Miracle-dz/UniFAR-FTUs huggingface dataset:
EVALUATION OF TIME-DEPENDENT CYTOCHROME P450 INHIBITION USING CULTURED HUMAN HEPATOCYTES

Primary human hepatocytes in culture are commonly used to evaluate cytochrome P450 (P450) induction via an enzyme activity endpoint. However, other processes can confound data interpretation. To this end, the impact of time-dependent P450 inhibition in this system was evaluated. Using a substrate-cassette approach, P450 activities were determined after incubation with the prototypic inhibitors tienilic acid (CYP2C9), erythromycin, troleandomycin, and fluoxetine (CYP3A4). Kinetic analysis of enzyme inactivation in hepatocytes was used to describe the effect of these time-dependent inhibitors and derive the inhibition parameters kinact and KI, which generally were in good agreement with the values derived using recombinant P450s and human liver microsomes (HLMs). Tienilic acid selectively inhibited CYP2C9-dependent diclofenac 4′-hydroxylation activity, and erythromycin, troleandomycin, and fluoxetine inhibited CYP3A4-dependent midazolam 1′-hydroxylation in a time- and concentration-dependent manner. Fluoxetine also inhibited CYP2C19-dependent S-mephenytoin 4′-hydroxylation in a time- and concentration-dependent manner in hepatocytes, HLMs, and recombinant CYP2C19 (KI 0.4 μM and kinact 0.5 min–1). As expected, the effect of fluoxetine on CYP2D6 in hepatocytes was consistent with potent yet reversible inhibition. A very weak time-dependent CYP2C9 inhibitor (AZ1, a proprietary AstraZeneca compound; KI 30 μM and kinact 0.02 min–1) effectively abolished CYP2C9 activity over 24 h at low (micromolar) concentrations in primary cultured human hepatocytes. This work demonstrates that caution is warranted in the interpretation of enzyme induction studies with metabolically stable, weak time-dependent inhibitors, which may have dramatic inhibitory effects on P450 activity in this system. Therefore, in addition to enzyme activity, mRNA and/or protein levels should be measured to fully evaluate the P450 induction potential of a drug candidate.
A low-complexity, broad-coverage probabilistic Dependency Parser for English

Large-scale parsing is still a complex and time-consuming process, often so much that it is infeasible in real-world applications. The parsing system described here addresses this problem by combining finite-state approaches, statistical parsing techniques and engineering knowledge, thus keeping parsing complexity as low as possible at the cost of a slight decrease in performance. The parser is robust and fast and at the same time based on strong linguistic foundations.
Cytokine Production by Peripheral Blood CD4+ and CD8+ T Cells in Atopic Childhood Asthma

There are conflicting studies on T cell cytokine production in childhood asthma. In this study intracellular cytokine expression of IL-2, IL-4, IL-10, IL-13, IFN-γ, and TNF-α in CD4+ and CD8+ T cells in children with atopic asthma were measured by flow cytometry. Results. A significant increase in the percentage of CD4+ and CD8+ T cells producing IL-4 and IL-13 and decrease in the percentage of CD4+ producing IFN-γ in asthmatic children was found. The percentage of CD4+/IL-13+ was significantly higher in severe asthma than in children with intermittent disease symptoms. Severity of asthma was associated with increased both serum IgE and frequencies of CD4+/IL-13+ T cells, as well as duration of disease. Moreover, a decrease in FEV1, FEV1/FVC was observed in relation to the severity of asthma. Changes in cytokine profile in CD8+ subpopulation didn't depend on the severity of the disease. Conclusions. Increased production of IL-4 and IL-13 in both CD4+ and CD8+ T cells accompanied by decreased IFN-γ expression in CD4+ T cells may be evidence that both lymphocyte subpopulations are implicated in the pathogenesis of asthma. Relationship of CD4+/IL-13+ T cells with disease activity suggests that this lymphocyte subset may have a prominent role in childhood asthma.
Basis pursuit over continuum applied to range-Doppler estimation problem

