Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibitors of the apurinic/apyrimidinic endonuclease 1 (APE1)/nucleophosmin (NPM1) interaction that display anti‐tumor properties

The apurinic/apyrimidinic endonuclease 1 (APE1) is a protein central to the base excision DNA repair pathway and operates in the modulation of gene expression through redox‐dependent and independent mechanisms. Aberrant expression and localization of APE1 in tumors are recurrent hallmarks of aggressiveness and resistance to therapy. We identified and characterized the molecular association between APE1 and nucleophosmin (NPM1), a multifunctional protein involved in the preservation of genome stability and rRNA maturation. This protein–protein interaction modulates subcellular localization and endonuclease activity of APE1. Moreover, we reported a correlation between APE1 and NPM1 expression levels in ovarian cancer, with NPM1 overexpression being a marker of poor prognosis. These observations suggest that tumors that display an augmented APE1/NPM1 association may exhibit increased aggressiveness and resistance. Therefore, targeting the APE1/NPM1 interaction might represent an innovative strategy for the development of anticancer drugs, as tumor cells relying on higher levels of APE1 and NPM1 for proliferation and survival may be more sensitive than untransformed cells. We set up a chemiluminescence‐based high‐throughput screening assay in order to find small molecules able to interfere with the APE1/NPM1 interaction. This screening led to the identification of a set of bioactive compounds that impair the APE1/NPM1 association in living cells. Interestingly, some of these molecules display anti‐proliferative activity and sensitize cells to therapeutically relevant genotoxins. Given the prognostic significance of APE1 and NPM1, these compounds might prove effective in the treatment of tumors that show abundant levels of both proteins, such as ovarian or hepatic carcinomas. © 2015 Wiley Periodicals, Inc.
Camera as Position Sensor for a Ball and Beam Control System

This paper describes a novel strategy to use a digital camera as a position sensor to control a ball and beam system. A linear control law is used to position the ball at the desired location on the beam. The experiments show how this method controls the positioning of the ball in any location on the beam using a camera with a sampling rate of 30 frames per second (fps), and these results are compared with those using an analog resistive sensor with a feedback signal sampled at rate 1000 samples per second. The mechanical characteristics of this ball and beam system are used to simplify the calculation of the ball position using our vision system, and in order to easy camera calibration with respect to the ball and beam system. Our proposal use circularity feature of blobs in a binary image, instead of the classic correlation or Hough transform techniques for ball’s tracking. The main control system is implemented in Simulink with Real Time Workshop (RTW) and the vision processing with OpenCV libraries.
The larval morphology and nest habits of Trypoxylon ( Trypargilum ) rogenhoferi Kohl 1884 (Insecta: Hymenoptera: Crabronidae)

The present study describes different preimaginal stages of Trypoxylon rogenhoferi examined by Scanning Electron Mi-croscopy (SEM) and compares the results with observations on closely related species. Some notes on the nesting habitsof this species, including their spider prey, nest parasites, and development time are provided. In short, T. rogenhoferi proved quite similar to the previous report on T. albitarse although SEM images are rarely presented in such descriptions.In fact the present study emphasized the importance of SEM images to describe fine morphological details that can beuseful characters for taxonomic and phylogenetic studies. Images of some earlier development stages (first and second larval instar and egg) are presented for the first time, and compared with the few available data from other hymenopterans.O presente estudo apresenta a descricao de diversos estagios do desenvolvimento da vespa cacadora Trypoxylon rogenhoferi por meio de microscopia eletronica de varredura (MEV). Os resultados obtidos sao comparados com achadoscom outras especies proximas. Tambem sao fornecidas informacoes a cerca da biologia da especie no local de estudo,como presas e parasitoides observados e tempo de desenvolvimento. A larva madura desta especie se demonstrou bastantesimilar ao pouco que foi descrito com T. albitarse, apesar de que raramente imagens de MEV sao apresentadas nestasdescricoes. O presente estudo demonstra a importância de imagens de ultraestrutura que podem revelar detalhes uteis paraa diagnose de especies e estudos filogeneticos. Pela primeira vez se descrevem estadios imaturos mais jovens de vespas deste grupo, que foram comparados com dados de outros grupos de himenopteros.
Metabolic characterization of AH-7921, a synthetic opioid designer drug: in vitro metabolic stability assessment and metabolite identification, evaluation of in silico prediction, and in vivo confirmation.

