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Object-sensitive pointer analysis, which separates the calling contexts of a method by its receiver objects, is known to achieve highly useful precision for object-oriented languages such as Java. Despite recent advances, all object-sensitive pointer analysis algorithms still suffer from the scalability problem due to the combinatorial explosion of contexts in large programs. In this article, we introduce a new approach, Conch , that can be applied to debloat contexts for all object-sensitive pointer analysis algorithms, thereby improving significantly their efficiency while incurring a negligible loss of precision. Our key insight is to approximate a recently proposed set of two necessary conditions for an object in a program to be context-sensitive, i.e., context-dependent (whose precise verification is undecidable) with a set of three linearly verifiable conditions in terms of the number of edges in the pointer assignment graph (PAG) representation of the program. These three linearly verifiable conditions, which turn out to be almost always necessary in practice, are synthesized from three key observations regarding context-dependability for the objects created and used in real-world object-oriented programs. To develop a practical implementation for Conch , we introduce an IFDS-based algorithm for reasoning about object reachability in the PAG of a program, which runs linearly in terms of the number of edges in the PAG. By debloating contexts for three representative object-sensitive pointer analysis algorithms, which are applied to a set of representative Java programs, Conch can speed up these three baseline algorithms substantially at only a negligible loss of precision (less than 0.1%) with respect to several commonly used precision metrics. In addition, Conch also improves their scalability by enabling them to analyze substantially more programs to completion than before (under a time budget of 12 hours). Conch has been open-sourced (http://www.cse.unsw.edu.au/~corg/tools/conch), opening up new opportunities for other researchers and practitioners to further improve this research. To demonstrate this, we introduce one extension of Conch to accelerate further the three baselines without losing any precision, providing further insights on extending Conch to make precision-efficiency tradeoffs in future research.

Object sensitivity is widely used as a context abstraction for computing the points-to information context-sensitively for object-oriented programming languages such as Java. Due to the combinatorial explosion of contexts in large object-oriented programs, k -object-sensitive pointer analysis (under k -limiting), denoted k -obj , is often inefficient even when it is scalable for small values of k , where k ⩽ 2 holds typically. A recent popular approach for accelerating k -obj trades precision for efficiency by instructing k -obj to analyze only some methods in a program context-sensitively, determined heuristically by a pre-analysis. In this article, we investigate how to develop a fundamentally different approach, Eagle , for designing a pre-analysis that can make k -obj run significantly faster while maintaining its precision. The novelty of Eagle is to enable k -obj to analyze a method with partial context sensitivity (i.e., context-sensitively for only some of its selected variables/allocation sites) by solving a context-free-language (CFL) reachability problem based on a new CFL-reachability formulation of k -obj . By regularizing one CFL for specifying field accesses and using another CFL for specifying method calls, we have formulated Eagle as a fully context-sensitive taint analysis (without k -limiting) that is both effective (by selecting the variables/allocation sites to be analyzed by k -obj context-insensitively so as to reduce the number of context-sensitive facts inferred by k -obj in the program) and efficient (by running linearly in terms of the number of pointer assignment edges in the program). As Eagle represents the first precision-preserving pre-analysis, our evaluation focuses on demonstrating its significant performance benefits in accelerating k -obj for a set of popular Java benchmarks and applications, with call graph construction, may-fail-casting, and polymorphic call detection as three important client analyses.

k-CFA provides the most well-known context abstraction for program analysis, especially pointer analysis, for a wide range of programming languages. However, its inherent context explosion problem has hindered its applicability. To mitigate this problem, selective context-sensitivity is promising as context-sensitivity is applied only selectively to some parts of the program. This paper introduces a new approach to selective context-sensitivity for supporting k-CFA-based pointer analysis, based on CFL-reachability. Our approach can make k-CFA-based pointer analysis run significantly faster while losing little precision, based on an evaluation using a set of 11 popular Java benchmarks and applications.