Sparse estimation and compressive sensing techniques have been recently considered for radar estimation problems. It is frequently observed that these methods are robust to model uncertainties and substantially improve performance in scenarios with a low signal-to-noise. However, since current sparsity-based techniques are computationally costly and require a suitable discretization (grid), which strongly restricts resolution, they practically receive less attention. In this work, we present an application of a new sparsity-based technique to the specific problem of range-Doppler estimation. The method, generalizing basis pursuit, is less computationally complex and its performance is independent of the grid selection. We demonstrate that the proposed technique can improve estimation performance in difficult cases, as compared to the SAGE technique.
Energy efficiency in MIMO large scale two-tier networks with beamforming and adaptive modulation

In this paper, the energy efficiency in the downlink of a two-tier network consisting of macro- and femtocells using beamforming is analyzed. Orthogonal subchannel allocation is used in order to eliminate inter-tier interference. The random locations of the interferers in both tiers are modeled via a Poisson Point Process. Improvements in the energy efficiency of the system (in b/J/Hz), when several femtocells are deployed in a network, are observed under different scenarios. Finally, using realistic implementation parameters, we examine how the energy efficiency is affected by different antenna configurations, and we also obtain the optimal configurations.
Query-based navigation in semantically indexed hypermedia

This paper discusses an approach to navigation based on queries made possible by a semantic hypermedia architecture. Navigation via query offers an augmented browsing capacity based on measures of semantic closeness between terms in an index space that models the classification of artefacts within a museum collection management system. The paper discusses some of the possibilities that automatic traversal of relationships in the index space holds for hybrid query/navigation tools, such as navigation via similarity and query generalisation. The example scenario suggests that, although these tools are implemented by complex queries, they fit into a browsing, rather than an analytical style of access. Such hybrid navigation tools are capable of overcoming some of the limitations of manual browsing and contributing to a smooth transition between browsing and query. A prototype implementation of the architecture is described, along with details of a social history application with three dimensions of classification schema in the index space. The paper discusses how queries can be used as the basis for navigation, and argues that this is integral to current efforts to integrate hypermedia and information retrieval.
Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease.

RATIONALE The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known. OBJECTIVES Characterize patients, treatment, and isolates in macrolide-resistant MAC lung disease. METHODS Retrospective chart review, susceptibility testing, molecular fingerprinting, and DNA sequence analyses of resistant MAC isolates. MEASUREMENTS AND MAIN RESULTS We identified 51 patients over a 15-yr period with clarithromycin-resistant MAC (minimum inhibitory concentration (MIC)>or=32 microg/ml) lung disease at a single referral center. Twenty-four (47%) patients had nodular disease with bronchiectasis and 27 (53%) had upper lobe cavitary disease. Most patients (77%) had M. intracellulare. Sequencing of the 23S r-RNA gene showed 49 of 51 isolates (96%) with the expected mutation in adenine 2058 or 2059. Risk factors for resistance included macrolide monotherapy or combination with a quinolone only (39/51 or 76%). Macrolide resistance developed in 12 of 303 (4.0%) patients started on the American Thoracic Society-recommended two companion drugs, with no risk difference in clarithromycin versus azithromycin and daily versus intermittent therapy. Sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79%) patients who received more than 6 mo of injectable aminoglycoside therapy and lung resection, compared with 2 of 37 (5%) who did not. The 1-yr mortality in patients who remained culture positive was 34% (13/38) compared with 0% (0/13) of patients who became culture negative (converted). CONCLUSIONS Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.
Exploiting error-control coding in blind channel estimation

Despite the widespread use of forward-error control (FEC) coding, most channel estimation techniques ignore its presence, and instead make the simplifying assumption that the transmitted symbols are uncoded. However, FEC induces structure in the transmitted sequence that can be exploited to improve channel estimates. Furthermore, soft-output decoding can improve decision-driven techniques. We propose a technique for exploiting FEC in channel estimation that combines iterative channel estimation with turbo equalization. We present one example showing that an estimator that exploits FEC can attain the same accuracy as one that ignores FEC, but with an SNR that is 6 dB lower.
Stream Runoff and Nitrate Recovery Times After Forest Disturbance in the USA and Japan

