Miracle-dz/UniFAR-FTUs huggingface dataset:
CYP2C9 Genotype-Dependent Effects on in Vitro Drug-Drug Interactions: Switching of Benzbromarone Effect from Inhibition to Activation in the CYP2C9.3 Variant

The CYP2C9.3 variant exhibits marked decreases in substrate turnover compared with the wild-type enzyme, but little is known regarding the effect this variant form may have on the occurrence of drug-drug interactions. To examine this possibility, the effect of the potent CYP2C9 inhibitor, benzbromarone, was studied with regard to CYP2C9.1- and CYP2C9.3-mediated flurbiprofen metabolism to evaluate whether the variant enzyme exhibits differential inhibition kinetics. Although benzbromarone inhibited CYP2C9.1 activity as expected, CYP2C9.3-mediated flurbiprofen 4′-hydroxylation was activated in the presence of benzbromarone. T1 relaxation studies revealed little change in distances of flurbiprofen protons from the heme iron of either CYP2C9.1 or CYP2C9.3 in the presence of benzbromarone compared with flurbiprofen alone. Spectral binding studies were also performed to investigate whether benzbromarone affected substrate binding, with the addition of benzbromarone having little effect on flurbiprofen-binding affinity in both CYP2C9.1 and CYP2C9.3. Docking studies with the 2C9.1 structure crystallized with a closed active site identified multiple but overlapping subsites with sufficient space for benzbromarone binding in the enzyme when flurbiprofen was positioned closest to the heme. If the closed conformation of 2C9.3 is structurally similar to 2C9.1, as expected for the conservative I359L mutation, then the dynamics of benzbromarone binding may account for the switching of drug interaction effects. In conclusion, the I359L amino acid substitution found in CYP2C9.3 not only reduces metabolism compared with CYP2C9.1 but can also dramatically alter inhibitor effects, suggesting that differential degrees of drug inhibition interactions may occur in individuals with this variant form of CYP2C9.
ADAMs and ADAMTSs in cancer

ADAMs and ADAMTSs are multi-domain proteins characterised by the presence of both metalloproteinase and disintegrin-like domains. ADAM proteins are usually type l transmembrane proteins, and ADAMTSs are secreted from cells. The dysregulated expression of ADAMs and ADAMTSs has been reported in a wide range of human cancers, where, in many cases, they are implicated as positive regulators of cancer progression. Proteolytically active ADAMs act as ectodomain sheddases, which release extracellular regions of membrane-bound proteins (e.g., adhesion molecules, growth factors, cytokines, chemokines and receptors). Certain ADAMTSs break down extracellular matrix (ECM) proteoglycans (e.g., aggrecan, brevican and versican). Through these actions they are able to sculpt the tumour microenvironment and modulate key processes involved in cancer progression, including cell proliferation, migration and angiogenesis. Members of both groups of protein can also act to inhibit or slow cancer progression: ADAMs can interact with specific integrins to elicit inhibitory effects on cancer dissemination, and certain ADAMTSs possess anti-angiogenic activity, which prevents an increase in tumour size. This review covers recent developments in the involvement of ADAM and ADAMTS proteins in human cancer.
An Ontology-enabled Context-aware Learning Record Store Compatible with the Experience API

In education, learners no longer perform learning activities in a well-defined and static environment like a physical classroom. Digital learning environments promote learners anytime, anywhere and anyhow learning. As such, the context in which learners undertake these learning activities can be very diverse. To optimize learning and the environment in which it occurs, learning analytics measure data about learners and their context. Unfortunately, current state of the art standards and systems are limited in capturing the context of the learner. In this paper we present a Learning Record Store (LRS), compatible with the Experience API, that is able to capture the learnersâ context, more concretely his location and used device. We use ontologies to model the xAPI and context information. The data is stored in a RDF triple store to give access to different services. The services will show the advantages of capturing context information. We tested our system by sending statements from 100 learners completing 20 questions to the LRS.
Detection of transcription factor binding in vivo using lambda exonuclease.

