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Location-Based Services are often used to find proximal Points of Interest (PoIs)—e.g., nearby restaurants and museums, police stations, hospitals, etc.—in a plethora of applications. An important recently addressed variant of the problem not only considers the distance/proximity aspect, but also desires semantically diverse locations in the answer-set. For instance, rather than picking several close-by attractions with similar features—e.g., restaurants with similar menus; museums with similar art exhibitions—a tourist may be more interested in a result set that could potentially provide more diverse types of experiences, for as long as they are within an acceptable distance from a given (current) location. Towards that goal, in this work we propose a novel approach to efficiently retrieve a path that will maximize the semantic diversity of the visited PoIs that are within distance limits along a given road network. Our approach allows to specify both a start and terminal location to return a (non-necessarily shortest) path that maximizes diversity rather than only minimizing travel cost, thus providing ample applications in tourist route recommendation systems. We introduce a novel indexing structure—the Diversity Aggregated R-tree, based on which we devise efficient algorithms to generate the answer-set—i.e., the recommended locations among a set of given PoIs—relying on a greedy searching strategy. Our experimental evaluations conducted on real datasets demonstrate the benefits of the proposed methodology over the baseline alternative approaches. [ABSTRACT FROM AUTHOR]

Background: RNA N6-methyladenosine (m6A) modification is primarily regulated by m6A regulators, which play significant epigenetic regulatory roles in tumorigenesis, tumor development, and tumor immune microenvironment. However, the correlation between m6A regulators and immune cell infiltration in breast cancer remains unclear. Methods: In this study, m6A modification patterns were evaluated based on 31 m6A modification regulators. m6A clusters were determined by consensus clustering. Immune landscape and immune cell infiltration subgroups were characterized by m6A clusters. Key module and hub genes related to m6A regulators and immune infiltration cells were identified by WGCNA. LASSO algorithm was applied to select prognostic signatures. Multivariate Cox regression analysis was applied to assess the prognostic value of gene signatures. Results: Two distinct m6A clusters were determined based on the expression of 31 m6A modification regulators and characterized by two tumor immune microenvironment (TIME) immune cell infiltration subgroups. Further, a total of 1971 differentially expressed genes between breast cancer patients and healthy controls were screened, nine modules associated with clinical characteristics of breast cancer patients were identified. Later, one key module and 13 hub genes correlated with m6A regulators and immune infiltration cells were identified. LASSO Cox regression analysis selected and constructed a ten-gene prognostic model to build a risk score system for individual breast cancer patient prognosis. The performance of the ten-gene-based risk score system was further validated in an independent dataset with an AUC of 0.659. Conclusions: This study revealed that m6A modification regulators played a significant role in the TIME regulation of breast cancer. The hub ten gene-based risk score system is valuable in predicting the prognosis of breast cancer patients, which may provide potential significance for breast cancer diagnosis, prognosis, and immunotherapy in the future. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether inhibition of endoplasmic reticulum stress (ERS) mediated the ameliorative effect of apelin on acute heart failure (AHF). Rabbit model of AHF was induced by sodium pentobarbital. Cardiac dysfunction and injury were detected in the rabbit models of AHF, including impaired hemodynamic parameters and increased levels of CK-MB and cTnI. Apelin treatment dramatically improved cardiac impairment caused by AHF. ERS, indexed by increased GRP78, CHOP, and cleaved-caspase12 protein levels, was simultaneously attenuated by apelin. Apelin also could ameliorate increased protein levels of cleaved-caspase3 and Bax, and improved decreased protein levels of Bcl-2. Two common ERS stimulators, tunicamycin (Tm) and dithiothreitol (DTT) blocked the ameliorative effect of apelin on AHF. Phosphorylated Akt levels increased after apelin treatment in the rabbit models of AHF. The Akt signaling inhibitors wortmannin and LY294002 could block the cardioprotective effect of apelin, which could be relieved by ERS inhibitor 4-phenyl butyric acid (4-PBA). The aforementioned beneficial effects of apelin could all be blocked by APJ receptor antagonist F13A. 4-PBA and SC79, an Akt activator, can restore the ameliorative effect of apelin on AHF blocked by F13A. Apelin treatment dramatically ameliorated cardiac impairment caused by AHF, which might be mediated by APJ/Akt/ERS signaling pathway. These results will shed new light on AHF therapy. [ABSTRACT FROM AUTHOR]