To understand mechanisms of long‐term hydrological and biogeochemical recovery after forest disturbance, it is important to evaluate recovery times (i.e., time scales associated with the return to baseline or predisturbance conditions) of stream runoff and nitrate concentration. Previous studies have focused on either the response of runoff or nitrate concentration, and some have specifically addressed recovery times following disturbance. However, controlling factors have not yet been elucidated. Knowing these relationships will advance our understanding of each recovery process. The objectives of this study were to explore the relationship between runoff and nitrate recovery times and identify potential factors controlling each. We acquired long‐term runoff and stream water nitrate concentration data from 20 sites in the USA and Japan. We then examined the relationship between runoff and nitrate recovery times at these multiple sites and use these relationships to discuss the ecosystem dynamics following forest disturbance. Nitrate response was detected at all study sites, while runoff responses were detected at all sites with disturbance intensities greater than 75% of the catchment area. The runoff recovery time was significantly correlated with the nitrate recovery time for catchments that had a runoff response. For these catchments, hydrological recovery times were slower than nitrate recovery times. The relationship between these two recovery times suggests that forest regeneration was a common control on both recovery times. However, the faster recovery time for nitrate suggests that nitrogen was less available or less mobile in these catchments than water.
Mechanisms of MHC class I‐restricted antigen processing and cross‐presentation

Summary: In this review, we discuss recent data from our laboratory that address two aspects of major histocompatibility complex (MHC) class I‐restricted antigen processing. First, we consider the nature of the peptide‐loading complex, which is the assembly of proteins in the endoplasmic reticulum (ER) into which newly synthesized MHC class I‐β2 microglobulin (β2m) heterodimers are incorporated, and the mechanisms involved in MHC class I assembly and peptide loading that are facilitated by the peptide‐loading complex. Second, we discuss mechanisms of cross‐presentation, the phenomenon whereby extracellular and luminal protein antigens can be processed by antigen‐presenting cells, particularly dendritic cells, and presented by MHC class I molecules to CD8+ T cells. The focus of the discussion is mainly on the human MHC class I system.
Nostalgia

Traditionally, nostalgia has been conceptualized as a medical disease and a psychiatric disorder. Instead, we argue that nostalgia is a predominantly positive, self-relevant, and social emotion serving key psychological functions. Nostalgic narratives reflect more positive than negative affect, feature the self as the protagonist, and are embedded in a social context. Nostalgia is triggered by dysphoric states such as negative mood and loneliness. Finally, nostalgia generates positive affect, increases self-esteem, fosters social connectedness, and alleviates existential threat.
Prohexadione calcium controls shoot growth of pear trees under mild winter conditions

The aim of this study was to evaluate the effects of prohexadione calcium (ProCa) on vegetative growth and yield of ‘Carrick’, ‘Packham’s Triumph’ and ‘William’s’ pear trees. The trial was performed at the experimental orchards of the Federal University of Pelotas, Capao do Leao, RS, Brazil (31° 52’ 00" S; 52° 21’ 24" W), during the growing seasons of 2011/12 and 2012/13. Treatments were applied to single-tree replications in a randomized complete block design with four replications as follows: Control (unsprayed), ProCa (ProCa - 750 g ha -1 i.a.). The ProCa was split in four (187.5 g ha -1 a.i. each) or three timings (250 g ha -1 a.i. each) applications in the 2011/12 and 2012/13 growing seasons, respectively. The assessed parameters were: one-year-old shoot length, number of nodes per shoot, average internode length per shoot, trunk cross sectional area (TCSA) increment, pruning weight, number of fruit per tree, average fruit weight, yield per tree and return bloom. The application of ProCa at 750 g ha-1 a.i. satisfactorily controlled shoot growth through the reduction of internode length of ‘Carrick’, ‘Packham’s Triumph’ and ‘William’s’ pears. Besides, return bloom was not negatively affected by ProCa. Therefore, this plant growth regulator is a potential management tool to reduce shoot growth and the need for pruning in pear orchards.
Sediment loading of alpine debris-flow channels by snow avalanches, Canadian Rocky Mountains

