantly associated with lymph node metastases, advanced TNM disease stage, poor differentiation, higher rate of disease recurrence, worse overall survival (OS), and shorter disease-free survival. High expression of ZNF148 was also associated with improved OS (P = .025) and disease-free survival (P = .042) in patients with stages II to III CRC. On multivariate Cox analysis, lower ZNF148 expression in tumors, advanced TNM stage, colon cancer, and elevated serum carbohydrate antigen 19-9 (CA19-9) were found to be significant factors for a worse OS. In 16 patients with familial adenomatous polyposis, ZNF148 expression was upregulated at steps toward carcinogenesis. In 21 patients with metastatic CRC, although ZNF148 expression was higher in primary tumors compared with adjacent mucosa, its expression in metastatic tumors was significantly lower than that in primary tumors. CONCLUSIONS Although ZNF148 expression is related to colorectal carcinogenesis, high ZNF148 expression in patients with CRC appears to be inversely associated with malignant phenotypes and may serve as a significant prognostic factor after surgery for patients with CRC. Cancer 2013;119:2212–2222. © 2013 American Cancer Society.

In this paper, we study the problem of assessing the quality of co-reference tuples extracted from multiple low-quality data sources and finding true values from them. It is a critical part of an effective data integration solution. In order to solve this problem, we first propose a model to specify the tuple quality. Then we present a framework to infer the tuple quality based on the concept of quality predicates. In particular, we propose an algorithm underlying the framework to find true values for each attribute. Last, we have conducted extensive experiments on real-life data to verify the effectiveness and efficiency of our methods.

Viral infection is a great challenge in healthcare and agriculture. The Singapore grouper iridovirus (SGIV) is highly infectious to numerous marine fishes and increasingly threatens mariculture and wildlife conservation. SGIV intervention is not available because little is known about key players and their precise roles in SGVI infection. Here we report the precise role of VP088 as a key player in SGIV infection. VP088 was verified as an envelope protein encoded by late gene orf088. We show that SGIV could be neutralized with an antibody against VP088. Depletion or deletion of VP088 significantly suppresses SGIV infection without altering viral gene expression and host responses. By precisely quantifying the genome copy numbers of host cells and virions, we reveal that VP088 deletion dramatically reduces SGIV infectivity through inhibiting virus entry without altering viral pathogenicity, genome stability and replication and progeny virus release. These results pinpoint that VP088 is a key player in SGIV entry and represents an ideal target for SGIV intervention.

It is known that the hypothalamic-pituitary-gonadal axis participates in the sex change of hermaphrodite teleosts, and gonadal steroid hormones mediate this physiological process. The secretion of gonadal steroids is directly regulated by signaling pathways involving gonadotropins (GtHs) and gonadotropin receptors (GtHRs) in teleosts. To gain insight into the involvement of GtH/GtHR systems in the sex change process, cDNAs encoding follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) were firstly isolated from gonads of orange-spotted grouper (Epinephelus coioides), a protogynous hermaphrodite fish. Reverse transcription-PCR (RT-PCR) analysis demonstrated that the expression of the FSHR was confined to the brain, pituitary gland, ovary, and testis, while the LHR was expressed only in the brain, ovary, and testis. Furthermore, the expression profiles of GtH subunits (FSHβ and LHβ) and their receptors were analyzed in parallel with the serum levels of estradiol-17β (E(2) ), testosterone (T), and 11-ketotestosterone (11-KT) during 17α-methyltestosterone (MT)-induced sex change. Quantitative real-time PCR determined that the abundances of FSHβ and FSHR were significantly inhibited after MT treatment for 2 and 4 weeks, but subsequently returned to the control level after 6 weeks. In contrast, the mRNA levels of LHβ and LHR were significantly elevated throughout the sex change process. During MT-induced sex change, serum concentrations of E(2) remained constant while T and 11-KT levels were significantly increased. Taken together, our results suggest that GtH/GtHR systems are involved in MT-induced sex change, and two signaling pathways may have distinct roles in modulating the variations of the corresponding steroid hormones in the orange-spotted grouper.