AH-7921 (3,4-dichloro-N-[(1-dimethylamino)cyclohexylmethyl]benzamide) is a new synthetic opioid and has led to multiple non-fatal and fatal intoxications. To comprehensively study AH-7921 metabolism, we assessed human liver microsome (HLM) metabolic stability, determined AH-7921's metabolic profile after human hepatocytes incubation, confirmed our findings in a urine case specimen, and compared results to in silico predictions. For metabolic stability, 1 µmol/L AH-7921 was incubated with HLM for up to 1 h; for metabolite profiling, 10 µmol/L was incubated with pooled human hepatocytes for up to 3 h. Hepatocyte samples were analyzed by liquid chromatography quadrupole/time-of-flight high-resolution mass spectrometry (MS). High-resolution full scan MS and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot™ (SCIEX) using multiple data processing algorithms. The presence of AH-7921 and metabolites was confirmed in the urine case specimen. In silico prediction of metabolite structures was performed with MetaSite™ (Molecular Discovery). AH-7921 in vitro half-life was 13.5 ± 0.4 min. We identified 12 AH-7921 metabolites after hepatocyte incubation, predominantly generated by demethylation, less dominantly by hydroxylation, and combinations of different biotransformations. Eleven of 12 metabolites identified in hepatocytes were found in the urine case specimen. One metabolite, proposed to be di-demethylated, N-hydroxylated and glucuronidated, eluted after AH-7921 and was the most abundant metabolite in non-hydrolyzed urine. MetaSite™ correctly predicted the two most abundant metabolites and the majority of observed biotransformations. The two most dominant metabolites after hepatocyte incubation (also identified in the urine case specimen) were desmethyl and di-desmethyl AH-7921. Together with the glucuronidated metabolites, these are likely suitable analytical targets for documenting AH-7921 intake. Copyright © 2015 John Wiley & Sons, Ltd.
Annotating speaker stance in discourse

: The aim of this study is to explore the possibility of identifying speaker stance in discourse, provide an analytical resource for it and an evaluation of the level of agreement across speakers. We also explore to what extent language users agree about what kind of stances are expressed in natural language use or whether their interpretations diverge. In order to perform this task, a comprehensive cognitive-functional framework of ten stance categories was developed based on previous work on speaker stance in the literature. A corpus of opinio-nated texts was compiled, the Brexit Blog Corpus (BBC). An analytical protocol and interface (Active Learning and Visual Analytics) for the annotations was set up and the data were independently annotated by two annotators. The annotation procedure, the annotation agreements and the co-occurrence of more than one stance in the utterances are described and discussed. The careful, analytical annotation process has returned satisfactory inter-and intra-annotation agreement scores, resulting in a gold standard corpus, the final version of the BBC.
Distinct Component Profiles and High Risk Among African Americans With Metabolic Syndrome

OBJECTIVE—Health of African Americans is seriously threatened by unremitting epidemics of diabetes and cardiovascular disease (CVD). However, the role of metabolic syndrome in the African-American population has not been investigated widely. This study examined the prevalence of metabolic syndrome and assessed its cross-sectional relationship to CVD in the Jackson Heart Study (JHS) cohort. RESEARCH DESIGN AND METHODS—A total of 5,302 participants aged ≥21 years who were recruited at baseline during 2000–2004 were analyzed for this study. Adjusted odds ratios (ORs) were estimated in a logistic regression analysis for coronary heart disease (CHD) and cerebrovascular disease (CBD) in those with and without coexisting metabolic syndrome. Diabetic participants were excluded. RESULTS—Among those aged 35–84 years, metabolic syndrome prevalence was 43.3% in women and 32.7% in men. Elevated blood pressure (70.4%), abdominal obesity (64.6%), and low HDL cholesterol (37.2%) were highly prevalent among those with metabolic syndrome. Prevalence rates for CVD, CHD, and CBD were 12.8, 8.7, and 5.8%, respectively. After adjustment for age and sex, metabolic syndrome was associated with increased age- and sex-adjusted ORs for CVD (OR 1.7 [95% CI 1.4–2.1]), CHD (1.7 [1.4–2.2]), and CBD (1.7 [1.3–2.3]) compared with those without CVD, CHD, or CBD. CONCLUSION—Metabolic syndrome prevalence in the JHS is among the highest reported for population-based cohorts worldwide and is significantly associated with increased ORs for CVD, CHD, and CBD. Abdominal obesity, increased blood pressure, and low HDL cholesterol (without triglyceride elevation) are surprisingly prominent. A high prevalence of low HDL emerges as a leading contributor to metabolic syndrome among African Americans in this large African-American cohort.
On the genericity of Whitehead minimality