ABSTRACT Measurements of sediment deposition by snow avalanches were carried out in five alpine debris-flow channels in the Canadian Rocky Mountains after five or six winters by employing on average 15–29 sampling polygons in each channel. Following the melting of the avalanche snow each summer, the sediment deposited inside each polygon was collected, weighed, and converted to a depth of deposition. The results show that deposition in the channels averages 0.09–0.38 cm a−1, with an overall average of 0.19 cm a−1 for the five channels. Most of this deposition is contributed by weak clastic rocks in the basins but the largest particles are derived from much stronger carbonate rocks. Taking into account the channel area over which the measurements were made and the basin area, the measured sediment depths are equivalent to 8.3–36.4 m3 a−1 of deposition per channel or 10.9–311.7 t km−2 a−1 basin sediment yield. For the five channels, the overall averages are 16.4 m3 a−1 and 95.8 t km−2 a−1, respectively. On average 8–38% of polygons in each channel had no sediment deposition after a winter, reflecting the high spatial variability of avalanche sediment deposition. Comparison of debris-flow volumes and return periods with the measured annual volumes of sediment deposition suggests that avalanches are by themselves incapable of loading these channels for debris flows, and other processes such as rockfall, creep and streamflow also play a role. The most important role of avalanches may be as a hillslope-channel coupling mechanism in the sediment cascade and to assist in debris-flow bulking on the fan.
A More Desirable Balanced Polyunsaturated Fatty Acid Composition Achieved by Heterologous Expression of Δ15/Δ4 Desaturases in Mammalian Cells

Arachidonic (ARA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are the most biologically active polyunsaturated fatty acids, but their biosyntheses in mammals are very limited. The biosynthesis of DHA is the most difficult, because this undergoes the Sprecher pathway–a further elongation step from docosapentaenoic acid (DPA), a Δ6-desaturase acting on a C24 fatty acid substrate followed by a peroxisomal chain shortening step. This paper reports the successful heterologous expression of two non-mammalian genes (with modification of codon usage), coding for Euglena gracilis Δ4-desaturase and Siganus canaliculatus Δ4-desaturase respectively, in mammalian cells (HEK293 cell line). Both of the Δ4-desaturases can efficiently function, directly converting DPA into DHA. Moreover, the cooperation of the E. gracilis Δ4-desaturase with C. elegans Δ15-desaturase (able to convert a number of n-6 PUFAs to their corresponding n-3 PUFAs) in transgenic HEK293 cells made a more desirable fatty acid composition – a drastically reduced n-6/n-3 PUFAs ratio and a high level of DHA as well as EPA and ARA. Our findings provide a basis for potential applications of the gene constructs for expression of Δ15/Δ4-desaturases in transgenic livestock to produce such a fatty acid profile in the related products, which certainly will bring benefit to human health.
Outage probability analysis for η-μ fading channels

In this Letter we derive exact closed-form expressions for the outage probability (OP) in η-μ fading channels. First, a general expression in terms of the confluent Lauricella function is derived for arbitrary values of μ. Next, we restrict the analysis to physical η-μ channel models, i.e. to integer values of 2μ, and obtain exact closed-form expressions for the OP in terms of Marcum Q, Bessel and elementary functions. The results in this Letter are applicable to the OP analysis of maximal ratio combining (MRC) over i.i. d. η-μ or Hoyt fading channels.
Extracellular Polymeric Matrix Production and Relaxation under Fluid Shear and Mechanical Pressure in Staphylococcus aureus Biofilms

