Miracle-dz/UniFAR-FTUs huggingface dataset:
Contribution of the N-Glucuronidation Pathway to the Overall in Vitro Metabolic Clearance of Midazolam in Humans

Midazolam (MDZ) is one of the most commonly used in vivo and in vitro CYP3A4 probe substrates for drug-drug interactions (DDI) studies. The major metabolic pathway of MDZ in humans consists of the CYP3A4-mediated 1′-hydroxylation followed by urinary excretion as 1′-O-glucuronide derivative. In the present study, following incubation of MDZ with human liver microsomes supplemented with UDP-glucuronic acid, two major high-performance liquid chromatography (HPLC) peaks were isolated. HPLC and liquid chromatography/tandem mass spectrometry analyses identified these two metabolites as quaternary direct N-glucuronides of MDZ, thus revealing an additional metabolic pathway for MDZ. 1H NMR spectrometry studies were performed showing that these two glucuronides were β-N-glucuronides, which could be considered as two different conformers of the same molecule. According to molecular modeling experiments, the two glucuronide derivatives could be involved in atropoisomerism equilibrium. The formation of MDZ N-glucuronide exhibited moderate intersubject variability (at most 4.5-fold difference, n = 10). Among the recombinant human UDP glucuronosyltransferase (UGT) isoforms tested, only isoform UGT1A4 catalyzed the N-glucuronidation of MDZ fitting a Michaelis-Menten model. Km and Vmax values were 29.9 ± 2.4 μM and 659.6 ± 19.0 pmol/min/mg protein, respectively. The N-glucuronide derivative was found in human hepatocytes incubated under control conditions but also in the presence of the well known CYP3A4 inhibitor, ketoconazole. In the context of the in vitro study of CYP3A4-mediated DDI using MDZ and ketoconazole, direct MDZ N-glucuronidation may partly compensate the decrease in MDZ metabolic clearance caused by the addition of the inhibitor, thus potentially leading to underestimation, at least in vitro, of the extent of DDI.
An Extension for Combination of Duty Constraints in Role-Based Access Control

Among access control models, Role Based Access Control (RBAC) is very useful and is used in many computer systems. Static Combination of Duty (SCD) and Dynamic Combination of Duty (DCD) constraints have been introduced recently for this model to handle dependent roles. These roles must be used together and can be considered as a contrary point of conflicting roles. In this paper, we propose several new types of SCD and DCD constraints. Also, we introduce strong dependent roles and define new groups of SCD constraints for these types of roles as SCD with common items and SCD with union items. In addition, we present an extension for SCD constraints in the presence of hierarchy.
A quad-band 8PSK/GMSK polar transceiver

The addition of 8PSK modulation to the GSM standard creates the need for architectural modifications to achieve necessary performance while maintaining a cost-effective solution. A large-signal polar modulation transmitter allows the use of an efficient nonlinear power amplifier (PA) for both GMSK and 8PSK. Digital interfaces are used for both receiver and transmitter, with analog options available for compatibility with older technology baseband systems. The receiver section of the transceiver is programmable to operate in direct conversion mode or multiple VLIF modes. All analog and digital filtering necessary to define the final channel is included. The transmit section of the transceiver uses an all digital system with a fractional-N digital modulator for the phase path. The amplitude path uses a Powerstar PA with both the ramp and the amplitude modulation applied to the collector. The transceiver meets or exceeds all specifications for both GMSK and 8PSK in all four cellular bands (850/900/1800/1900).
Integrated Planning and Executionfor Satellite Tele-CommunicationsChristian Plaunt

