Miracle-dz/UniFAR-FTUs huggingface dataset:
Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice

Neuritic plaques in the brain of Alzheimer's disease patients are characterized by beta-amyloid deposits associated with a glia-mediated inflammatory response. Non-steroidal anti-inflammatory drug (NSAID) therapy reduces Alzheimer's disease risk and ameliorates microglial reactivity in Alzheimer's disease brains; however, the molecular mechanisms subserving this effect are not yet clear. Since several NSAIDs bind to and activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) which acts to inhibit the expression of proinflammatory genes, this receptor appears a good candidate to mediate the observed anti-inflammatory effects. Recent data in vitro suggested that NSAIDs negatively regulate microglial activation and immunostimulated amyloid precursor protein processing via PPARgamma activation. We report that an acute 7 day oral treatment of 10-month-old APPV717I mice with the PPARgamma agonist pioglitazone or the NSAID ibuprofen resulted in a reduction in the number of activated microglia and reactive astrocytes in the hippocampus and cortex. Drug treatment reduced the expression of the proinflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). In parallel to the suppression of inflammatory markers, pioglitazone and ibuprofen treatment decreased beta-secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of Abeta1-42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27% reduction in the levels of soluble Abeta1-42 peptide. These findings demonstrate that anti-inflammatory drugs can act rapidly to inhibit inflammatory responses in the brain and negatively modulate amyloidogenesis.
What is the number needed to treat when exercise training heart failure patients

Smart NA. What is the Number Needed to Treat When Exercise Training Heart failure Patients? JEPonline 2009;12(3):1-. 5. Debate exists on the number needed to treat (NNT) to prevent one mortality with exercise training in heart failure patients. The primary aim of this work was to conduct a sensitivity analysis, removing outlying mortality data from a published meta-analysis of exercise training in heart failure patients. A sensitivity analysis was conducted by removing data from one randomized controlled trial that reported particularly high mortality rates and may be considered a data outlier. Annualized NNTs were subsequently calculated for mortality data from a meta-analysis of exercise training in heart failure patients. Sensitivity analysis showed that the mortality benefit reported by Piepoli was greatly influenced by Belardinelli’s data. Moreover Belardinelli’s data may be considered an outlier because of the increased mortality rate and therefore favorable odds ratio in comparison to the other 8 included studies. This working example highlights that reporting of NNTs can be misleading. Exercise training remains a relatively safe, non-pharmacological therapy for people with heart failure.
Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3+ T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 × 109 T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3+CD8+ cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I–mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I–mediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0–3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.
Investigating preferred relationship through fuzzy sets in social networking sites

The aim of this paper is to identify the strength of socio-demographic factors that motivate a user to send friend request on social networks. The study is supported by a primary survey that identifies five factors of the user's namely, age, sex, mutual friends, school and relationship status which are important in sending friend request. Fuzzy numbers are used to represent the identified factors because they allow expert opinions, uncertainty and impreciseness to be incorporated into the model. A multiple input, single output MISO model has been developed using Mamdani fuzzy inference system FIS and sensitivity analysis has been done. The results obtained show how the fuzzy logic approach translates vague, ambiguous, qualitative and imprecise information into numerical terms, which helps to identify the most informative contents while sending friend request. The paper also integrates primary survey and expert judgement to gain a deeper insight about the social behaviour.
Multiple fruit-flavored alcoholic drinks in a can (MFAC): an overlooked class of potentially harmful alcohol products

Abstract This article examines an overlooked class of alcohol products, described herein as multiple fruit-flavored alcoholic drinks in a can (MFAC). The article describes how characteristics of these products likely contribute to hazardous alcohol consumption among youth. Government regulation of these products may be needed to protect adolescent and young adult populations. National substance abuse surveillance systems should consider immediate adoption of MFAC use indicators to determine use and harm associated with these products, and to assess the effectiveness of future regulatory actions.
Curl: a language for web content

We describe a language designed for the representation of a broad spectrum of web content, including formatted text, graphics, and programmed application-level function. The approach described maps conventional markup tags to underlying, more general programming constructs, and provides local extensibility of the markup language by addition of programmed objects, procedures, and macros to the underlying object-oriented programming language. An implementation strategy based on a mix of static and dynamic just-in-time compilation techniques is described. The discussion focuses on a number of specific technical challenges raised by the language's breadth and performance goals, and the impact of these issues on Curl's architecture.
Dopamine D3 receptors as a therapeutic target for methamphetamine dependence

