Miracle-dz/UniFAR-FTUs huggingface dataset:
HPLC determination of erythrocyte methotrexate polyglutamates after low-dose methotrexate therapy in patients with rheumatoid arthritis.

BACKGROUND Methotrexate (MTX) may produce antiarthritic effects through polyglutamation to methotrexate polyglutamates (MTXPGs), a process that covalently attaches sequential gamma-linked glutamic residues to MTX. We sought to develop an innovative HPLC method for the quantification of these metabolites in erythrocytes. METHODS Two alternative approaches were developed. In the first approach, MTXPGs from 50 micro L of packed erythrocytes were converted to MTX in the presence of plasma gamma-glutamyl hydrolase and mercaptoethanol at 37 degrees C. In the second approach, MTXPG species (up to the hepta order of glutamation) from 100 micro L packed erythrocytes were directly quantified in a single run. In both methods, the MTXPGs were extracted from the biological matrix by a simple perchloric acid deproteinization step with direct injection of the extract into the HPLC. The chromatography used a C(18) reversed-phase column, an ammonium acetate/acetonitrile buffer, and postcolumn photo-oxidation of MTXPGs to fluorescent analytes. RESULTS Intra- and interday imprecision (CVs) were <10% at low and high concentrations of analytes for both methods. The limit of quantification was 5 nmol/L. In 70 patients with rheumatoid arthritis receiving weekly low-dose MTX, the mean (SD) total MTXPG concentration measured after conversion of MTXPGs to MTX was similar to the total MTXPG concentration calculated from the sum of individual MTXPG species [117 (56) vs 120 (59) nmol/L; r = 0.97; slope = 1.0]. The triglutamate predominated over all other MTXPG species (36% of total), the pentaglutamate was the highest order of glutamation detected, and a stability study revealed no change in the polyglutamation pattern in erythrocytes 48 h after phlebotomy when the specimen was stored at 2-8 degrees C. CONCLUSION The proposed method for quantification of erythrocyte MTXPGs is rapid, sensitive, and accurate and can be applied to the routine monitoring of MTX therapy.
Somatic versus Dendritic Resonance: Differential Filtering of Inputs through Non-Uniform Distributions of Active Conductances

Synaptic inputs to neurons are processed in a frequency-dependent manner, with either low-pass or resonant response characteristics. These types of filtering play a key role in the frequency-specific information flow in neuronal networks. While the generation of resonance by specific ionic conductances is well investigated, less attention has been paid to the spatial distribution of the resonance-generating conductances across a neuron. In pyramidal neurons – one of the major excitatory cell-types in the mammalian brain – a steep gradient of resonance-generating h-conductances with a 60-fold increase towards distal dendrites has been demonstrated experimentally. Because the dendritic trees of these cells are large, spatial compartmentalization of resonant properties can be expected. Here, we use mathematical descriptions of spatially extended neurons to investigate the consequences of such a distal, dendritic localization of h-conductances for signal processing. While neurons with short dendrites do not exhibit a pronounced compartmentalization of resonance, i.e. the filter properties of dendrites and soma are similar, we find that neurons with longer dendrites ( space constant) can show distinct filtering of dendritic and somatic inputs due to electrotonic segregation. Moreover, we show that for such neurons, experimental classification as resonant versus nonresonant can be misleading when based on somatic recordings, because for these morphologies a dendritic resonance could easily be undetectable when using somatic input. Nevertheless, noise-driven membrane-potential oscillations caused by dendritic resonance can propagate to the soma where they can be recorded, hence contrasting with the low-pass filtering at the soma. We conclude that non-uniform distributions of active conductances can underlie differential filtering of synaptic input in neurons with spatially extended dendrites, like pyramidal neurons, bearing relevance for the localization-dependent targeting of synaptic input pathways to these cells.
Deep mutational scanning reveals tail anchor characteristics important for mitochondrial targeting

Proteins localized to mitochondria by a carboxyl-terminal tail anchor (TA) play roles in apoptosis, mitochondrial dynamics, and mitochondrial protein import. To reveal characteristics of TAs that are important for mitochondrial targeting, we examined the TA of the Saccharomyces cerevisiae Fis1 protein. We generated a library of Fis1p TA variants fused to the Gal4 transcription factor, then selected for mutations allowing Gal4 activity in the nucleus. Next-generation sequencing allowed quantification of TA variants in our mutant library both before and after selection for loss of TA targeting. High-throughput results were confirmed by further analysis of individual Fis1p TA mutants. Intriguingly, positively charged residues were more acceptable at several positions within the membrane-associated domain of the Fis1p TA than negatively charged residues. These findings provide strong, in vivo evidence that lysine and arginine can "snorkel" when associated with a lipid bilayer and place their terminal charges at the membrane interface. Our work provides the first high-resolution analysis of an organelle targeting sequence by deep mutational scanning.
The wisdom hierarchy: representations of the DIKW hierarchy

