Miracle-dz/UniFAR-FTUs huggingface dataset:
Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model

Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach.
Catch-up and Convergence in Global Agricultural Productivity

In this paper we examine levels and trends in agricultural output and productivity in 97 developed and developing countries that account for a major portion of the world population and agricultural output. We make use of data drawn from the Food and Agriculture Organization of the United Nations and cover the period 1980-1995. Due to the non-availability of reliable input price data, the study uses data envelopment analysis (DEA) to derive Malmquist productivity indexes. The study examines trends in agricultural productivity over the period. Issues of catch-up and convergence, or in some cases possible divergence, in productivity in agriculture are examined within a global framework.
Berberine Regulated Gck, G6pc, Pck1 and Srebp-1c Expression and Activated AMP-activated Protein Kinase in Primary Rat Hepatocytes

The effects of hormonal and dietary stimuli on hepatic glucose and lipid homeostasis include regulation of gene expression. Berberine, an effective compound in certain Chinese medicinal herbs, has been reported to lower plasma glucose and lipid levels in diabetic and hypercholesterolemic patients. We hypothesized that it may affect the expression of hepatic genes involved in glucose and lipid metabolism. The effects of berberine hydrochloride on viability, gene expression, and activation of AMP activated protein kinase (AMPK) in primary hepatocytes from Sprague-Dawley (SD), Zucker lean (ZL) or fatty (ZF) rats were examined with MTT assay, real-time PCR, and western blotting, respectively. Berberine hydochloride at 50 µM or higher caused cytotoxic effects on hepatocytes. In SD and ZL hepatocytes, it induced Gck and suppressed G6pc expression at 10 and 25 µM, but not as potent as 1 nM insulin. Its effects on Pck1, and insulin-regulated Gck and G6pc expression depended on the hepatocyte sources and the dosage used. In ZF hepatocytes, it increased Gck, and suppressed Pck1 and G6pc expression without insulin. Its effects on Gck and G6pc, but not Pck1 expression, were additive with insulin. Berberine hydrochloride at 25 µM attenuated insulin-suppressed Pck1 (ZL/ZF cells), and insulin-induced Srebp-1c expression (SD/ZL/ZF cells), suggesting modulation of insulin action. Berberine hydrochloride did not alter these genes' mRNA stability. Its treatment caused a dose-dependent increase of phosphorylation of AMPKα, and its substrate, acetyl-CoA carboxylase, in primary hepatocytes. We conclude that berberine hydrochloride regulated the transcription of hepatic genes involved in glucose and fatty acid metabolism.
Determinants of Metabotropic Glutamate Receptor-5-mediated Ca2+ and Inositol 1,4,5-Trisphosphate Oscillation Frequency

Diverse patterns of Ca2+ i release differentially regulate Ca2+-sensitive enzymes and gene transcription, and generally the extent of agonist activation of phospholipase C-linked G protein-coupled receptors determines the type of Ca2+signal. We have studied global Ca2+ oscillations arising through activation of the metabotropic glutamate receptor mGluR5a expressed in Chinese hamster ovary cells and find that these oscillations are largely insensitive to agonist concentration. Using an inducible receptor expression system and a non-competitive antagonist, in conjunction with the translocation of eGFP-PHPLCδ to monitor inositol 1,4,5-trisphosphate (InsP3) oscillations in single cells, we show that mGluR5a density determines the frequency of these oscillations. The predominant underlying mechanism resulted from a negative feedback loop whereby protein kinase C (PKC) inhibited InsP3 generation. Down-regulation of PKC by prolonged exposure to phorbol ester revealed a second form of Ca2+ i oscillation at low agonist concentrations. These Ca2+ i signals showed features typical of classic repetitive Ca2+-induced Ca2+ release and were sensitive to agonist concentration. Therefore, a single receptor can stimulate two types of InsP3-mediated Ca2+ signal dependent upon feedback inhibition, producing two distinct means of controlling the final pattern of Ca2+ i release. Our results have physiological implications for Ca2+ signaling in general and emphasize the importance of mGluR5 surface expression for modulating synaptic plasticity.
Magnetically Driven Accretion in the Kerr Metric. III. Unbound Outflows