Object-sensitivity is widely used as a context abstraction for computing the points-to information context-sensitively for object-oriented languages like Java. Due to the combinatorial explosion of contexts in large programs, k -object-sensitive pointer analysis (under k -limiting), denoted k -obj, is scalable only for small values of k , where k ⩽2 typically. A few recent solutions attempt to improve its efficiency by instructing k -obj to analyze only some methods in the program context-sensitively, determined heuristically by a pre-analysis. While already effective, these heuristics-based pre-analyses do not provide precision guarantees, and consequently, are limited in the efficiency gains achieved. We introduce a radically different approach, Eagle, that makes k -obj run significantly faster than the prior art while maintaining its precision. The novelty of Eagle is to enable k -obj to analyze a method with partial context-sensitivity, i.e., context-sensitively for only some of its selected variables/allocation sites. Eagle makes these selections during a lightweight pre-analysis by reasoning about context-free-language (CFL) reachability at the level of variables/objects in the program, based on a new CFL-reachability formulation of k -obj. We demonstrate the advances made by Eagle by comparing it with the prior art in terms of a set of popular Java benchmarks and applications.

Uremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production., Graphical abstract

Chronic kidney disease (CKD) is a worldwide public health problem. Uremic retention solutes such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are accumulated in CKD patients and are associated with the incidence of CKD progression. Amino acids are the major precursors of uremic retention solutes in gut. The dynamic change of amino acid metabolism in the gut during CKD progression has not been reported previously. In this paper, we studied the dynamic change of gut IS/PCS precursor and amino acid metabolism profile during CKD progression in 5/6 nephrectomized (5/6Nx) rats model. The related gut microbiota and metagenome profile was also studied. Rat plasma, urine and feces were collected at different time points after nephrectomization. Plasma IS and PCS, fecal indole (the precursor of IS), p-cresol (the precursor of PCS) and 19 kinds of amino acids were analyzed by LC-MS. During CKD progression, 5/6 Nx rats showed increased plasma IS, PCS concentration and increased fecal indole, p-cresol concentration. 5/6 Nx rats also showed disordered gut amino acids metabolism profile which became more significant along with the progession of CKD. The abundance of some specific gut bacteria also changed significantly in 5/6 Nx rats. The 16S rDNA sequencing data of gut microbiota was further analyzed by an online tool PICRUSt, a large-scale computational method for metagenomes prediction with 16S rDNA sequencing data. The content of each gene was compared between the two groups by Mann-Whitney U test, and then the significantly regulated genes in 5/6 Nx group were subjected to KEGG website. The amino acid metabolism related genes were picked out. Most of these genes are more abundant in 5/6 Nx groups. Our study showed that gut amino acids metabolism profile was disordered with CKD progression, which was highly related to the gut microbiota dysbiosis and metagenome change. And that regulation of gut amino acids metabolism pathway may be a possible way to intervene the progression of CKD.

We rapidly prepared N-doped photoluminescent carbon nanodots (CNDs) with the one-step microwave irradiation method using diammonium hydrogen citrate as the carbon source. The as-prepared CNDs possessed quasispherical morphology and a high quantum yield of about 26.8%, which was higher than the CNDs obtained by most other microwave-assisted methods. Moreover, the luminescent CNDs could be efficiently uptaken by BGC-823 cells and CT26.WT cells, and exhibited low cytotoxicity and favorable biocompatibility, making them suitable candidates for cell imaging. In addition, the CNDs could be utilized for Fe3+ ions sensitive detection with a detection limit of 180 nM.