This paper revisits the data-information-knowledge-wisdom (DIKW) hierarchy by examining the articulation of the hierarchy in a number of widely read textbooks, and analysing their statements about the nature of data, information, knowledge, and wisdom. The hierarchy referred to variously as the ‘Knowledge Hierarchy’, the ‘Information Hierarchy’ and the ‘Knowledge Pyramid’ is one of the fundamental, widely recognized and ‘taken-for-granted’ models in the information and knowledge literatures. It is often quoted, or used implicitly, in definitions of data, information and knowledge in the information management, information systems and knowledge management literatures, but there has been limited direct discussion of the hierarchy. After revisiting Ackoff’s original articulation of the hierarchy, definitions of data, information, knowledge and wisdom as articulated in recent textbooks in information systems and knowledge management are reviewed and assessed, in pursuit of a consensus on definitions and transformation processes. This process brings to the surface the extent of agreement and dissent in relation to these definitions, and provides a basis for a discussion as to whether these articulations present an adequate distinction between data, information, and knowledge. Typically information is defined in terms of data, knowledge in terms of information, and wisdom in terms of knowledge, but there is less consensus in the description of the processes that transform elements lower in the hierarchy into those above them, leading to a lack of definitional clarity. In addition, there is limited reference to wisdom in these texts.
Divisão sexual do trabalho e democracia

The aim of this article is to analyze the connections between the sexual division of labor, understood here as a fundamental factor in the production of gender, and the limits of contemporary democracies. The analysis is supported by extensive literature on the subject, accompanied by empirical contributions that allow us to situate the discussion in the Brazilian context. Two axioms and one guiding hypothesis form the three main sections of the article, as follows: (A1) the sexual division of labor is at the heart of gender hierarchies in contemporary societies; (A2) these hierarchies assume different forms according to women’s class and race; (H) the resultant discrepancies – particularly in the form of unequal access to leisure time and income – restrict women’s political participation. Recognition of the impact of the sexual division of labor is made according to a broad vision of politics that takes into account everyday power relations. The analysis highlights how these relations combine to affect access to the political system, in order to help construct theoretical models that incorporate this fundamental dimension of gender relations, the sexual division of labor, and the critical analysis of the limits of democracy.
UK QE reconsidered: the real economy effects of monetary policy in the UK, 1990-2012 – an empirical analysis

Empirical studies of so called ‘unconventional’ monetary policy – ‘Quantitative Easing’ or ‘Large Scale Asset Purchases’ - since the North Atlantic Financial Crisis of 2007-2009 in the United Kingdom and elsewhere have mainly focussed on the effect of policy on intermediate variables rather than the stated ultimate goal of such policies, boosting nominal demand and GDP growth. Secondly and relatedly they tend to focus on the crisis and post-crisis period, a time of extraordinary economic and financial dislocation, which creates counterfactual and attribution problems and fails to capture typical macroeconomic lag dynamics. Adopting the approach of Voutsinas and Werner (2010), and building on Lyonnet and Werner’s (2012) study of UK QE, this paper addresses these weaknesses by 1) examining the impact of various different monetary policy instruments (including Quantitative Easing) directly on UK nominal GDP growth; and 2) using a quarterly time series beginning in the first quarter of 1990 and up to the last quarter of 2012 (92 observations in total). We use the Hendry ‘general-to-specific’ econometric methodology to estimate a parsimonious model. The results show that disaggregated bank credit to the real economy (households and firms) has the most significant impact on nominal GDP growth. Changes to the central bank’s interest rate, central bank reserves, and total central bank asset ratios drop out of the model as insignificant. The policy implication it that, as private banks continue to shrink their balance sheets in the UK and Europe following the North Atlantic Crisis of 2008, central banks might wish to consider ‘unconventional’ monetary policies that more directly boost credit to the real economy and thus nominal GDP growth
Review of bystander approaches in support of preventing violence against women

Violence against women is a major public health problem and its prevalence remains unacceptably high in Australia. One in three women experience physical violence, and almost one in five experience sexual violence in their lifetime, most often from an intimate male partner. When witnessing an incident of violence, sexism or discrimination against women, an individual, or bystander, makes a decision as to whether to take some form of action to intervene or not. This report provides a systematic review of the research literature and theoretical origins of bystander approaches to preventing violence against women.
The Integrated Structural and Measurement Models of Existential Annihilation Anxieties (EAA) and Their Potential Contribution to Clinical Science: Two Studies on Western and Non-Western Samples