The objective was to investigate the effect of exclusive enteral nutrition (EEN) on T helper (Th) 17 cells by observing the effects of EEN on colon and serum interleukin (IL)-17A levels in juvenile inflammatory bowel disease (IBD) rat models and to reveal the potential mechanism of the therapeutic effect of EEN on IBD. ATNBS-induced IBD rat model was established. Feeding Peptison, a type of enteric nutrition (EN) for EEN-IBD group and EEN group, normal feed for IBD model group and control group for six consecutive days. Four groups of juvenile rats were sacrificed on day 7. The pathology of the intestinal mucosa was examined, the expression of IL-17A in serum was detected by ELISA, and the expression of IL-17A in intestinal tissue was detected by both western blot and real-time PCR (RT-PCR). Diarrhea, bloody stools, and weight loss were found in both the IBD group and the EEN-IBD group. After 5 days of EEN feeding, the stool characteristics, and blood in the stools of the rats in the EEN-IBD group were significantly relieved compared with those of the IBD group. There was no significant difference in the body mass growth rate between the IBD group and EEN-IBD group (P > 0.05). The growth rate of the EEN group was 51.29 ± 3.61%, which was significantly lower than that of the control group (60.17 ± 9.32%) with P < 0.05. The disease activity index (DAI) score of the EEN-IBD group was significantly lower than that of the IBD group (P < 0.05). In the IBD group, colonic congestion and edema were obvious, scattered ulcers were observed, and the intestinal mucosa had a large amount of inflammatory cell infiltration. In the EEN-IBD group, the intestinal mucosa was slightly congested and a small amount of inflammatory cell infiltrated. The serum IL-17A expression level in the IBD group was significantly higher than in the EEN-IBD group, control group, and EEN group (P < 0.05). Both the gene and protein expressions of IL-17A in the intestinal tissue of the EEN-IBD group were significantly lower than in the IBD group (P < 0.01), and it was significantly higher in the IBD group than in the control and EEN groups (P < 0.01). EEN effectively reduced the intestinal inflammation in the juvenile rats with IBD. The mechanism could be related to the regulation of Th17 cells and the expression of the corresponding cytokine, IL-17A. EEN may play a role in downregulating the expression of IL-17A in the intestinal mucosa. [ABSTRACT FROM AUTHOR]

The change in plasma apelin level in heart failure (HF) patients is controversial. We investigated the change in plasma apelin level in HF patients versus control and non-HF patients. The plasma level of apelin was measured by ELISA and plasma level of B-type natriuretic peptide (BNP) by fluorescence immunoassay. We included 101 patients with HF, 32 patients without HF and 20 controls. The three groups did not differ in general and clinical characteristics. Plasma levels of apelin and BNP were both higher in HF patients than non-HF patients and controls. Plasma levels of apelin and BNP were not correlated. Plasma level of BNP was increased with increasing New York Heart Association grade and apelin level was decreased. Apelin level was lower in HF patients with NYHA grade IV than in controls and non-HF patients. Apelin level had 75% diagnostic value for HF, and BNP level had 96.8% diagnostic value. At a cutoff of 6.44 ng/mL apelin level, sensitivity was 69.3%, and specificity 97.1%. However, the diagnostic of apelin for NYHA II patients was higher than that of BNP (99.6% vs. 96.1%). These results suggested that apelin might be particularly useful in association with BNP in mild HF patients. [ABSTRACT FROM AUTHOR]

