Miracle-dz/UniFAR-FTUs huggingface dataset:
Polymorphic Variants of Cytochrome P450 2B6 (CYP2B6.4–CYP2B6.9) Exhibit Altered Rates of Metabolism for Bupropion and Efavirenz: A Charge-Reversal Mutation in the K139E Variant (CYP2B6.8) Impairs Formation of a Functional Cytochrome P450-Reductase Complex

In this study, metabolism of bupropion, efavirenz, and 7-ethoxy-4-trifluoromethylcoumarin (7-EFC) by CYP2B6 wild type (CYP2B6.1) and six polymorphic variants (CYP2B6.4 to CYP2B6.9) was investigated in a reconstituted system to gain a better understanding of the effects of the mutations on the catalytic properties of these naturally occurring variants. All six variants were successfully overexpressed in Escherichia coli, including CYP2B6.8 (the K139E variant), which previously could not be overexpressed in mammalian COS-1 cells (J Pharmacol Exp Ther 311:34–43, 2004). The steady-state turnover rates for the hydroxylation of bupropion and efavirenz and the O-deethylation of 7-EFC showed that these mutations significantly alter the catalytic activities of CYP2B6. It was found that CYP2B6.6 exhibits 4- and 27-fold increases in the Km values for the hydroxylation of bupropion and efavirenz, respectively, and CYP2B6.8 completely loses its ability to metabolize any of the substrates under normal turnover conditions. However, compared with CYP2B6.1, CYP2B6.8 retains 77% of its 7-EFC O-deethylase activity in the presence of tert-butyl hydroperoxide as an alternative oxidant, indicating that the heme and the active site are catalytically competent. Presteady-state measurements of the rate of electron transfer from NADPH-dependent cytochrome P450 reductase (CPR) to CYP2B6.8 using stopped-flow spectrophotometry revealed that CYP2B6.8 is incapable of accepting electrons from CPR. These observations provide conclusive evidence suggesting that the charge-reversal mutation in the K139E variant prevents CYP2B6.8 from forming a functional complex with CPR. Results from this work provide further insights to better understand the genotype–phenotype correlation regarding CYP2B6 polymorphisms and drug metabolism.
Exploring teachers' professional development and digital literacy: a grounded theory study

Many aspects of living and working now involve the use of technology and this trend will continue to grow. Over 93 per cent of jobs in the UK now require at least basic digital skills. Outside of work, many aspects of day to day life are also mediated by technology; from banking and shopping to socialising. In this increasingly digital society, an individual requires the knowledge and understanding to make use of technology to suit their own unique needs. One response to this was the inclusion of digital literacy as part of the National Curriculum, viewed as a key foundation skill equivalent to traditional literacy and numeracy. But in order for teachers to help students develop their digital literacy they need support too. This became particularly important in relation to educational technology when in 2012 the UK's primary organisation for supporting the professional development of teachers with technology was abolished. This thesis has taken a constructivist grounded theory approach to investigating how current professional development strategies support teachers’ digital literacy continuing professional development (DL CPD). Focus groups, interviews and observations collected the experiences and opinions of in-service teachers, creating a theory that has been developed by prioritising teacher voice. The emerging theory suggests that within a climate of increasing accountability and performativity, teachers do not have the luxury of time and support to effectively engage with DL CPD. Due to restrictions on their available time and resources teachers must be discerning about the CPD with which they engage to ensure that they meet statutory requirements and school priorities. In particular four spheres of concern were identified that hold significant influence over a teacher’s decision to engage with DL CPD: professional, personal, environmental and cultural. These spheres were synthesised with existing theory to create the Teachers’ Digital Engagement Framework, a tool which can be used to both explore an existing DL CPD programme and support the design of future DL CPD programmes. The Teachers’ Digital Engagement Framework was applied to the data collected in order to formulate recommendations for teachers, schools, educational research and Government policy.
Omalizumab in patients with severe asthma: the XCLUSIVE study

Background and Aims: Although the efficacy and safety of omalizumab (OMA) in uncontrolled severe allergic asthma has been demonstrated in several randomised controlled trials (RCTs), information on the treatment in a practice‐related setting is limited. Thus, the purpose of this prospective multi‐centre study (XCLUSIVE) was to investigate the efficacy, compliance and utilisation of OMA therapy in real‐life clinical practice in Germany.
Wine consumers’ reaction to prices, organic production and origins at the point of sale: an analysis of household panel data