Current study integrated the existential annihilation anxieties (EAA) models and identified four EAA types: psychic, collective, status, and physical. Based on this conceptual framework, the authors developed a scale to measure the four types and assessed the scale’s construct and predictive validity, reliability and stability in two Western (UK, N = 178) and non-Western (Egypt, N = 490) samples. The study measured trauma types, PTSD, psychopathology, depression, self-esteem, will to exist and other related variables. Exploratory and confirmatory factor analysis confirmed the four-factor structure of the construct that was strictly invariant across groups in both samples. EAA and its four subscales were highly correlated with psychopathology, depression, and PTSD, and negatively correlated with “will to exist” and self-esteem in both samples. Path analysis and PROCESS macro indicated that EAA had strong direct effects, and mediated the effects of cumulative trauma on psychopathology. While personal identity trauma predicted psychic EAA, collective identity traumas predicted collective EAA, and status identity trauma predicted status EAA, survival trauma did not predict physical death EAA in either sample. Curve estimation clarified the non-linear dynamics involved in EAA’s types’ intersections and the discrepancy in physical EAA results. We discussed the inclusion of EAA in clinical practice and in the future development of intervention and prevention strategies.
Evaluation of the Effect of Different Food Media on the Marginal Integrity of Class V Compomer, Conventional and Resin-Modified Glass-Ionomer Restorations: An In Vitro Study

Background: Cervical lesions of anterior and posterior teeth are a common finding in routine dental practice. They are of much concern to the patient, if present in esthetically sensitive regions. Adhesive tooth-colored restorative materials are generally recommended for treating such lesions. The aim of the present study was to evaluate and compare the effect of various food media (lime juice, tea, coffee, and Coca-Cola) on the marginal integrity of Class V compomer (Dyract®), conventional glass-ionomer (Fuji II) and resin-modified glass-ionomer (Fuji II LC improved) restorations along their cemental and enamel margins with saline as control media. Materials and Methods: After restoration of prepared Class V cavities in human premolars with the three different materials (n = 8), they were immersed in the test media for 7 days and then stained with methylene blue dye. Buccolingual sections were prepared and examined under stereomicroscope and scores (0-2) were given. Results: Data were analyzed statistically using one-way analysis of variance in SPSS version 16.0. P < 0.05 were considered statistically significant. Conclusions: Among the three tested materials Compomer (Dyract®) showed more marginal integrity than the other two. Micro leakage values of Fuji II and Fuji II LC improved were statistically significant in acidic media (lime juice and Coca-Cola) compared to saline. Enamel margins showed more marginal adaptation than cemental margins.
Aerodynamic effects in the break-up of liquid jets: on the first wind-induced break-up regime

We present both numerical and analytical results from a spatial stability analysis of the coupled gas–liquid hydrodynamic equations governing the first wind-induced (FWI) liquid-jet break-up regime. Our study shows that an accurate evaluation of the growth rate of instabilities developing in a liquid jet discharging into a still gaseous atmosphere requires gas viscosity to be included in the stability equations even for low ${\it We}_g$, where ${\it We}_g{=}\rho_gU_l^2R_0/\sigma$, and $\rho_g, U_l, R_0$ and $\sigma$ are the gas density, the liquid injection velocity, the jet radius and the surface tension coefficient, respectively. The numerical results of the complete set of equations, in which the effect of viscosity in the gas perturbations is treated self-consistently for the first time, are in accordance with recently reported experimental growth rates. This permits us to conclude that the simple stability analysis presented here can be used to predict experimental results. Moreover, in order to throw light on the physical role played by the gas viscosity in the liquid-jet break-up process, we have considered the limiting case of very high Reynolds numbers and performed an asymptotic analysis which provides us with a parameter, $\alpha$, that measures the relative importance of viscous effects in the gas perturbations. The criterion $|\alpha|{\ll} 1$, with $\alpha$ computed a priori using only the much simpler inviscid stability results is a guide to assess the accuracy of a stability analysis in which viscous diffusion is neglected. We have also been able to explain the origin of the ad hoc constant 0.175 introduced by Sterling & Sleicher (J. Fluid Mech. vol. 68, 1975, p. 477) to correct the discrepancies between Weber's results (Z. Angew. Math. Mech. vol. 11, 1931, p. 136) and the experimental ones.
Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer – a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation

Nitroxoline is an antibiotic by chelating Zn2+ and Fe2+ from biofilm matrix. In this study, nitroxoline induced G1 arrest of cell cycle and subsequent apoptosis in prostate cancer cells through ion chelating-independent pathway. It decreased protein levels of cyclin D1, Cdc25A and phosphorylated Rb, but activated AMP-activated protein kinase (AMPK), a cellular energy sensor and signal transducer, leading to inhibition of downstream mTOR-p70S6K signaling. Knockdown of AMPKα significantly rescued nitroxoline-induced inhibition of cyclin D1-Rb-Cdc25A axis indicating AMPK-dependent mechanism. However, cytoprotective autophagy was simultaneously evoked by nitroxoline. Comet assay and Western blot analysis demonstrated DNA damaging effect and activation of Chk2 other than Chk1 to nitroxoline action. Instead of serving as a DNA repair transducer, nitroxoline-mediated Chk2 activation was identified to function as a pro-apoptotic inducer. In conclusion, the data suggest that nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest of cell cycle and apoptosis. AMPK-dependent activation of Chk2, at least partly, contributes to apoptosis. The data suggest the potential role of nitroxoline for therapeutic development against prostate cancers.
A machine-checked model for a Java-like language, virtual machine, and compiler

We introduce Jinja, a Java-like programming language with a formal semantics designed to exhibit core features of the Java language architecture. Jinja is a compromise between the realism of the language and the tractability and clarity of its formal semantics. The following aspects are formalised: a big and a small step operational semantics for Jinja and a proof of their equivalence, a type system and a definite initialisation analysis, a type safety proof of the small step semantics, a virtual machine (JVM), its operational semantics and its type system, a type safety proof for the JVM; a bytecode verifier, that is, a data flow analyser for the JVM, a correctness proof of the bytecode verifier with respect to the type system, and a compiler and a proof that it preserves semantics and well-typedness. The emphasis of this work is not on particular language features but on providing a unified model of the source language, the virtual machine, and the compiler. The whole development has been carried out in the theorem prover Isabelle/HOL.
Technology-Enhanced Performance-Based Feedback to Support Teacher Practice and Child Outcomes

We investigated the effect of real-time technology-enhanced performance-based feedback delivered during three different routines on teacher practice and child outcomes. Participants were three early childhood special education teachers and three focus preschool children identified with autism spectrum disorder. We used a multiple-probe single-case design to provide real-time technology-enhanced performance-based feedback across child-led, teacher-led, and mealtime routines. We collected generalization data across a fourth novel routine, clean-up. We analyzed teachers’ use of communicative antecedents and consequences, children’s responses to antecedents, and children’s expressive communication. Real-time technology-enhanced performance-based feedback enhanced teachers’ use of communicative antecedents and consequences, and when teachers used antecedents, children responded to these opportunities and practiced their expressive communication.
Mapping quantitative effects of oligogenes by allelic association

Regression analysis of a quantitative trait as a function of a single diallelic polymorphism has been extended to allelic association by composite likelihood under the Malecot model for multiple markers. We applied the method to 10 single nucleotide polymorphisms (SNPs) spanning 27 kb of the angiotensin‐I converting enzyme (ACE) gene in British families, localising a causal SNP between G2530A and 4656(CT)3/2 in the 3′ region, at a distance of 21.6±0.9 kb from the most proximal SNP T‐5491C. Neither they nor the I/D polymorphism is causal. To clarify genetic parameters we applied combined segregation, linkage and association analysis. Stronger evidence for the 3′ region was obtained, with significant evidence of a lesser 5′ effect as reported in French and Nigerian families. However, rigorous confirmation requires that the causal SNPs be identified. Both Malecot and parametric analysis appear to have high power by comparison with alternative methods for localizing oligogenes and their causal polymorphisms.
User-designed web services to support heterogeneous biological data retrieval

Biological data retrieval from web resources often necessitates multi-step access to several information sources. Web services are being developed to interact in a unified manner with heterogeneous databases. Composition of web services is then required to chain several elementary queries. However, web services are not yet available for any data sources thus limiting the scope of such strategy. The X-collect generic application has been designed to execute user-defined multi-step scenarios. Demos can be scheduled at the workshop. Encapsulation into web services makes such user scenarios re-usable and available for invocation by any application. Demos can be scheduled at the workshop. Work in progress deals with metadata registries to facilitate databases and/or web services discovery.
Near-field imaging with a loaded wire medium

Chandra S. R. Kaipa,1,* Alexander B. Yakovlev,1 Stanislav I. Maslovski,2 and Mário G. Silveirinha2 1Department of Electrical Engineering, The University of Mississippi, University, Mississippi 38677, USA 2Department of Electrical Engineering-Instituto de Telecomunicações, University of Coimbra, 3030 Coimbra, Portugal (Received 25 June 2012; revised manuscript received 4 September 2012; published 1 October 2012)