The objective of this study is to explore the value of fecal calprotectin (FC) for early screening of the abdominal type of Henoch-Schonlein purpura (AHSP) in children. The study cohort included 40 children with AHSP treated at Shengjing Hospital of China Medical University from November 2014 to November 2015, and 40 children hospitalized in the Division of Pediatric Orthopedics in the corresponding period were selected as a control group. Fresh fecal samples were collected in the acute phase of the first visit (FC1), 3 days after treatment (FC2), and 7 days after treatment (FC3) from the AHSP group and the control group. Calprotectin levels in the fecal samples were measured using an enzyme-linked immunosorbent assay. At the same time, gastrointestinal performance and the laboratory examination indicators white blood cell (WBC) count and C-reactive protein (CRP) level were recorded. The median levels of FC1 (3053 μg/g) and FC2 (2778.3 μg/g) were higher than in the control group (102.5 μg/g), with significant differences among the three groups (p < 0.001). FC levels gradually decreased in remission, and the level of FC3 on day 7 was close to that of the control samples (p > 0.05). When the optimal cut-off was 264.5 μg/g, the area under the receiver operating characteristic (ROC) curve of FC for diagnosis of AHSP was 0.961 with a corresponding sensitivity and specificity of 93.1 and 87.5%, respectively. The levels of FC in children with AHSP were positively correlated with WBC count (rs = 0.688) and CRP value (rs = 0.513). The area under the ROC curve of WBC count for screening AHSP was 0.785 when the optimal cut-off value was 11.1 × 109/L with a corresponding sensitivity and specificity of 81.5 and 62.5%, respectively. The area under the ROC curve of CRP was 0.963 when the optimal cut-off value was 5.72 mg/dL with a corresponding sensitivity and specificity of 88.9 and 100%, respectively. Comparisons of FC, WBC count, and CRP level as diagnostic indicators of AHSP showed that the sensitivity of FC was higher than that of the WBC count and CRP level, and its diagnostic value was better than that of the WBC count. The levels of FC began to increase in the early stages of AHSP, showing a decreasing tendency in remission and tending to be within a normal range after a week or so. For the early diagnosis of AHSP, FC with a cut-off level of 264.5 μg/g has good sensitivity and specificity. The sensitivity of FC is better than that of the traditional inflammation indicators CRP and WBC count, and its diagnostic performance is better than WBC count; FC can be suitable as a new marker for the early diagnosis of AHSP. [ABSTRACT FROM AUTHOR]

Henoch-Schönlein purpura (HSP) is a vasculitic disorder resulting from autoinflammatory-mediated tissue injury. Procalcitonin (PCT) and C-reactive protein (CRP) are two biomarkers of the immune response that recognize bacterial infection and inflammation, respectively. This study tested whether levels of PCT and CRP were associated with selected clinical features, disease severity, and organ damage in HSP. Eighty-nine pediatric patients with HSP were analyzed for clinical manifestations and organ damage. Serum CRP, PCT, and occult blood in the urine and stool (prior to steroid therapy) were measured. Disease severity was classified according to previously established clinical classifications. Sixty patients (67.4 %) had a low clinical score (LCS) of <4 (group A) while 29 patients (32.5 %) had a high clinical score (HCS) of ≥4 (group B). When patients were then classified by the presence of gastrointestinal bleeding, 66 (74.2 %) cases lacked alimentary tract hemorrhage (group C) while 23 (25.8 %) cases presented with gastrointestinal bleeding (group D). There were no significant differences in CRP (group A: median = 5.26, range = 1.00-77.60 vs. group B: median = 8.59, range = 1.00-144.00 mg/l; u = 1.397) or PCT levels (group A: median = 0.05, range = 0.05-0.24 vs. group B: median = 0.08, range = 0.05-1.02 ng/ml; u = 1.709) between groups A and B. When serum PCT levels were examined in relation to gastrointestinal bleeding, the levels of serum PCT were higher in group D than group C patients (group D: median = 0.09, range = 0.05-1.02 vs. group C: median = 0.05, range = 0.05-0.32 ng/ml; u = 2.849). It is important to note that the average PCT level was below the threshold for a systemic bacterial infection (0.5 ng/ml). We did not observe a correlation between CRP levels and the absence or presence of GI bleeding in groups C or D (group C: median = 4.66, range = 1.00-144.00 vs. group D: median = 9.44, range = 1.06-124.00 mg/l; u = 1.783), respectively. In all patients, there was a significant correlation between the concentrations of PCT and CRP ( r = 0.721, p = 0.002). In patients with HSP, inflammatory markers are not uniformly associated with the disease and instead, show variable association depending on the clinical severity and level of organ damage. In patients with severe HSP, elevated serum PCT was significantly associated with gastrointestinal bleeding. In contrast, CRP was not a specific predictor for different clinical classifications of HSP, despite a similar pattern of concentration changes to PCT. [ABSTRACT FROM AUTHOR]