Abstract Background: Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. Objectives: (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals. Methods: Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60 mg daily). Results: The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n = 5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment. Conclusion: Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.
Prevalencia de fluorosis dental y fuentes adicionales de exposición a fluoruro como factores de riesgo a fluorosis dental en escolares de Campeche, México

Objective. To determine the prevalence and severity of dental fluorosis, and to evaluate supplementary fluoride sources as potential risk factors to fluorosis in school children aged 6-9. Material and methods. A cross-sectional study was carried out in 320 children attending elementary schools protected by a public preventive dental program in the city of Campeche, Mexico. A self-administered questionnaire directed to the mothers was delivered through the schools and collected in the same way. The examiners were trained and calibrated (kappa > 0.90) in modified Dean’s Index. The fluorosis community index (FCI) was calculated. Bivariate analyses were made with χ 2 test; odds ratios (OR) and 95% confidence intervals were calculated. Logistic regression was used in the final model. Results. Fluorosis prevalence was 56.3%, with very mild fluorosis present in 45% of children, mild in 10%, and severe in just 1.3%. The FCI was 0.7. The multivariate model showed that the effect of the supplementary fluoride sources was different between children that started brushing with toothpaste before two years of age (OR = 6.15; IC 95% = 2.03-18.67) and after (OR = 2.14; IC 95% = 1.16-3.94). Conclusions. Fluorosis prevalence was high for mild modalities, and low for more severe levels. According to FCI the dental fluorosis constitute a public health problem in the studied sample. Exposure to diverse fluoride sources –above and beyond the fluoridated salt program– was a risk factor for dental fluorosis in this community. Results suggest that toothpaste use in children two years of age and younger should be cautious, limited to follow current guidelines, and supervised by parents to minimize the risk of dental fluorosis.
Does stress mediate the development of substance use disorders among youth transitioning to young adulthood?

Abstract Background: Stress is a well-documented factor in the development of addiction. However, no longitudinal studies to date have assessed the role of stress in mediating the development of substance use disorders (SUD). Our previous results have demonstrated that a measure called Transmissible Liability Index (TLI) assessed during pre-adolescent years serves as a significant predictor of risk for substance use disorder among young adults. However, it remains unclear whether life stress mediates the relationship between TLI and SUD, or whether stress predicts SUD. Methods: We conducted a longitudinal study involving 191 male subjects to assess whether life stress mediates the relationship between TLI as assessed at age 10–12 and subsequent development of SUD at age 22, after controlling for other relevant factors. Results: Logistic regression demonstrated that the development of SUD at age 22 was associated with stress at age 19. A path analysis demonstrated that stress at age 19 significantly predicted SUD at age 22. However, stress did not mediate the relationship between the TLI assessed at age 10–12 and SUD in young adulthood. Conclusions and scientific significance: These findings confirm that stress plays a role in the development of SUD, but also shows that stress does not mediate the development of SUD. Further studies are warranted to clarify the role of stress in the etiology of SUD.
Nonmedical use of pain medications in dental patients

Abstract Background: Substance use is overrepresented in dental clinics that provide affordable care and dental clinics provide potential access to opioid analgesics. Research is needed to better understand prescription opioid misuse in this population. Objective: The purpose of this study was to assess the prevalence and correlates of the misuse of prescription opioids in adults seeking dental care from a low-cost dental training clinic. Methods: Patients were recruited from a university school’s dentistry patient emergency and admission services clinic. Patients (n = 369) within the waiting area of the clinic completed a self-report questionnaire about their nonmedical use of prescription pain medications, medication diversion and use of substances. Results: Approximately 37.9% (140/369) of those who completed the study survey reported at least some nonmedical use of pain medications within the past 30 days. Use was associated with diversion of medication, and use of tobacco, marijuana, and sedatives. Conclusions: Within this sample from a dental clinic, nonmedical use of prescription pain medications was more common than in the general population. This suggests that dental clinics may be an appropriate setting for provider education and patient-based intervention strategies to reduce nonmedical use of pain medications.
Clustering facilitated web services discovery model based on supervised term weighting and adaptive metric learning