ABSTRACT The viscoelasticity of a biofilm's EPS (extracellular polymeric substance) matrix conveys protection against mechanical challenges, but adaptive responses of biofilm inhabitants to produce EPS are not well known. Here, we compare the responses of a biofilm of an EPS-producing (ATCC 12600) and a non-EPS producing (5298) Staphylococcus aureus strain to fluid shear and mechanical challenge. Confocal laser scanning microscopy confirmed absence of calcofluor-white-stainable EPS in biofilms of S. aureus 5298. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy combined with tribometry indicated that polysaccharide production per bacterium in the initial adhering layer was higher during growth at high shear than at low shear and that this increased EPS production extended to entire biofilms, as indicated by tribometrically measured coefficients of friction (CoF). CoF of biofilms grown under high fluid shear were higher than those when grown under low shear, likely due to wash-off polysaccharides. Measurement of a biofilm's CoF implies application of mechanical pressure that yielded an immediate increase in the polysaccharide band area of S. aureus ATCC 12600 biofilms due to their compression. Compression decreased after relief of pressure to the level observed prior to mechanical pressure. For biofilms grown under high shear, this coincided with a higher percent whiteness in optical coherence tomography-images indicative of water outflow, returning back into the biofilm during stress relaxation. Biofilms grown under low shear, however, were stimulated during tribometry to produce EPS, also after relief of stress. Knowledge of factors that govern EPS production and water flow in biofilms will allow better control of biofilms under mechanical challenge and better understanding of the barrier properties of biofilms against antimicrobial penetration. IMPORTANCE Adaptive responses of biofilm inhabitants in nature to environmental challenges such as fluid shear and mechanical pressure often involve EPS production with the aim of protecting biofilm inhabitants. EPS can assist biofilm bacteria in remaining attached or can impede antimicrobial penetration. The TriboChemist is a recently introduced instrument, allowing the study of initially adhering bacteria to a germanium crystal using ATR-FTIR spectroscopy, while simultaneously allowing measurement of the coefficient of friction of a biofilm, which serves as an indicator of the EPS content of a biofilm. EPS production can be stimulated by both fluid shear during growth and mechanical pressure, while increased EPS production can continue after pressure relaxation of the biofilm. Since EPS is pivotal in the protection of biofilm inhabitants against mechanical and chemical challenges, knowledge of the factors that make biofilm inhabitants decide to produce EPS, as provided in this study, is important for the development of biofilm control measures.
Digital forensics in VoIP networks

With VoIP being deployed on large scale, forensic analysis of captured VoIP traffic is of major practical interest. In this paper, we present a new fingerprinting approach that identifies the types of devices (name, version, brand, series) in captured VoIP traffic. We focus only on the signaling plane and discard voice related data. Although we consider only one signaling protocol for the illustration, our tool relies on structural information trees and can easily be adapted to any protocol of that has a known syntax. We have integrated our tool within the well known tshark application in order to provide an easy to use support for forensic analysts.
EFNS guideline on the management of status epilepticus in adults

The objective of the current article was to review the literature and discuss the degree of evidence for various treatment strategies for status epilepticus (SE) in adults. We searched MEDLINE and EMBASE for relevant literature from 1966 to January 2005 and in the current updated version all pertinent publications from January 2005 to January 2009. Furthermore, the Cochrane Central Register of Controlled Trials (CENTRAL) was sought. Recommendations are based on this literature and on our judgement of the relevance of the references to the subject. Recommendations were reached by informative consensus approach. Where there was a lack of evidence but consensus was clear, we have stated our opinion as good practice points. The preferred treatment pathway for generalised convulsive status epilepticus (GCSE) is intravenous (i.v.) administration of 4–8 mg lorazepam or 10 mg diazepam directly followed by 18 mg/kg phenytoin. If seizures continue more than 10 min after first injection, another 4 mg lorazepam or 10 mg diazepam is recommended. Refractory GCSE is treated by anaesthetic doses of barbiturates, midazolam or propofol; the anaesthetics are titrated against an electroencephalogram burst suppression pattern for at least 24 h. The initial therapy of non‐convulsive SE depends on type and cause. Complex partial SE is initially treated in the same manner as GCSE. However, if it turns out to be refractory, further non‐anaesthetising i.v. substances such levetiracetam, phenobarbital or valproic acid should be given instead of anaesthetics. In subtle SE, in most patients, i.v. anaesthesia is required.