In vivo footprinting techniques have revealed the complex interplay between transacting proteins and DNA in the context of chromatin (1). One simple yet elegant approach to detect such interactions utilizes Exonuclease m (Exo m) to map transcription factor boundaries (2). Exo IH is introduced in vivo onto the promoter of interest via an adjacent restriction endonuclease site and proceeds to digest the DNA in a 3' to 5' direction (Figure 1). Digestion continues until the exonuclease encounters a bound factor that impedes or blocks digestion. Following digestion, the DNA is purified, single stranded (ss) overhangs are trimmed with either S1(2,3) or Mung Bean (4) nucleases, then analyzed by Southern blotting (2,3) or more recently by reiterative Taq polymerase based techniques (4,5). this
Evaluating intensive family preservation programs: a methodological review.

OBJECTIVES To determine the adequacy of evaluations of family preservation services (FPS), which are designed to support families and prevent out-of-home placements of children at risk of abuse or neglect, and to assess the effectiveness of FPS at reducing out-of-home placements of children. DATA SOURCES References published from 1977 to 1993 were identified from a computerized search of databases for English-language publications using the key phrases "family preservation," "child abuse," and "family-based services. " Unpublished references were identified by mail or phone from a listing of more than 200 programs in a national directory. SELECTION OF STUDIES Of 802 references initially identified, 46 program evaluations were reviewed. Ten studies met the following inclusion criteria: (1) evaluated an intensive family preservation program, (2) included outcome data in the report, and (3) used a comparison group. Five were randomized trials, and 5 were quasi-experimental studies (nonrandomized). DATA EXTRACTION Descriptive information about the programs and evaluations was collected. To determine methodological quality, two independent raters used a 15-item questionnaire to examine the assignment of families to treatment groups, the interventions provided, and the outcomes assessed. A composite score of 11 or greater represented an acceptable study, 6 to 10 represented an adequate study, and 5 or less represented an unacceptable study. RESULTS Only two studies were rated acceptable, four were adequate, and four were unacceptable. Methodological shortcomings included poorly defined assessment of risk, inadequate descriptions of the interventions provided, and nonblinded determination of the outcomes. Rates of out-of-home placements were 21% to 59% among families who received FPS and 20% to 50% among comparison families. The relative risk of placement was significantly reduced by FPS in only two studies (one randomized trial and one quasi-experimental study). CONCLUSIONS Despite current widespread use of FPS to prevent out-of-home placements of children, evaluations of FPS are methodologically difficult and show no benefit in reducing rates of out-of-home placements of children at risk of abuse or neglect in 8 of 10 studies. Consistent, methodologically rigorous evaluations are needed to determine the effectiveness of FPS and to guide social policy for high-risk children and their families.
Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease?

OBJECTIVES Preterm infants are known to remain small during childhood. We previously found that evidence of neonatal metabolic bone disease was associated with reduced length at 18 months. We aimed to further investigate factors predicting childhood height and to test the hypothesis that evidence of early metabolic bone disease is associated with reduced later height. STUDY DESIGN A cohort of preterm infants was measured prospectively at 18 months (n = 765), 7. 5 to 8 years (n = 772), and 9 to 12 years of age (n = 503). RESULTS Preterm infants remained short for their age and sex at all follow-ups. Later height was most strongly predicted by parental height and, at 9 to 12 years, by pubertal status. Neonatal factors associated with later height were birth weight SD score, maternal hypertension/toxemia, and a high peak plasma alkaline phosphatase during the neonatal period. After adjustment for these factors plus interim heights, height at 9 to 12 years was greatest in those who were tallest at 7.5 to 8 years, those who had shown the greatest increase in height percentile between 18 months and 7.5 to 8 years and, as expected, those who were pubertal, whereas children with a peak neonatal plasma alkaline phosphatase >1200 IU were significantly shorter. CONCLUSIONS Childhood height in preterm infants is strongly influenced by genetic factors. However, biochemical evidence of metabolic bone disease during the neonatal period may have a long-term stunting effect persisting up to 12 years later, providing support for current practices that aim to prevent this condition.
Applying Genetic Algorithm to minimize the oil spill damage and optimize the location of the cleaning vessels