With the explosive growth of web services, the research on how to rapidly find the desired services becomes increasingly important and challenging. In this paper, we focus on non-semantic web services discovery and present an efficient clustering facilitated web services discovery model CFWSFinder. Compared with the existing models, CFWSFinder has several characteristics. First, in services representing process, CFWSFinder imports WordNet and latent semantics index to represent non-semantic web services as the low-dimensional compact semantic feature vectors; Second, in services clustering process, CFWSFinder employs a modified Kernel batch self-organising map KBSOM neural network to minimise the services discovery duration; Third and most importantly, in services matching process, by using the category label information achieved from services clustering process, CFWSFinder can adopt supervised term weighting scheme and adaptive metric learning method to ameliorate the services discovery precision. Finally, experimental results performed on the real-world web services collection demonstrate the feasibility of the CFWSFinder.
Antimitochondrial Antibody Recognition and Structural Integrity of the Inner Lipoyl Domain of the E2 Subunit of Pyruvate Dehydrogenase Complex

Antimitochondrial autoantibodies (AMAs), the serological hallmark of primary biliary cirrhosis, are directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2). However, comprehensive analysis of the amino acid residues of PDC-E2 lipoyl β-sheet with AMA specificity is lacking. In this study, we postulated that specific residues within the lipoyl domain are critical to AMA recognition by maintaining conformational integrity. We systematically replaced each of 19 residue peptides of the inner lipoyl domain with alanine and analyzed these mutants for reactivities against 60 primary biliary cirrhosis and 103 control sera. Based on these data, we then constructed mutants with two, three, or four replacements and, in addition, probed the structure of the substituted domains using thiol-specific spin labeling and electron paramagnetic resonance (EPR) of a 5Ile→Ala and 12Ile→Ala double mutant. Single alanine replacement at 5Ile, 12Ile, and 15Glu significantly reduced AMA recognition. In addition, mutants with two, three, or four replacements at 5Ile, 12Ile, and 15Glu reduced AMA reactivity even further. Indeed, EPR reveals a highly flexible structure within the 5Ile and 12Ile double-alanine mutant. Autoreactivity is largely focused on specific residues in the PDC-E2 lipoyl domain critical in maintaining the lipoyl loop conformation necessary for AMA recognition. Collectively, the AMA binding studies and EPR analysis demonstrate the necessity of the lipoyl β-sheet structural conformation in anti–PDC-E2 recognition.
Shark IgW C Region Diversification through RNA Processing and Isotype Switching

Sharks and skates represent the earliest vertebrates with an adaptive immune system based on lymphocyte Ag receptors generated by V(D)J recombination. Shark B cells express two classical Igs, IgM and IgW, encoded by an early, alternative gene organization consisting of numerous autonomous miniloci, where the individual gene cluster carries a few rearranging gene segments and one C region, μ or ω. We have characterized eight distinct Ig miniloci encoding the nurse shark ω H chain. Each cluster consists of VH, D, and JH segments and six to eight C domain exons. Two interspersed secretory exons, in addition to the 3′-most C exon with tailpiece, provide the gene cluster with the ability to generate at least six secreted isoforms that differ as to polypeptide length and C domain combination. All clusters appear to be functional, as judged by the capability for rearrangement and absence of defects in the deduced amino acid sequence. We previously showed that IgW VDJ can perform isotype switching to μ C regions; in this study, we found that switching also occurs between ω clusters. Thus, C region diversification for any IgW VDJ can take place at the DNA level by switching to other ω or μ C regions, as well as by RNA processing to generate different C isoforms. The wide array of pathogens recognized by Abs requires different disposal pathways, and our findings demonstrate complex and unique pathways for C effector function diversity that evolved independently in cartilaginous fishes.
Fatal Eosinophilic Myocarditis Develops in the Absence of IFN-γ and IL-17A