We have carried out fully relativistic numerical simulations of accretion disks in the Kerr metric. In this paper we focus on the unbound outflows that emerge self-consistently from the accretion flow. These outflows are found in the axial funnel region and consist of two components: a hot, fast, tenuous outflow in the axial funnel proper and a colder, slower, denser jet along the funnel wall. The funnel-wall jet is excluded from the axial funnel by elevated angular momentum and is also pressure-confined by a magnetized corona. Inside the funnel, a large-scale poloidal magnetic field spontaneously arises from the coupled dynamics of accretion and outflow, although there was no large-scale field in the initial state. Black hole rotation is not required to produce these unbound outflows, but their strength is enhanced by black hole spin. When the black hole spins rapidly, the energy ejected can be tens of percent of the accreted rest mass. At low spin, kinetic energy and enthalpy of the matter dominate the outflow energetics; at high spin, the balance shifts to Poynting flux. We compare the outflows observed in our simulations with those seen in other simulations.
Writing History in International Criminal Trials

1. Assessing court histories of mass crimes 2. What does the 'international' actually mean for international criminal trials? 3. Contrasting evidence: international and common law approaches to expert testimony 4. Does history have any legal relevance in international criminal trials? 5. From monumental history to micro-histories 6. Exoneration and mitigation in defense histories 7. Misjudging Rwandan society and history at the international criminal tribunal for Rwanda 8. Permanent justice: the international criminal court 9. Conclusion: new directions in international criminal trials.
The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo

A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the alpha 4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the alpha 4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for approximately 50% of the leukocyte rolling whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti-alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the alpha 4- integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the alpha 4- integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and beta 2-integrins.
American College of Radiology Acr Appropriateness Criteria ® Pediatric Hodgkin Lymphoma Expert Panel on Radiation Oncology–lymphoma: Summary of Literature Review

Introduction Historically children and adults were treated with the same chemotherapy regimens, radiation therapy fields, and doses. However, irradiation techniques suitable for adults produced significant morbidities in children, such as impaired musculoskeletal development, an increased risk for subsequent benign and malignant neoplasms, and cardiopulmonary toxicities that became unacceptable. A desire to reduce these morbidities has motivated the development of new treatment strategies for pediatric Hodgkin lymphoma (HL) [1,2].
Minor Galaxy Interactions: Star Formation Rates and Galaxy Properties

We study star formation in a sample of 1204 galaxies in minor ( ≥ 2) pair and compact groups, drawn from the Sloan Digital Sky Survey Data Release 5. We analyze an analogous sample of 2409 galaxies in major ( < 2) pair and compact groups to ensure that our selection reproduces previous results, and we use a "field" sample of 65,570 galaxies for comparison. Our major and minor pair samples include only galaxies in spectroscopically confirmed pair, where the recessional velocity separation ΔV < 500 km s-1 and the projected spatial separation ΔD < 50 kpc h-1. The relative magnitude (a proxy for the mass ratio) of the pair is an important parameter in the effectiveness of the tidally triggered star formation in minor interactions. As expected, the secondary galaxies in minor pair show evidence for tidally triggered star formation, whereas the primary galaxies in the minor pair do not. The galaxy color is also an important parameter in the effectiveness of triggered star formation in the major galaxy pair. In the major pair sample, there is a correlation between the specific Hα star formation rate (SSFR) and ΔD in the blue primary and blue secondary galaxies; for the red primary and red secondary galaxies, there is none. Galaxies in pair have a higher mean SSFR at every absolute magnitude compared to matched sets of field galaxies, and the relative increase in mean SSFR becomes larger with decreasing intrinsic luminosity. We also detect a significantly increased AGN fraction in the pair galaxies compared to matched sets of field galaxies.
The Transition to Full-Time Work of Young People Who Do Not Go to University. Longitudinal Surveys of Australian Youth. Research Report 49.