Abstract We show that a finitely generated subgroup of a free group, chosen uniformly at random, is strictly Whitehead minimal with overwhelming probability. Whitehead minimality is one of the key elements of the solution of the orbit problem in free groups. The proofs strongly rely on combinatorial tools, notably those of analytic combinatorics. The result we prove actually depends implicitly on the choice of a distribution on finitely generated subgroups, and we establish it for the two distributions which appear in the literature on random subgroups.
Morphological decomposition based on the analysis of orthography

Recent theories of morphological processing have been dominated by the notion that morphologically complex words are decomposed into their constituents on the basis of their semantic properties. In this article we argue that the weight of evidence now suggests that the recognition of morphologically complex words begins with a rapid morphemic segmentation based solely on the analysis of orthography. Following a review of this evidence, we discuss the characteristics of this form of decomposition, speculate on what its purpose might be, consider how it might be learned in the developing reader, and describe what is known of its neural bases. Our discussion ends by reflecting on how evidence for semantically based decomposition might be (re)interpreted in the context of the orthographically based form of decomposition that we have described.
Cutting Edge: IL-1α Is a Crucial Danger Signal Triggering Acute Myocardial Inflammation during Myocardial Infarction

Myocardial infarction (MI) induces a sterile inflammatory response that contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile proinflammatory signal activating MAPKs and NF-κB in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88−/− fibroblasts but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88 dependency, the response was TLR independent, as explored in TLR reporter cells, pointing to a contribution of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1α, but not IL-1β, and the immune activation of cardiac fibroblasts was abrogated by an IL-1R antagonist and an IL-1α–blocking Ab. Moreover, immune responses triggered by necrotic Il1a−/− cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL-1α in the plasma, and postischemic inflammation was attenuated in Il1a−/− mice. Thus, our findings identify IL-1α as a crucial early danger signal triggering post-MI inflammation.
A Model Checking Based Approach for Containment Checking of UML Sequence Diagrams

The main challenge in software development process is to detect and fix the deviations of system's behaviors at different abstraction levels in early phases. For this purpose, UML 2 sequence diagrams are widely used for describing and analyzing the communication behavior of software systems. This paper describes a containment checking approach for UML 2 sequence diagrams to verify whether the behavior (or functions) described by a low-level model conforms those specified in the high-level counterpart based on model checking techniques, in order to improve the system's quality. However, creating consistency constraints and formal specifications for the sequence diagrams is a labor-intensive and error prone task. To alleviate this issue, we propose an automated transformation of sequence diagrams into formal specifications and consistency constraints that enable us to leverage the analytical powers of model checking to automatically verify the containment relationship. In addition, our approach provides the stakeholders more informative and comprehensive feedbacks regarding the inconsistency issues, and therefore helps them to efficiently identify and resolve the problems. The approach is implemented and validated using three realistic scenarios.
Medications development to treat alcohol dependence: a vision for the next decade

More than 76 million people world‐wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism's (NIAAA's) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long‐range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real‐world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder.
Taxing Cognitive Capacities Reduces Choice Consistency Rather Than Preference: A Model-Based Test

How do people make preferential choices in situations where their cognitive capacities are limited? Many studies link the manipulation of cognitive resources to qualitative changes in preferences. However, there is a widely overlooked alternative hypothesis, namely, that a reduction in cognitive capacities leads to an increase in choice inconsistency. We developed a mathematical model and followed a hierarchical Bayesian estimation approach to test to what extent a reduction in cognitive capacities leads to a shift in preference or an increase in choice inconsistency. Using a within-subject n-back task to manipulate cognitive load, we conducted three experiments across different choice domains: risky choice, temporal discounting, and strategic interaction. Across all three domains, results show that a reduction in cognitive capacities predominantly affected participants’ level of choice consistency rather than their respective preference. These results hold on an individual and a group level. In sum, our approach and the mathematical model we used provide a rigorous and general test of how reduced cognitive capacities affect people’s decision-making.
Cytokine gene polymorphisms, cytokine levels and the risk of colorectal neoplasia in a screened population of Northeast Scotland