The next generation of communications satellites may be designed as a fast packet-switched constellation of spacecraft able to withstand substantial bandwidth capacity uctuation ranging from unstable weather phenomena to intentional jamming of communication. We have designed and partially implemented an architecture for managing satellite telecommunations network resources. Our approach supports advance reservations and dynamic requests, negotiation and fulll-ment of prioritized Quality of Service (QoS) contracts, graceful degradation in the presence of dynamic tasks and environmental changes, and optimization of geometrically constrained resources. Our integration of planning and execution to address this task uses planning to avoid resource contentions among requested activities and to conngure an independently competent execution system. Our system can be used in routine operations or as a simulation-based design tool.
Selection using Gini Measure of Income Inequality

A variety of measures are used to compare income inequalities, many of which have been derived from Lorenz curve. However, classical Gini coefficient and its variations are probably the most commonly used measures of income inequality. They are considered as the best measures by many scientists, but it is also recognized that the choice of age-grouping affects the Gini measures (Formby, et al. 1989). Bhattacharya and Mahalanobis (1967) recognized that because income distributions overlap extensively, the effect of age group on inequality is overestimated. Many procedures are available for ordering and ranking income distributions where the ordering is not linear. However, the researchers often are not interested in ordering the populations but selecting the best (or worst) of available populations indicating a lower (or higher) level of disparities in incomes within the population. This paper will discuss the estimation of overlap of income distributions and selection in terms of Gini Measure of income inequality.
Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity

Our current understanding of human tumor-resident myeloid cells is, for the most part, based on a large body of work in murine models or studies enumerating myeloid cells in patient tumor samples using immunohistochemistry (IHC). This has led to the establishment of the theory that, by and large, tumor-resident myeloid cells are either “protumor” M2 macrophages or myeloid-derived suppressor cells (MDSC). This concept has accelerated our understanding of myeloid cells in tumor progression and enabled the elucidation of many key regulatory mechanisms involved in cell recruitment, polarization, and activation. On the other hand, this paradigm does not embrace the complexity of the tumor-resident myeloid cell phenotype (IHC can only measure 1 or 2 markers per sample) and their possible divergent function in the hostile tumor microenvironment. Here, we examine the criteria that define human tumor-infiltrating myeloid cell subsets and provide a comprehensive and critical review of human myeloid cell nomenclature in cancer. We also highlight new evidence characterizing their contribution to cancer pathogenesis based on evidence derived from clinical studies drawing comparisons with murine studies where necessary. We then review the mechanisms in which myeloid cells are regulated by tumors in humans and how these are being targeted therapeutically.
Vertical and Exchange Equity in a Tax Morale Experiment

Tax morale and tax compliance seems to be a quite complex phenomenon. This experiment does not focus on traditional topics as the audit rate or the audit probability but on vertical and exchange equity. We used event history models to analyse temporal dynamics of processes. Our findings show that vertical equity factors significantly influence the probability to undertake full tax evasion. The effect of exchange inequity is not so clear. The tendency is that positive (negative) actions are intended to increase (reduce) taxpayers’ commitment to tax-payments JEL classification: H26, H41, C90, D63
Moduli of surfaces with an anti-canonical cycle

Abstract We prove a global Torelli theorem for pairs $(Y,D)$ where $Y$ is a smooth projective rational surface and $D\in |-K_{Y}|$ is a cycle of rational curves, as conjectured by Friedman in 1984. In addition, we construct natural universal families for such pairs.
On the relevance of music genre-based analysis in research on musical tastes

The investigation of the link between personality and musical tastes has led certain psychology researchers to examine the latent dimensions of musical tastes. In this area of research, investigators have largely relied on genre-based analysis, the relevance of which remains unclear. In this study, we examined the impact of changes in the selection of musical items on the identification of musical taste dimensions. Indeed, investigators have employed heterogeneous sets of music genres in prior research. Such a heterogeneity may partly explain why no clearly reproducible structure of musical tastes has emerged in the literature. Based on principal component analysis, our results indicate that the apparent structure of musical tastes is highly affected by even subtle variations in the items selected. Our findings also suggest that the identified structure of musical tastes strongly depends on the social background and cultural capital of respondents. Finally, our results highlight the limitations of the models that interpret the dimensions of musical tastes in terms of intrinsic musical properties.
Opioidergic Interactions between Striatal Projection Neurons