The results linking body iron stores to the risk of gestational diabetes mellitus (GDM) are conflicting. We aimed to measure the serum ferritin level of women in early pregnancy and evaluate the risk of GDM in a Chinese urban population. In total, 851 pregnant women between 10 and 20 weeks of gestation took part in the prospective, observational study conducted. The women were divided into four groups by quartiles of serum ferritin levels (Q1–4). Their blood samples were collected and assayed for several biochemical variables at the beginning of the study, and the women were followed up with a 75-g oral glucose tolerance test at 24–28 weeks of gestation. The participants had an average serum ferritin concentration of 65.67 μg/L. GDM prevalence within each serum ferritin quartile was 9.4%, 14.6%, 18.8% and 19.3%, respectively, (P = 0.016). The odds ratio for GDM in the ferritin Q2–4 was 1.64 (CI: 0.90–2.99), 2.23 (CI: 1.26–3.96) and 2.31 (CI: 1.30–4.10), compared with Q1, respectively. This association persisted after adjusting for potential confounders factors. In addition, in Q4, pregnant women with a pre-pregnancy body mass index ≥24 kg/m2, maternal age ≤35 years old or haemoglobin≥ 110 g/L did have an increased risk of developing GDM. Elevated serum ferritin concentrations in early gestation are associated with an increased risk of GDM, especially in pregnant women who have a high baseline iron storage status with no anaemia or who are overweight/obese. Individual iron supplementation should be considered to minimize the risk of GDM.

Aging is associated with an increased incidence of venous thromboembolism (VTE), resulting in significant morbidity and mortality in the elderly. Platelet hyperactivation is linked to aging-related VTE. However, the mechanisms through which aging enhances platelet activation and susceptibility to VTE are poorly understood. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) signaling is essential for aging-related platelet hyperactivation and VTE. mTORC1 was hyperactivated in platelets and megakaryocytes (MKs) from aged mice, accompanied by elevated mean platelet volume (MPV) and platelet activation. Inhibition of mTORC1 with rapamycin led to a significant reduction in susceptibility to experimental deep vein thrombosis (DVT) in aged mice (P < .01). To ascertain the specific role of platelet mTORC1 activation in DVT, we generated mice with conditional ablation of the mTORC1-specific component gene Raptor in MKs and platelets (Raptor knockout). These mice developed markedly smaller and lighter thrombi, compared with wild-type littermates (P < .01) in experimental DVT. Mechanistically, increased reactive oxygen species (ROS) production with aging induced activation of mTORC1 in MKs and platelets, which, in turn, enhanced bone marrow MK size, MPV, and platelet activation to promote aging-related VTE. ROS scavenger administration induced a significant decrease (P < .05) in MK size, MPV, and platelet activation in aged mice. Our findings collectively demonstrate that mTORC1 contributes to enhanced venous thrombotic susceptibility in aged mice via elevation of platelet size and activation.

Background Reported studies have showed that Thrombin Activatable Fibrinolysis Inhibitor (TAFI) may be associated with an increased risk of venous thromboembolism. But the relation of VT with TAFI gene SNPs could not be clearly demonstrated. Thus, we conducted a meta-analysis to analyze the associations between three TAFI variants − 438G/A, 505G/A and 1040C/T and the risk of venous thrombosis. Methods We carried out a systematic search to obtain all the eligible studies published before 30th October 2014. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to assess the association. Results 13 eligible studies were enrolled including 2321 patients and 2464 controls. There was a significant association between 505G/A and the risk of VTD under all models except recessive model (G vs. A: OR = 1.13, 95% CI: 1.02, 1.26; GG vs. AA:OR = 1.47, 95% CI: 1.14, 1.88; GA vs. AA: OR = 1.36, 95% CI: 1.06, 1.73; GG + GA vs. AA: OR = 1.41, 95% CI: 1.12, 1.77). Similarly, obvious relationship was observed in subgroup analyses in light of type of disease and ethnicity. Likewise, for 1040C/T variant, significant associations were identified under homozygote, heterozygote and dominant models (CC vs. TT: OR = 1.65, 95% CI: 1.06, 2.59; CT vs. TT: OR = 1.55, 95% CI: 1.19, 2.03; CC + CT vs. TT: OR = 1.55, 95% CI: 1.20, 2.00). Sub-analysis presented significant associations in non-CVT and non-Asian group under homozygote, heterozygote, and dominant models and CVT group in recessive model. Conclusion This meta-analysis showed that − 438G/A variant was not associated with the incidence of venous thrombosis. But in non-Asian populations, G allele and GG genotype of 505G/A may increase the risk of venous thrombosis diseases. GG genotype of 505G/A and one C carrier (CC and CT) of 1040C/T gave rise to the development of venous thrombosis diseases except CVT. Additionally, the heterozygote CT may be a potential contributing factor of gene effect in venous thrombosis.