To explore the relationship of the MOV10, A3G, and IFN-α mRNA levels with chronic hepatitis B virus (HBV) infection, Blood samples from 96 patients with chronic hepatitis B (CHB) and 21 healthy individuals as control were collected. HBV DNA load and aminotransferase in the serum were tested using real time PCR and velocity methods, respectively. The MOV10, A3G, and IFN-α mRNA levels in the peripheral blood mononuclear cells (PBMC) were examined through qRT-PCR. The MOV10, A3G, and IFN-α mRNA levels in CHB group was significantly lower than those in the control group (P<0.01, P<0.05, P<0.01, respectively). The A3G mRNA level in the high-HBV DNA load group was lower than that in the low-HBV DNA load group (P<0.05). However, no statistical difference was found in the MOV10 and IFN-α mRNA levels between the two HBV DNA load groups. Furthermore, the MOV10 mRNA level showed positive correlation with IFN-α in the control group. These results indicated that the expression of the innate immune factors MOV10, A3G, and IFN-α is affected by chronic HBV infection. [ABSTRACT FROM AUTHOR]

Our previous work reported that endoplasmic reticulum stress (ERS)-mediated apoptosis was activated during vascular calcification (VC). Activating transcription factor 4 (ATF4) is a critical transcription factor in osteoblastogenesis and ERS-induced apoptosis. However, whether ATF4 is involved in ERS-mediated apoptosis contributing to VC remains unclear. In the present study, in vivo VC was induced in rats by administering vitamin D plus nicotine. Vascular smooth muscle cell (VSMC) calcification in vitro was induced by incubation in calcifying media containing β-glycerophosphate and CaCl. ERS inhibitors taurine or 4-phenylbutyric acid attenuated ERS and VSMC apoptosis in calcified rat arteries, reduced calcification and retarded the VSMC contractile phenotype transforming into an osteoblast-like phenotype in vivo. Inhibition of ERS retarded the VSMC phenotypic transition into an osteoblast-like cell phenotype and reduced VSMC calcification and apoptosis in vitro. Interestingly, ATF4 was activated in calcified aortas and calcified VSMCs in vitro. ATF4 knockdown attenuated ERS-induced apoptosis in calcified VSMCs. ATF4 deficiency blocked VSMC calcification and negatively regulated the osteoblast phenotypic transition of VSMCs in vitro. Our results demonstrate that ATF4 was involved at least in part in the process of ERS-mediated apoptosis contributing to VC. [ABSTRACT FROM AUTHOR]

The treatment of infection with lamivudine-resistant mutants of hepatitis B virus (HBV) with mutations in the YMDD motif has become a crucial issue in the clinic. In this work, the plasmids pcDNA3.1 (+)-HBV/C-YVDD and pcDNA3.1 (+)-HBV/C-YMDD were constructed and injected into BALB/c mice using a hydrodynamics-based procedure to investigate viral replication and expression of HBV lamivudine-resistant YVDD mutants in vivo. Compared with the YMDD group, HBsAg levels were higher in sera of mice in the YVDD group, but HBeAg levels were lower on day 1 after injection. Levels of HBcAg in hepatocytes were higher in the YVDD group on day 1, whereas the HBsAg levels were lower. The levels of HBV mRNA in the liver were higher in mice in the YVDD group on day 1 after injection. The results showed that injection with these plasmids resulted in efficient initiation of replication of HBV in mice and also suggested that the combined mutations in YVDD mutants could affect the replication process. [ABSTRACT FROM AUTHOR]