To optimize the capacity and positioning of the cleaning vessels, Genetic Algorithm is used for ports and coastal areas in the Persian Gulf due to economical and environmental damages. Local wind is recognized as the principal driving force to simulate the trajectory of oil spill events. In this regard, the wind field is determined by Weibull probability distribution to adjust the prevailing wind. The wind field is combined to the water current to determine the transportation and fate of the contaminants to obtain a model using Kelvin wave expansion. By using the results, optimization of the oil contaminant on the Persian Gulf and the characteristics of the vessels such as speed and cleaning capacity are invoked to present the qualitative results.
Determining the Attitude of Undergraduate Students towards Physics through Concept Mapping

The aim of this study was to investigate the effect of using concept mapping strategy in teaching physics on the attitude towards physics. Participants were (46) first year students from two classes enrolled to the course “Fundamentals of Physics I”, in Dhofar University, Oman. One of the classes was randomly selected as experimental group (23), while the other was a control group (23). The data was collected via the pre- and post attitude scale. The study was conducted within a period of 8 weeks and the class had three lessons in a week. The material covered was about mechanics. The results showed that there was a significant difference at (α=0.05) in the attitude towards physics between the experimental and the control group. The study also showed that there was no significant difference attributed to the gender and the interaction between teaching methods and gender. DOI: 10.5901/mjss.2013. v4n3p331
Aqueous humor induces transforming growth factor-beta (TGF-beta)-producing regulatory T-cells.

PURPOSE The intraocular microenvironment is an immune-privileged site where immunogenic inflammation is suppressed. Suppression of immunogenic inflammation has been associated with immunosuppressive factors found in aqueous humor produced by ocular tissues. To further understand the mechanisms suppressing immunogenic inflammation in the eye, we have examined the production of lymphokines by primed T-cells activated in the presence of aqueous humor. METHODS Enriched in vivo primed T-cells were T-cell receptor-stimulated in the presence of fresh aqueous humor. The culture supernatant was assayed for IFN-gamma and IL-4 by sandwich ELISA. TGF-beta production by T-cells stimulated in the presence of aqueous humor was assayed by a TGF-beta bioassay of the culture supernatant and by quantitative RT-PCR for TGF-beta 1 mRNA expression. Aqueous humor-treated T-cells were assayed for their capacity to suppress IFN-gamma production by stimulated, primed T-cells. RESULTS Aqueous humor-enhanced proliferation but irreversibly suppressed production of both IFN-gamma and IL-4 by in vitro-activated, in vivo-primed T-cells. Aqueous humor induced in vivo primed T-cells to produce TGF-beta in vitro, and these TGF-beta-producing T-cells suppressed IFN-gamma production by other T-cells activated in co-cultures. CONCLUSIONS Aqueous humor alters the functional program of TCR-ligand-activated, primed T-cells, converting the cells to TGF-beta-producing regulatory cells.
Skeletal muscle loss : cachexia , sarcopenia , and inactivity 1 – 3

Loss of skeletal muscle mass occurs during aging (sarcopenia), disease (cachexia), or inactivity (atrophy). This article contrasts andcompares the metabolic causes of loss of muscle resulting from these conditions. An understanding of the underlying causes of muscle loss is critical for the development of strategies and therapies to preserve musclemass and function.Loss of skeletalmuscle protein results from an imbalance between the rate of muscle protein synthesis and degradation. Cachexia, sarcopenia, and atrophy due to inactivity are characterized by a loss of muscle mass. Each of these conditions results in a metabolic adaptation of increased protein degradation (cachexia), decreased rate ofmuscle protein synthesis (inactivity), or an alteration in both (sarcopenia). The clinical consequences of bedrestmaymimic those of cachexia, including rapid loss of muscle, insulin resistance, and weakness. Prophylaxis against bedrest-induced atrophy includes nutrition support with an emphasis on high-quality protein. Nutritional supplementation alone may not prevent muscle loss secondary to cachexia, but, in combination with the use of an anabolic agent, it may slow or prevent muscle loss. Am J Clin Nutr 2010;91
Nonsymmetric PDF approximation by artificial neurons: application to statistical characterization of reinforced composites