Background:Indirect immunofluorescence (IIF) assays are recommended as the gold standard method for the detection of antinuclear antibodies (ANAs). This study aimed to investigate the reliability of an automated system.Methods:We compared 3745 serum samples using NOVA View archived images with manual analysis via microscopy. A custom cutoff value was established to distinguish ANA titers and was validated in two clinical laboratories. The automatic ANA pattern recognition system was evaluated, and all ANA-positive sera were subjected to two commercial ANA IIF kits to compare the consistency of the pattern interpretation results. For inconsistent patterns, a third ANA IIF testing kit was utilized.Results:Agreement of the interpretation of the ANA IIF test using the platform of NOVA View and manual microscopy was 96.9%. The local cutoff value to discriminate ANA titers in four main ANA patterns was calculated based on 1390 serum samples. In our laboratory, the titer prediction accuracy was superior to the preset cutoff in NOVA View (pConclusions:It is necessary to establish a custom value-added ANA report. However, confirmation of the digital immunofluorescence images by expert technicians was essential, and suspect results of an ANA pattern should be reconfirmed by another commercial ANA IIF kit to achieve more reliable results.

Scientific Reports 6: Article number: 18764; published online: 08 January 2016; updated: 19 August 2016. In the original version of this Article, there was an error in Affiliation 1 which was incorrectly given as ‘Department of Health Management, Southern Medical University, Guangzhou 510515, Guangdong, China’.

Dendritic cells (DCs) are the key regulators of immune responses. In this study, the effect of an exopolysaccharide (EPS) from the culture broth of Trichoderma pseudokoningii on the phenotypic and functional maturation of murine DCs and its underlying molecular mechanisms were investigated. It showed that EPS induced the morphological changes of DCs and the enhanced expression of DCs featured surface molecules CD11c, CD86, CD80 and major histocompatibility complex II (MHC-II). Flow cytometry analysis showed that the treatment with EPS could reduce FITC-dextran uptake by DCs. Sequentially, the results of ELISA indicated that EPS could increase the production of interleukin-12p70 (IL-12p70) in culture supernatant of DCs. Immunofluorescence staining and western blot analysis further revealed that EPS significantly prompted nuclear factor (NF)-κB subunit p65 translocation, IκB-α protein degradation, and p38 mitogen-activated protein kinase (MAPK) phosphorylation. And the production of IL-12p70 was significantly decreased in condition of the inhibition of p38 or NF-κB signaling pathway. These findings suggested that EPS could induce DCs maturation through both p38 MAPK and NF-κB signaling pathways.

Atherosclerosis is the primary cause of cardiovascular events and its molecular mechanism urgently needs to be clarified. In our study, atheromatous plaques (ATH) and macroscopically intact tissue (MIT) sampled from 32 patients were compared and an integrated series of bioinformatic microarray analyses were used to identify altered genes and pathways. Our work showed 816 genes were differentially expressed between ATH and MIT, including 443 that were up-regulated and 373 that were down-regulated in ATH tissues. GO functional-enrichment analysis for differentially expressed genes (DEGs) indicated that genes related to the “immune response” and “muscle contraction” were altered in ATHs. KEGG pathway-enrichment analysis showed that up-regulated DEGs were significantly enriched in the “FcεRI-mediated signaling pathway”, while down-regulated genes were significantly enriched in the “transforming growth factor-β signaling pathway”. Protein-protein interaction network and module analysis demonstrated that VAV1, SYK, LYN and PTPN6 may play critical roles in the network. Additionally, similar observations were seen in a validation study where SYK, LYN and PTPN6 were markedly elevated in ATH. All in all, identification of these genes and pathways not only provides new insights into the pathogenesis of atherosclerosis, but may also aid in the development of prognostic and therapeutic biomarkers for advanced atheroma.