Stromal cell-derived factor 1 (SDF-1) is a chemokine that is expressed in some cancer cells and is involved in tumor cell migration and metastasis. CXCR7, a novel receptor for SDF-1, has been identified recently. Researches demonstrated that interaction between SDF-1 and CXCR7 could play an important role in cancer progression. In this study, we aimed to investigate the expressions of SDF-1 and CXCR7 and the relationship between their expressions and clinicopathological characteristics in papillary thyroid carcinoma (PTC). Expressions of SDF-1 and CXCR7 in 33 cases of thyroid benign lesion tissue and 79 cases of PTC tissue and peritumoral non-malignant tissue were detected by immunohistochemical staining. Expressions of SDF-1 and CXCR7 were negative in peritumoral non-malignant tissues. Respectively, positive expression rates of SDF-1 and CXCR7 were 69.6 and 65.8 % in PTC, 12.1 and 30.3 % in thyroid benign tissue. The expression of SDF-1 and CXCR7 were positively correlated with lymph node metastasis. SDF-1 and CXCR7 expressions were related with the lymph nodes metastasis of PTC. [ABSTRACT FROM AUTHOR]

Intestinal barrier dysfunction plays an important role in the pathogenesis of inflammatory bowel disease (IBD). To evaluate the effect of intestinal trefoil factor (ITF) on increased intestinal permeability and its association with tight junction proteins, an in vitro intestinal epithelia barrier model was established with Caco-2 cells and treated with platelet-activating factor (PAF). We found that exposing cells to 0.3 M ITF (30 min before or 30 min after PAF treatment) attenuated the PAF-induced changes in transepithelial electrical resistance and Lucifer yellow flux. A quantitative RT-PCR and western blot analysis revealed that ITF suppressed PAF-induced downregulation of tight junction proteins claudin-1 and ZO-1 expression; furthermore, an abnormal localization and distribution of these proteins was inhibited, as assessed by immunofluorescence staining. These results suggest that ITF decreases mucosal permeability and shows potential as a therapy for treating IBD. [ABSTRACT FROM AUTHOR]

Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We aimed to explore whether the cardioprotective effect of IMD is mediated by inhibiting myocardial endoplasmic reticulum (sarcoplasmic reticulum) stress (ERS). In vitro, IMD (10, 10, and 10 mol/l) directly inhibited the upregulation of ERS markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and caspase-12 induced by the ERS inducers tunicamycin (Tm, 10 mg/ml) or dithiothreitol (DTT, 2 mmol/l) in cardiac tissue. IMD also inhibited Tm- or DTT-induced upregulation of cleaved activating transcription factor 6 and 4. These inhibitory effects of IMD were abolished by the IMD receptor antagonist IMD (10 mol/l) and phosphoinositide 3-kinase inhibitor LY294002 (10 μmol/l). However, preincubation with PD98059 (20 μmol/l), an extracellular signal-regulated protein kinase inhibitor, and H89 (10 μmol/l), a protein kinase A inhibitor, could not block the ERS-inhibiting effects of IMD. Furthermore, in an in vivo model of myocardium ischemia/reperfusion (I/R) in rats, administration of IMD (20 nmol/kg, intravenously) greatly attenuated ERS and ameliorated myocardium impairment induced by I/R. IMD could exert its cardioprotective effect by inhibiting myocardial ERS, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

To explore whether platelet-activating factor (PAF) can disrupt the intestinal epithelial barrier directly and is associated with structural alterations of the F-actin-based cytoskeleton, and to observe the protective effect of intestinal trefoil factor (ITF), we establish an intestinal epithelia barrier model using Caco-2 cells in vitro. Transepithelial electrical resistance and unidirectional flux of lucifer yellow were measured to evaluate barrier permeability; immunofluorescent staining and flow cytometry were applied to observe morphological alterations and to quantify proteins of the F-actin cytoskeleton: the tight junction marker ZO-1 and Claudin-1 were observed using immunofluorescent staining. PAF significantly increased paracellular permeability, at the same time, F-actin and tight junction proteins were disrupted. It was thought that ITF could reverse the high permeability by restoring normal F-actin, ZO-1 and Claudin-1 structures. These results collectively demonstrated that PAF plays an important role in the regulation of mucosal permeability and the effects of PAF are correlated with structural alterations of the F-actin-based cytoskeleton and of tight junctions. ITF can protect intestinal epithelium against PAF-induced disruption by restricting the rearrangement of the F-actin cytoskeleton and of tight junctions. [ABSTRACT FROM AUTHOR]