Cytokine gene polymorphisms modify expression and their circulating protein levels reflect inflammatory response. Chronic inflammation plays a key role in the pathogenesis of colorectal neoplasia (CRN) associated with inflammatory bowel disease, but it is not clear whether inflammation is a cause or an effect of tumours in sporadic CRN. We therefore investigated the association of cytokine gene polymorphisms and circulating cytokine levels on the risk of CRN in Northeast Scotland, which has a high incidence of CRN. We recruited two groups of patients from a screening colonoscopy cohort, either preprocedure or 3–24 months postprocedure. Participants with CRN were compared with participants with no evidence of CRN (controls). Blood-derived DNA was used to genotype polymorphisms in IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes. Circulating levels of high-sensitivity C-reactive protein and six cytokines [interleukin-1&bgr; (IL-1&bgr;), IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-&agr; (TNF-&agr;)] were measured. To examine the effect of CRN resection on marker levels, we used propensity score matching. A total of 884 patients were eligible for analysis, including 388 CRN cases and 496 controls. Cases were older (mean age 64 vs. 62 years, P<0.01) and more likely to be men (67 vs. 55%, P<0.001). Controls were more likely to be regular users of NSAID (P<0.0001). Compared with homozygous carriage of respective common alleles, proinflammatory CC genotypes of IL1B-31C>T [odds ratio (OR) (95% confidence interval (CI) 1.68 (1.03–2.73)] and PTGS2-765 C>G [OR (95% CI) 2.97 (1.05–8.46)] were each associated with an increased risk of CRN. Conversely, carriage of the A allele of IL8-251A>T was associated with a lower risk of CRN compared with the TT genotype [ORs (95% CI) 0.60 (0.41–0.86) for heterozygous, 0.88 (0.57–1.37) for homozygous, and 0.68 (0.48–0.95) for heterozygous and homozygous combined]. Compared with postprocedure cases, IL8, TNF-&agr; and C-reactive protein levels were significantly higher in preprocedure cases, but IL4 and IL10 protein levels were significantly lower. Proinflammatory cytokine gene polymorphisms in IL1B-31 and PTGS2-765 increase the risk of developing CRN. Levels of proinflammatory IL8, TNF-&agr; and C-reactive protein markers are significantly higher while CRN is in situ. Along with the NSAID findings, these data point to inflammation as an underlying pathogenetic mechanism in CRN.
Relationship of Body Mass, Height, and Weight Gain to Prostate Cancer Risk in the Multiethnic Cohort

We investigated the relationship of body size and prostate cancer risk in the Multiethnic Cohort, a longitudinal study of individuals ages 45 to 75 in Hawaii and in California. Self-reported measures of height and weight were obtained at baseline. Of 83,879 men enrolled from 1993 to 1996, a total of 5,554 were diagnosed with prostate cancer during an average of 9.6 years of follow-up. The influence of baseline weight and weight change since age 21 varied by ethnic group. Whites gaining more than 10 lbs had a nonlinear, increased risk of advanced and high-grade prostate cancer [relative risks (RR), 2.12; 95% confidence intervals (CI), 1.19-3.78 for 25-39.9 lbs; P trend 0.43; and RR, 1.49; 95% CI, 1.04-2.14, for ≥40 lbs; P trend 0.20, respectively]. African American men gaining 40 lbs or more (relative to <10 lbs) had a nonmonotonic, increased risk of localized prostate cancers (RR, 1.26; 95% CI, 1.02-1.54; P trend 0.09) and those who gained 25 lbs or more were at increased risk of low-grade disease (RR, 1.28; 95% CI, 1.03-1.58, for ≥40 versus 10 lbs, respectively; P trend 0.07). Japanese men had a statistically significant, inverse association of weight gain and localized disease (RR, 0.80; 95% CI, 0.65-0.99 for ≥40 versus 10 lbs; P trend 0.05). Our findings provide evidence that adiposity and changes in adiposity between younger and older adulthood influence the development of prostate cancer. Ethnic differences in risk may be explained by variation in the distribution of accumulated body fat that could differentially affect prostate carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2413–21)
gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma.

BACKGROUND Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).