This report focuses on the transition to full-time employment of young people who do not go to university. The majority of Australia’s school leavers do not enrol in university, and it is important to better understand the pathways that they follow. The report uses a substantial longitudinal dataset to map the dynamics of the youth labour market, and identify the factors that are important in securing full-time work.
Archaeal MCM has separable processivity, substrate choice and helicase domains

The mini-chromosome maintenance (MCM) complex is the principal candidate for the replicative helicase of archaea and eukaryotes. Here, we describe a functional dissection of the roles of the three principal structural modules of the homomultimeric MCM of the hyperthermophilic archaeon Sulfolobus solfataricus. Our results include the first analysis of the central AAA+ domain in isolation. This domain possesses ATPase and helicase activity, defining this as the minimal helicase domain. Reconstitution experiments show that the helicase activity of the AAA+ domain can be stimulated by addition of the isolated N-terminal half in trans. Addition of the N-terminus influences both the processivity of the helicase and the choice of substrate that can be melted by the ATPase domain. The degenerate helix-turn-helix domain at the C-terminus of MCM exerts a negative effect on the helicase activity of the complex. These results provide the first evidence for extensive regulatory inter-domain communication within the MCM complex.
1001 ways to reward employees

The vice president of a leading management-training and consulting company has delved extensively into the issue of employee rewards and put together an idea-filled reference to making the person/achievement/reward equation work.Whether you manage a department, oversee a division, lead a company -- or run a family business with just one employee -- there's an essential principle to follow that's too often overlooked: What most motivates the people who work for you is recognition.A chock-full guide to rewards of every conceivable type for every conceivable situation, "1001 Ways to Reward Employees" polls the whole of the American business community, finding innovative ideas in every corner. From the spontaneous gesture of praise to formal company-wide programs, it presents hundreds of ways to say thank you to the people who truly deserve it.
Effect of Denture-Related Stomatitis Fluconazole Treatment on Oral Candida albicans Susceptibility Profile and Genotypic Variability

Denture-related stomatitis (DRS) is the most common condition affecting removable-denture wearers, and Candida albicans the most frequent pathogenic agent. Systemic antifungal treatment is indicated but recurrences are frequent. The aim of this study was to characterize the oral load, fluconazole susceptibility profile and genotypic variability of oral C. albicans isolates from patients with DRS before (T0), immediately after fluconazole treatment (Tat) and after 6-months follow-up (T6m). Eighteen patients presenting DRS and treated with fluconazole were followed at the Faculty of Dentistry of Oporto University. Seventy C. albicans isolates were obtained and identified using standard cultural and biochemical multi-testing. Fluconazole susceptibility was tested by E-test®. Microsatellite-primed PCR was performed to assess the genotypic variability of C. albicans isolates. The patients’ mean age was 58.0±3.2 years, and 55.6%/44.4% had total/partial dentures. Before treatment, 22.2%, 44.4% and 33.3% of the patients presented DRS type I, II or III, respectively. Fluconazole treatment healed or improved DRS in 77.8% of the patients, accompanied by an 83.5% reduction in oral C. albicans load. However, after 6-months, oral C. albicans load increased significantly and DRS severity was similar to the one observed before treatment. Moreover, the prevalence of patients presenting fluconazole resistant isolates of C. albicans increased significantly throughout the study: T0-5.6%, Tat-10.0% and T6m-42.9%. A change in the genotypic variability of C. albicans isolates was also verified, being mostly associated to fluconazole susceptibility profile change. In conclusion, fluconazole presents a good short-term DRS treatment efficiency, but may be associated to a long-term emergence of C. albicans fluconazole resistance.
Far-infrared observations of an unbiased sample of gamma-ray burst host galaxies

Gamma-ray bursts (GRBs) are the most energetic phenomena in the Universe; believed to result from the collapse and subsequent explosion of massive stars. Even though it has profound consequences for our understanding of their nature and selection biases, little is known about the dust properties of the galaxies hosting GRBs. We present analysis of the far-infrared properties of an unbiased sample of 20 BeppoSAX and Swift GRB host galaxies (at an average redshift of z = 3.1) located in the Herschel Astrophysical Terahertz Large Area Survey, the Herschel Virgo Cluster Survey, the Herschel Fornax Cluster Survey, the Herschel Stripe 82 Survey and the Herschel Multi-tiered Extragalactic Survey, totalling 880 deg2, or ∼3 per cent of the sky in total. Our sample selection is serendipitous, based only on whether the X-ray position of a GRB lies within a large-scale Herschel survey – therefore our sample can be considered completely unbiased. Using deep data at wavelengths of 100–500 μm, we tentatively detected 1 out of 20 GRB hosts located in these fields. We constrain their dust masses and star formation rates (SFRs), and discuss these in the context of recent measurements of submillimetre galaxies and ultraluminous infrared galaxies. The average far-infrared flux of our sample gives an upper limit on SFR of 500 M⊙ yr−1 is consistent with the contribution of such luminous galaxies to the cosmic star formation density.
Adaptive Potential of Maritime Pine (Pinus pinaster) Populations to the Emerging Pitch Canker Pathogen, Fusarium circinatum