Medium spiny striatal projection neurons (MSNs) release opioid neuropeptides, but the role of these neurotransmitters is still poorly understood. While presynaptic inhibition of corticostriatal axons by opioid receptors has been demonstrated using exogenous ligands, the action of synaptically released opioids in the striatum has not been investigated. We performed single and paired whole-cell recordings from rat MSNs while corticostriatal fibers were electrically activated. In single recording experiments, we also activated antidromically the axons of a population of MSNs. Corticostriatal fibers were stimulated once every 10 s and every other stimulation was preceded by 5 antidromic spikes (at 100 Hz). This burst of antidromic spikes produced robust inhibition of evoked corticostriatal responses. This inhibition was not affected by the δ-opioid receptor antagonist SDM25N, but was completely abolished by the μ-opioid receptor antagonist CTOP. Inhibitory effects were maximal (on average 29.6 ± 11.4%) when the burst preceded the corticostriatal stimulation by 500 ms and became undetectable for intervals >2 s. Paired recordings from MSNs located <100 μm apart revealed that, in 30 of 56 (54%) pairs, a burst of five action potentials in one of the MSNs caused significant inhibition (17.1 ± 5.7%) of evoked glutamatergic responses in the other MSN. In 5 of these pairs, reciprocal inhibition of corticostriatal inputs was present. These effects were maximal 500 ms after the burst and were completely blocked by CTOP. Thus, these results reveal a novel, strong opioid-mediated communication between MSNs and provide a new cellular substrate for competitive dynamics in the striatum.
Sum Versus Vote Fusion in Multiple Classifier Systems

Amidst the conflicting experimental evidence of superiority of one over the other, we investigate the Sum and majority Vote combining rules in a two class case, under the assumption of experts being of equal strength and estimation errors conditionally independent and identically distributed. We show, analytically, that, for Gaussian estimation error distributions, Sum always outperforms Vote. For heavy tail distributions, we demonstrate by simulation that Vote may outperform Sum. Results on synthetic data confirm the theoretical predictions. Experiments on real data support the general findings, but also show the effect of the usual assumptions of conditional independence, identical error distributions, and common target outputs of the experts not being fully satisfied.
Protein flexibility and rigidity predicted from sequence

Structural flexibility has been associated with various biological processes such as molecular recognition and catalytic activity. In silico studies of protein flexibility have attempted to characterize and predict flexible regions based on simple principles. B‐values derived from experimental data are widely used to measure residue flexibility. Here, we present the most comprehensive large‐scale analysis of B‐values. We used this analysis to develop a neural network–based method that predicts flexible–rigid residues from amino acid sequence. The system uses both global and local information (i.e., features from the entire protein such as secondary structure composition, protein length, and fraction of surface residues, and features from a local window of sequence‐consecutive residues). The most important local feature was the evolutionary exchange profile reflecting sequence conservation in a family of related proteins. To illustrate its potential, we applied our method to 4 different case studies, each of which related our predictions to aspects of function. The first 2 were the prediction of regions that undergo conformational switches upon environmental changes (switch II region in Ras) and the prediction of surface regions, the rigidity of which is crucial for their function (tunnel in propeller folds). Both were correctly captured by our method. The third study established that residues in active sites of enzymes are predicted by our method to have unexpectedly low B‐values. The final study demonstrated how well our predictions correlated with NMR order parameters to reflect motion. Our method had not been set up to address any of the tasks in those 4 case studies. Therefore, we expect that this method will assist in many attempts at inferring aspects of function. Proteins 2005. © 2005 Wiley‐Liss, Inc.
Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat

Background Although the higher prevalence of depression in women than in men is well known, the neuronal basis of this sex difference is largely elusive. Methods Male and female rats were exposed to chronic variable mild stress (CVMS) after which immediate early gene products, corticotropin-releasing factor (CRF) mRNA and peptide, various epigenetic-associated enzymes and DNA methylation of the Crf gene were determined in the hypothalamic paraventricular nucleus (PVN), oval (BSTov) and fusiform (BSTfu) parts of the bed nucleus of the stria terminalis, and central amygdala (CeA). Results CVMS induced site-specific changes in Crf gene methylation in all brain centers studied in female rats and in the male BST and CeA, whereas the histone acetyltransferase, CREB-binding protein was increased in the female BST and the histone-deacetylase-5 decreased in the male CeA. These changes were accompanied by an increased amount of c-Fos in the PVN, BSTfu and CeA in males, and of FosB in the PVN of both sexes and in the male BSTov and BSTfu. In the PVN, CVMS increased CRF mRNA in males and CRF peptide decreased in females. Conclusions The data confirm our hypothesis that chronic stress affects gene expression and CRF transcriptional, translational and secretory activities in the PVN, BSTov, BSTfu and CeA, in a brain center-specific and sex-specific manner. Brain region-specific and sex-specific changes in epigenetic activity and neuronal activation may play, too, an important role in the sex specificity of the stress response and the susceptibility to depression.
Scale and Scope in Research

The issue of economies of scale and scope in research is arguably as old as research itself. Recently, however, deep changes in the way we organize research and an improved understanding of the relationship between research and growth have rekindled interest in the subject. A case in point is the concept of the European Research Area (ERA), which appears to be founded on the implicit understanding that economies of scale and scope matter in research funding and execution and that coordination and collaboration (at various levels) are therefore beneficial, whereas fragmentation and dispersal are inefficient. Hence the emphasis on ‘critical mass’. The rest of the chapter is divided into the following sections. Section 1 defines scale and scope economies in research and identifies reasons why empirical verification of such effects may be fraught with difficulties. Section 2 traces the extensive literature on the neo-Schumpeterian hypotheses that laid the foundation for the modern discussion on scale and scope effects in research. Section 3 introduces cooperative research as a reaction to a perceived need for correcting market failure and the inadequacies of individual organizations to go it alone. The section also describes how assumptions of research cooperation are built on the concepts of economies of scale and scope. Finally, Section 4 concludes by relating the discussion on scale and scope, and the related need for government intervention, to the evolution of the European Framework Programmes for Research and the development of the ERA.
Supportive features of a new hybrid scaffold for urothelium engineering

Introduction Different clinical conditions can compromise the urinary bladder function and structure. Routine regenerative practices in urology for bladder augmentation have been associated with diverse side effects. The internal lining of the bladder, the urothelium, plays an integral role in normal bladder function. Tissue engineering has provided novel therapeutic strategies through scaffolding and cell transplantation. Nano-scale surface features of scaffolds are valuable parameters for enhancement of cell behavior and function. Material and methods We fabricated a new hybrid scaffold of poly ɛ-caprolactone (PCL) and poly-L-lactide acid (PLLA) using an electrospinning system to exploit each polymer's advantages at nano-scale in the same scaffold. Dog urothelial cells were isolated, characterized by immunocytochemistry, and expanded for loading on the scaffold. Cell viability and proliferation on the scaffold surface were assessed by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, cytoarchitecture, distribution and detailed morphology of cells, and expression of cell specific markers were examined using hematoxylin and eosin (H + E) staining, scanning electron microscopy (SEM), and immunohistochemistry, respectively. Results According to MTT results, the scaffold did not exert any cytotoxic effect, and also supported cell proliferation and viability for 14 days of culture, which led to a significant increase in the number of cells. Scanning electron microscopy images revealed evenly distributed and normal appearing colonies of urothelial cells. A well-defined layer of cells was observed using H + E staining, which preserved their markers (pan-cytokeratin and uroplakin III) while growing on the scaffold. Conclusions Our findings confirmed favorable properties of PCL/PLLA regarding biocompatibility and applicability for upcoming new methods of bladder augmentation and engineering.
Maximum euclidean distance network coded modulation for asymmetric decode-and-forward two-way relaying