C-type lectins are one family of pattern recognition receptors (PRRs) that play important roles in innate immunity. In this work, cDNA and genomic sequences for a new C-type lectin ( FcLec5) were obtained from the Chinese white shrimp Fenneropenaeus chinensis. FcLec5 cDNA contains an open reading frame of 1,008 bp and its genomic sequence is 1,137 bp with 4 exons and 3 introns. The predicted FcLec5 protein contains a signal peptide and two carbohydrate recognition domains (CRDs). The N-terminal CRD of FcLec5 has a predicted carbohydrate recognition motif of Gln-Pro-Asp (QPD), while the C-terminal CRD contains a motif of Glu-Pro-Gln (EPQ). Northern blot analysis showed that FcLec5 mRNA was specifically expressed in hepatopancreas. FcLec5 protein was expressed in hepatopancreas and secreted into hemolymph. Real-time PCR showed that FcLec5 transcript exhibited different expression profiles after immune-challenged with Vibrio anguillarum or White Spot Syndrome Virus (WSSV). Recombinant FcLec5 and its two individual CRDs could agglutinate most bacteria tested, and the agglutinating activity was Ca-dependent. Besides, the agglutinating activity to gram-negative bacteria is higher than that to gram-positive bacteria. Direct binding assay showed that recombinant FcLec5 could bind to all microorganisms tested (five gram-positive and four gram-negative bacteria, as well as yeast) in a Ca-independent manner. Recombinant FcLec5 also directly bound to bacterial peptidoglycan, lipopolysaccharide and lipoteichoic acids. These results suggest that FcLec5 may act as a PRR for bacteria via binding to bacterial cell wall polysaccharides in Chinese white shrimp. [ABSTRACT FROM AUTHOR]

Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We investigated the cardioprotective mechanism of IMD1–53 in the in vivo rat model of myocardial ischemia/reperfusion (I/R) injury and in vitro primary neonatal cardiomyocyte model of hypoxia/reoxygenation (H/R). Myocardial infarct size was measured by 2,3,5-triphenyl tetrazolium chloride staining. Cardiomyocyte viability was determined by trypan blue staining, cell injury by lactate dehydrogenase (LDH) leakage, and cardiomyocyte apoptosis by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assay, Hoechst staining, gel electrophoresis and caspase 3 activity. The translocation of mitochondrial cytochrome c of myocardia and expression of apoptosis-related factors Bcl-2 and Bax, phosphorylated Akt and phosphorylated GSK-3β were determined by western blot analysis. IMD1–53 (20 nmol/kg) limited the myocardial infarct size in rats with I/R; the infarct size was decreased by 54%, the apoptotic index by 30%, and caspase 3 activity by 32%; and the translocation of cytochrome c from mitochondria to cytosol was attenuated. IMD1–53 increased the mRNA and protein expression of Bcl-2 and ratio of Bcl-2 to Bax by 81 and 261%, respectively. IMD1–53 (1 × 10−7 mol/L) inhibited the H/R effect in cardiomyocytes by reducing cell death by 43% and LDH leakage by 16%; diminishing cellular apoptosis; decreasing caspase 3 activity by 50%; and increasing the phosphorylated Akt and GSK-3β by 41 and 90%, respectively. The cytoprotection of IMD1–53 was abolished with LY294002, a PI3K inhibitor. In conclusion, IMD1–53 exerts cardioprotective effect against myocardial I/R injury through the activation of the Akt/GSK-3β signaling pathway to inhibit mitochondria-mediated myocardial apoptosis. [ABSTRACT FROM AUTHOR]