There is a concern on how emerging pests and diseases will affect the distribution range and adaptability of their host species, especially due to different conditions derived from climate change and growing globalization. Fusarium circinatum, which causes pitch canker disease in Pinus species, is an exotic pathogen of recent introduction in Spain that threatens its maritime pine (P. pinaster) stands. To predict the impact this disease will have on the species, we examine host resistance traits and their genetic architecture. Resistance phenotyping was done in a clonal provenance/progeny trial, using three-year-old cuttings artificially inoculated with the pathogen and maintained under controlled environmental conditions. A total number of 670 ramets were assessed, distributed in 10 populations, with a total of 47 families, 2 to 5 half-sibs per family, and 3–7 ramets per clone. High genetic variation was found at the three hierarchical levels studied: population, family and clone, being both additive and non-additive effects important. Narrow-sense and broad-sense heritability estimates were relatively high, with respective values of 0.43–0.58 and 0.51–0.8, depending on the resistance traits measured (lesion length, lesion length rate, time to wilting, and survival). These values suggest the species' high capacity of evolutionary response to the F. circinatum pathogen. A population originated in Northern Spain was the most resistant, while another from Morocco was the most susceptible. The total number of plants that did not show lesion development or presented a small lesion (length<30 mm) was 224 out of 670, indicating a high proportion of resistant trees in the offspring within the analyzed populations. We found large differences among populations and considerable genetic variation within populations, which should allow, through natural or artificial selection, the successful adaptation of maritime pine to pitch canker disease.
Drag force with different charges in STU background and AdS/CFT

In this paper we consider the drag force problem in the STU model. This problem and related topics were already studied in SYM theory. Here we study the same problem in supergravity theory with an R-charge black hole (the STU model). This paper extends our previous work (Sadeghi J and Pourhassan B 2008 J. High Energy Phys. JHEP12(2008)026; Sadeghi J, Setare M R, Pourhassan B and Hashmatian S 2009 Eur. Phys. J. C 61 527) by studying more general charge configurations and by taking into account the effect of a constant electromagnetic field and higher derivative corrections. We consider a single quark and a pair in a three-charge non-extremal black hole background. First, by using the AdS/CFT correspondence, we obtain the drag force, the diffusion coefficient, the total energy and momentum, quasi-normal modes and the effect of higher derivative corrections for the single quark. Next we calculate the drag force for a pair which rotates around its center of mass. For the first time we study the motion of a rotating pair in this background. We show that our results in the near-extremal limit and finite chemical potential agree with the energy loss of the moving quark which was calculated in the SYM plasma.
Correlation between compact radio quasars and ultrahigh energy cosmic rays

Some proposals to account for the highest energy cosmic rays predict that they should point to their sources. We study the five highest energy events (E>10^20 eV) and find they are all aligned with compact, radio-loud quasars. The probability that these alignments are coincidental is 0.005, given the accuracy of the position measurements and the rarity of such sources. The source quasars have redshifts between 0.3 and 2.2. If the correlation pointed out here is confirmed by further data, the primary must be a new hadron or one produced by a novel mechanism.
R&D Subsidies, Research Joint Ventures, and Industry Concentration

We show that the presumed incompatibility of R&D and competition in Spence (1984) is not fundamental, but hinges on a critical modeling choice. Specifically, we show that for a widely used class of R&D technology, that is, the functional form mapping R&D effort into cost reduction, the incompatibility disappears and Spence's subsidy-based solution becomes a viable alternative to Research Joint Ventures (RJVs). This is the case especially if RJVs carry with them a risk of cartelization, a risk we show to be particularly high for the models used in this literature, if only their simplifying restriction to symmetric firms is dropped.