We present a generalized adaptive activation function neuron structure which learns through an information-theoretic-based principle, which is able to blindly estimate the probability density function of incoming input. We illustrate the behavior of the learning theory by the help of numerical experiments performed on real-world data with particular emphasis to statistical characterization of polypropylene composites reinforced with vegetal fibers.
Holes in the Brain

A number of conditions in childhood are associated with areas of lowered density in the region of the basal ganglia on CT scanning. They may be unilateral or bilateral (Table I ) . The cause of some of the disorders may well present no particular diagnostic difficulties, such as head trauma, arterial infarcts, cerebral abscess, co poisoning, anoxic brain damage and tumours. Others will need all the help that can be obtained from the results of investigations, and this annotation highlights the value of the CT-scan appearance in rare conditions such as Wilson’s disease, Leigh’s disease and mitochondria1 disorders. In Wilson’s disease’ the CTScan shows a number of changes, including ventricular dilatation, cortical atrophy, brainstem atrophy and cerebellar atrophy. In addition, about 45 per cent of patients show hypodense areas in the basal ganglia. These findings are most common in patients with a neurological presentation, but can occur in those with evidence of only hepatic involvement, and even in the presymptomatic group. Very occasionally patients with neurological disease can have normal CT scans. After treatment with penicillamine or triethylene tetramine the findings on repeating the CT scans are unaltered except for the hypodense areas in the basal ganglia, which frequently become less marked or even disappear. There is also a close correlation with clinical improvement. It is suggested that the resolution of the CTscan appearances may be due to an extensive loss of dendrites and glial cells rather than neurons, initially replaced by exudate, and regenerating rapidly when the toxic copper is removed by chelating agents. If the low-density areas persist in q
Cutting Edge: All-Trans Retinoic Acid Sustains the Stability and Function of Natural Regulatory T Cells in an Inflammatory Milieu

Recent studies have demonstrated that plasticity of naturally occurring CD4+Foxp3+ regulatory T cells (nTregs) may account for their inability to control chronic inflammation in established autoimmune diseases. All-trans retinoic acid (atRA), the active derivative of vitamin A, has been demonstrated to promote Foxp3+ Treg differentiation and suppress Th17 development. In this study, we report a vital role of atRA in sustaining the stability and functionality of nTregs in the presence of IL-6. We found that nTregs treated with atRA were resistant to Th17 and other Th cell conversion and maintained Foxp3 expression and suppressive activity in the presence of IL-6 in vitro. atRA decreased IL-6R expression and signaling by nTregs. Of interest, adoptive transfer of nTregs even from arthritic mice treated with atRA suppressed progression of established collagen-induced arthritis. We suggest that nTregs treated with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.
“Weather bomb” induced seismic signals

Seismic waves generated by intense storms can reveal details of Earth's interior The atmosphere-ocean system interacts with the solid Earth to produce seismic signals called microseisms, which are observed globally. This interaction results from large-scale, slowly moving extratropical storms but also from smaller, intense weather systems such as tropical cyclones (called hurricanes in the Atlantic and eastern Pacific, and typhoons in the western Pacific). These are smaller storms, often travel much faster, and have steeper atmospheric pressure gradients that produce very strong winds. All storm systems generate various types of microseisms, which have been studied extensively. A special case of fast-developing, small, extratropical storms in which the central pressure intensifies rapidly, dropping by more than 1 mbar/hour for 24 hours, is called a “weather bomb” (1). On page 919 of this issue, Nishida and Takagi (2) report on the detection of previously unobserved S wave microseisms generated under a weather bomb between Greenland and Iceland.
Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine.