CD4+ T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with Th cell effector function as a necessary mediator of this pathophysiology. IFN-γ–deficient mice developed severe experimental autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, whereas IL-17A–deficient mice were protected from progression to dilated cardiomyopathy. We generated IFN-γ−/−IL-17A−/− mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN-γ−/− mice. Surprisingly, IFN-γ−/−IL-17A−/− mice developed a rapidly fatal EAM. Eosinophils constituted a third of infiltrating leukocytes, qualifying this disease as eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, as well as Th2 deviation, among heart-infiltrating CD4+ cells. Ablation of eosinophil development improved survival of IFN-γ−/−IL-17A−/− mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFN-γ and IL-17A constitutes a novel model of eosinophilic heart disease in humans. This is also, to our knowledge, the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.
Towards measurement of structural complexity for ontologies

Ontologies represent knowledge of a particular domain and form an elementary unit for inference techniques on the semantic web. It is important to measure the complexity of ontologies in order for users to better understand, maintain, reuse and integrate them. Existing measures for the complexity of an ontology either handle complexity at schema and instance levels or define subjective parameters to measure ontology complexity. To this end, we present a semi-automated framework to measure the structural complexity at different abstraction levels of an ontology. Moreover, our metrics leverage the information provided by ontology editors, which can be useful to the ontology designer for selection of the ontology with optimum complexity among alternative ontologies. Our framework is inspired by the concept of component-based software complexity metrics and its metrics have been validated against Briand's and Weyuker's benchmarks. We have also performed comparative analysis on public ontologies.
The prevalence of binge drinking and receipt of provider drinking advice among US veterans with military service in Iraq or Afghanistan

ABSTRACT Background: Binge drinking is a significant public health concern linked to a number of health and psychosocial problems. Military service in Afghanistan (OEF) and Iraq (OIF) has been associated with posttraumatic stress disorder (PTSD) and increased hazardous drinking. Brief alcohol interventions may reduce hazardous drinking but are infrequently provided to at-risk drinkers. Objectives: This study examined the association of combat exposure, PTSD symptoms, binge drinking, use of VA and non-VA healthcare services, and the incidence of provider drinking advice. Methods: OEF/OIF veterans (n = 1087) completed measures of demographics, military history, combat exposure, PTSD symptoms, and binge drinking as part of a confidential mail survey study conducted in 2009 and 2010 (response rate = 29%). Patient report of receiving advice in the past year from a provider about their drinking was queried for frequent binge drinkers. The association of demographic variables, combat exposure, PTSD, and use of healthcare services with binge drinking and receipt of provider drinking advice was estimated using logistic regression. Results: Overall, 51% of the sample reported at least one episode of binge drinking in the past year and 19% were identified as frequent binge drinkers. PTSD was related to frequent binge drinking. At-risk veterans using VA healthcare services were significantly more likely to receive provider drinking advice (50%) than veterans not using VA (13.4%). Conclusions: There is a need for increased vigilance and action to identify and counsel at-risk veterans about alcohol misuse in this population.
Mitochondrial Reactive Oxygen Species Induces NLRP3-Dependent Lysosomal Damage and Inflammasome Activation

The nucleotide-binding oligomerization domain–like receptor family, pyrin domain–containing 3 (NLRP3) inflammasome drives many inflammatory processes and mediates IL-1 family cytokine release. Inflammasome activators typically damage cells and may release lysosomal and mitochondrial products into the cytosol. Macrophages triggered by the NLRP3 inflammasome activator nigericin show reduced mitochondrial function and decreased cellular ATP. Release of mitochondrial reactive oxygen species (ROS) leads to subsequent lysosomal membrane permeabilization (LMP). NLRP3-deficient macrophages show comparable reduced mitochondrial function and ATP loss, but maintain lysosomal acidity, demonstrating that LMP is NLRP3 dependent. A subset of wild-type macrophages undergo subsequent mitochondrial membrane permeabilization and die. Both LMP and mitochondrial membrane permeabilization are inhibited by potassium, scavenging mitochondrial ROS, or NLRP3 deficiency, but are unaffected by cathepsin B or caspase-1 inhibitors. In contrast, IL-1β secretion is ablated by potassium, scavenging mitochondrial ROS, and both cathepsin B and caspase-1 inhibition. These results demonstrate interplay between lysosomes and mitochondria that sustain NLRP3 activation and distinguish cell death from IL-1β release.