In our previous study, low expression of FAM172A protein was found in colon cancer tissues. This research was planned to explore the functions of FAM172A gene and examine the mechanisms of its transcriptional regulation. Firstly, flow cytometry showed that FAM172A inhibited proliferation and promoted apoptosis and differentiation of colon cancer cells. Then through continuous truncation, we identified the minimal functional promoter region of FAM172A. Subsequently, we found that STAT1, as a transcription factor, could bind to the minimal FAM172A promoter, as evaluated using Chromatin immunoprecipitation (ChIP) and Electrophoreticmobility shift assay (EMSA). The results of Western blot analysis and qRT-PCR indicated that STAT1 was able to upregulate the expression of FAM172A. Our results showed that FAM172A could suppress proliferation of colon cancer cells, and STAT1 could bind to the minimum promoter region of FAM172A and upregulated the expression of FAM172A. These results may provide advanced insights into the functions of FAM172A and its regulatory mechanisms.

In this study, the effect of antitumor and immune activities of extracellular polysaccharides (EPS) from Rhizopus nigricans Ehrenb were investigated using S180 bearing mice. The results revealed that EPS in the concentration range 50-1000 μg/mL can inhibited S180 cell proliferation in a dose dependent manner. EPS at the highest dose of 1000 μg/mL showed significantly antitumor activity against S180 with inhibition rate of 47.53%. However, EPS significantly simulated spleen lymphocytes in the concentration of 500 μg/mL, and the increase proliferation ability showed a dose-dependent effect with EPS at the dose of 50-500 μg/mL. In comparison with the control groups, the weights of tumor were declined and the inhibition rates of tumor were remarkably decreased in the treated groups. Pretreatment with EPS at the dose of 75 mg/kg/day, the inhibition rate was decreased by 44.38% (P

The migration and proliferation of vascular smooth muscle cells (VSMCs) are essential elements during the development of atherosclerosis and restenosis. An increasing number of studies have reported that extracellular matrix (ECM) proteins, including the CCN protein family, play a significant role in VSMC migration and proliferation. CCN4 is a member of the CCN protein family, which controls cell development and survival in multiple systems of the body. Here, we sought to determine whether CCN4 is involved in VSMC migration and proliferation. We examined the effect of CCN4 using rat cultured VSMCs. In cultured VSMCs, CCN4 stimulated the adhesion and migration of VSMCs in a dose-dependent manner, and this effect was blocked by an antibody for integrin α5β1. CCN4 expression was enhanced by the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). Furthermore, knockdown of CCN4 by siRNA significantly inhibited the VSMC proliferation. CCN4 also could up-regulate the expression level of marker proteins of the VSMCs phenotype. Taken together, these results suggest that CCN4 is involved in the migration and proliferation of VSMCs. Inhibition of CCN4 may provide a promising strategy for the prevention of restenosis after vascular interventions.

We fetch facial digital vision information from 98 healthy persons using digital camera. With functional help of NIKON CAPTURE NX's software point U key technology, we catch black, white and neutral color control points. We correct the color differences of facial digital vision with self-improved facial functional software. According to the principle of Adaboost objective category, we improve the software. Under Traditional Chinese Medicine (TCM), facial information was cut into 5 divisions which are forehead, nose, left malar, right malar and chin. We do the CIE1976L*a*b* color quantity analysis using after we take 8 color pieces with size 5*5 from each part. The experiment result shows that there are differences of value of L*, a* and b* from different part of healthy persons face. That means there are color differences from different part of face. With the figures of L*, a* and b* from different face part, it generally follows the TCM clinic fact. This task technologically found the patients facial inspection in future.

Abernethy malformation is a rare anomaly of the splanchnic venous system. We report a case of an unusual portosystemic shunt via a dilated inferior mesenteric vein. A 20-year-old woman was referred to our hospital with complains of nonspecific abdominal pain for almost 3 years and hematochezia since 15 months old. Computed tomography and further transhepatic splenoportography revealed a hypoplastic portal vein and a giant inferior mesenteric vein, via which part of the portal venous blood drained into the inferior vena cava. The patient underwent a surgical ligation of the portocaval shunt and recovered well. We believe that this is the first case of type II Abernethy malformation presenting as a portosystemic shunt via the giant inferior mesenteric vein.