W e read with interest paper entitled ‘Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine’, written by Mancia et al. and published in the February 2015 issue of Journal of Hypertension [1]. In this paper, the authors claim that the perindopril/amlodipine strategy was superior to corresponding valsartan/amlodipine strategy in lowering blood pressure in hypertensive patients, based upon a clinical trial they conducted. However, we have recognized serious problems related with the study design and also the communication of the results. These problems, which are denoted below, compromise the inferences drawn from the study. In this study, hypertensive patients had been randomized to two arms labelled as ‘perindopril/amlodipine strategy’ and ‘valsartan/amlodipine strategy’, and were treated for 6 months. Though these definitions make the readers think that the two arms were similar except for perindopril and valsartan, this was not the case. Actually, the patients in the ‘perindopril/amlodipine strategy’ had been treated apparently more effectively than those in the ‘valsartan/amlodipine strategy’, at any single time point during the 6 months’ treatment period with regards to classes, and numbers and doses of drugs administered. Thanks to this dissimilarity that was planned a priori, it should be very easy to anticipate that ‘perindopril/amlodipine’ would be found to be more effective than ‘valsartan/ amlodipine’ even before conducting the study and analysing the data. The dissimilarities that make the conclusions invalid are given below:
Subcellular Localization of the Spindle Proteins Aurora A, Mad2, and BUBR1 Assessed by Immunohistochemistry

The spindle checkpoint, the primary mechanism to ensure that two daughter cells receive the same amount of DNA, is compromised in many malignant tumors and has been implicated as a contributor to aneuploidy and carcinogenesis. The extent of expression and subcellular localization of the spindle proteins Aurora A, Mad2, and BUBR1 varies considerably in different immunohistochemical (IHC) reports from archival tumor tissues. Given the conflicting reports in the literature about the localization of these proteins, we examined the subcellular localization of Aurora kinase A, Mad2, and BUBR1 in normal and cancerous human tissues by IHC. In normal tissues, Aurora A was mainly localized to the nucleus when monoclonal or purified polyclonal antibodies were used, and Mad2 was localized to the nucleus, whereas BUBR1 was localized to the cytoplasm. In malignant tissues, Aurora A showed additional staining in the cytoplasm in the majority of tumors analyzed. Furthermore, BUBR1 was also localized to both the nucleus and cytoplasm in a significant fraction of tumors. Subcellular localization of Mad2 was similar in normal and malignant tissues. Thus, the validity of some earlier IHC studies of Aurora A, Mad2, and BUBR1 should be reconsidered, indicating that high-quality antibodies and a high-alkaline antigen-retrieval technique are required to achieve optimal results. We conclude that the subcellular localizations of these spindle proteins are different, although they have overlapping biological functions, and that Aurora A and BUBR1 undergo a shift in the subcellular localization during malignant transformation.
Theory of polariton photoluminescence in arbitrary semiconductor microcavity structures.

A quantum theory of quantum well polaritons in semiconductor microcavities is developed. The model takes into account the coupling between the exciton level and the structured continuum of electromagnetic modes relative to the particular geometry of the microcavity. A general equation for the polariton dispersion is obtained as a function of the cavity and exciton parameters. The equation is valid in both weak and strong coupling regimes and reproduces the existing measurements of microcavity polariton dispersion. A model for the polariton luminescence is then derived from the theory. It is possible to define a polariton decay rate only when the resonances in the polariton density of states can be considered as quasimodes. The two limiting cases of very weak and very strong coupling regimes are consequently identified. In these cases the polariton radiative probabilities are derived for light emitted on the left and right sides of the microcavity separately. The influence of the microcavity structure on the polariton dispersion and radiative rates is discussed and in particular the role of the microcavity leaky modes is described in detail. A discussion of the luminescence mechanism in the intermediate coupling case is also presented.