Network coding (NC) compresses two traffic flows with the aid of low-complexity algebraic operations, hence holds the potential of significantly improving both the efficiency of wireless two-way relaying, where each receiver is collocated with a transmitter and hence has prior knowledge of the message intended for the distant receiver. In this contribution, network coded modulation (NCM) is proposed for jointly performing NC and modulation. As in classic coded modulation, the Euclidean distance between the symbols is maximised, hence the symbol error probability is minimised. Specifically, the authors first propose set-partitioning-based NCM as an universal concept which can be combined with arbitrary constellations. Then the authors conceive practical phase-shift keying/quadrature amplitude modulation (PSK/QAM) NCM schemes, referred to as network coded PSK/QAM, based on modulo addition of the normalised phase/amplitude. To achieve a spatial diversity gain at a low complexity, a NC oriented maximum ratio combining scheme is proposed for combining the network coded signal and the original signal of the source. An adaptive NCM is also proposed to maximise the throughput while guaranteeing a target bit error probability (BEP). Both theoretical performance analysis and simulations demonstrate that the proposed NCM can achieve at least 3 dB signal-to-noise ratio gain and two times diversity gain.
Recent Progress in Development of Tnt1 Functional Genomics Platform for Medicago truncatula and Lotus japonicus in Bulgaria

Legumes, as protein-rich crops, are widely used for human food, animal feed and vegetable oil production. Over the past decade, two legume species, Medicago truncatula and Lotus japonicus, have been adopted as model legumes for genomics and physiological studies. The tobacco transposable element, Tnt1, is a powerful tool for insertional mutagenesis and gene inactivation in plants. A large collection of Tnt1-tagged lines of M. truncatula cv. Jemalong was generated during the course of the project ‘GLIP’: Grain Legumes Integrated Project, funded by the European Union (www.eugrainlegumes.org). In the project ‘IFCOSMO’: Integrated Functional and COmparative genomics Studies on the MOdel Legumes Medicago truncatula and Lotus japonicus, supported by a grant from the Ministry of Education, Youth and Science, Bulgaria, these lines are used for development of functional genomics platform of legumes in Bulgaria. This review presents recent advances in the evaluation of the M. truncatula Tnt1 mutant collection and outlines the steps that are taken in using the Tnt1-tagging for generation of a mutant collection of the second model legume L. japonicus. Both collections will provide a number of legume-specific mutants and serve as a resource for functional and comparative genomics research on legumes. Genomics technologies are expected to advance genetics and breeding of important legume crops (pea, faba bean, alfalfa and clover) in Bulgaria and worldwide.
Pendampingan Remaja Melalui Empowering Community Psychology Untuk Meningkatkan Orientasi Masa Depan

The purpose of this program is to change the adolescent mindset as well as improve the future orientation of youth in education. Furthermore, the community is expected to have awareness to run its the role as a support system in improving the future orientation of adolescents. The method of implementation of this program is empowering community psychology approach implemented through several stages, namely providing group counseling and motivation to adolescents, counseling to improve the participation of parents and teachers in improving the future orientation of adolescents. Parents tales of psycho education about educating teenagers, the importance of continu-ing adolescent education and improving parental patterns of concern about adolescents who find it difficult to get a mate. To the group of teachers given counseling effective communication with adolescents. The result of this assistance is the emergence of awareness of students (adolescents) to continue education to a higher level such as high school or vocational school by 85% from the previous only 40 %, while those who have motivation to continue education to college increased 10% from 0 %. Teenagers are still worried about getting children’s labels unsold by the public, but have started to decrease. Parents begin to have an awareness of the importance of their role in the future of their teenagers. Teachers gain insight and discover new methods of effective communication with adoles-cents. Key word: Community Psychology, teens, Future Orientation