Abstract Price premiums are considered as major purchase barriers for organic products and therefore may prevent organic market growth. For wine, however, prices take a double and conflicting effect: they also serve as quality signal for consumers. Therefore, it is of high relevance to examine if price is a major barrier for organic wine as well. Even though many studies already examined price behavior for organic wine through surveys and experiments, it is still to be clarified how consumers’ react to price changes in a real market context. So far, no study analyzed consumer preferences for organic labeled wine in daily shopping situations. Through the analysis of the GfK household panel—a high-frequency data set of extensive population coverage—implications for price setting and price promotions in different market segments can be given. In contrast to previous studies, consumers’ overall price sensitivity was found to be low for organic wine and consumers’ preferred organic over conventional wine. The effect of price as quality cue or purchase barrier and the effect of an organic label on consumers’ behavior varied between price categories. Organic wine was valued highest in the low-price category, whereas no price premium for the organic label was examined in the high-price segment. Price sensitivity was extremely high for organic wine in the low-price segment, while price functioned as quality signal in the premium segment for organic and conventional wine similarly. This study verified previous stated preference studies on organic wine through the analysis of actual purchase data. Moreover, new insights for price setting in different price categories were generated through the examination of a large amount of disaggregated data on single consumer purchases.
Predictive Capacity of Risk Assessment Scales and Clinical Judgment for Pressure Ulcers: A Meta-analysis

A systematic review with meta-analysis was completed to determine the capacity of risk assessment scales and nurses' clinical judgment to predict pressure ulcer (PU) development. Electronic databases were searched for prospective studies on the validity and predictive capacity of PUs risk assessment scales published between 1962 and 2010 in English, Spanish, Portuguese, Korean, German, and Greek. We excluded gray literature sources, integrative review articles, and retrospective or cross-sectional studies. The methodological quality of the studies was assessed according to the guidelines of the Critical Appraisal Skills Program. Predictive capacity was measured as relative risk (RR) with 95% confidence intervals. When 2 or more valid original studies were found, a meta-analysis was conducted using a random-effect model and sensitivity analysis. We identified 57 studies, including 31 that included a validation study. We also retrieved 4 studies that tested clinical judgment as a risk prediction factor. Meta-analysis produced the following pooled predictive capacity indicators: Braden (RR = 4.26); Norton (RR = 3.69); Waterlow (RR = 2.66); Cubbin-Jackson (RR = 8.63); EMINA (RR = 6.17); Pressure Sore Predictor Scale (RR = 21.4); and clinical judgment (RR = 1.89). Pooled analysis of 11 studies found adequate risk prediction capacity in various clinical settings; the Braden, Norton, EMINA (mEntal state, Mobility, Incontinence, Nutrition, Activity), Waterlow, and Cubbin-Jackson scales showed the highest predictive capacity. The clinical judgment of nurses was found to achieve inadequate predictive capacity when used alone, and should be used in combination with a validated scale.
Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake

Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low density lipoprotein (LDL) uptake, thus it plays a crucial role in maintaining cholesterol homeostasis. Here, we found that overexpressing microRNA (miR)-185 in HepG2 cells repressed SREBP-2 expression and protein level. miR-185-directed inhibition caused decreased SREBP-2-dependent gene expression, LDL uptake, and HMG-CoA reductase activity. In addition, we found that miR-185 expression was tightly regulated by SREBP-1c, through its binding to a single sterol response element in the miR-185 promoter. Moreover, we found that miR-185 expression levels were elevated in mice fed a high-fat diet, and this increase correlated with an increase in total cholesterol level and a decrease in SREBP-2 expression and protein. Finally, we found that individuals with high cholesterol had a 5-fold increase in serum miR-185 expression compared with control individuals. Thus, miR-185 controls cholesterol homeostasis through regulating SREBP-2 expression and activity. In turn, SREBP-1c regulates miR-185 expression through a complex cholesterol-responsive feedback loop. Thus, a novel axis regulating cholesterol homeostasis exists that exploits miR-185-dependent regulation of SREBP-2 and requires SREBP-1c for function.
Current Treatment for Alzheimer Disease and Future Prospects

A cascade of pathophysiological events is triggered in Alzheimer disease (AD) that ultimately involves common cellular signaling pathways and leads to cellular and network dysfunction, failure of neurotransmission, cell death, and a common clinical outcome. The process is asynchronous, meaning that viable neurons remain as targets for therapy even in the diseased state, and each stage of the cascade affords the possibility for therapeutic intervention. Cholinesterase inhibitors are the only available treatment in the United States for patients with mild to moderate AD, helping maintain cognitive and functional abilities in most patients and conferring beneficial behavioral effects in some. Memantine is an NMDA receptor antagonist that has recently been approved in Europe for treatment of moderately severe to severe AD and is under investigation in the United States. Its mechanism of action may include enhanced neurotransmission in several systems as well as antiexcitotoxic effects. There are data regarding the effectiveness of the combination of memantine with cholinesterase inhibitors that will be useful for the practicing clinician. Other agents have shown some benefit in clinical trials, including the antioxidants vitamin E, selegiline, and Ginkgo biloba extracts, although the weight of evidence regarding their effects is not sufficient to define clinical practice. Potential future therapies currently are in development that target multiple aspects of the illness cascade, including aberrant inflammation, neurotrophic function, and processing of beta amyloid and tau proteins. These newer approaches hold promise for disease modification but are as yet unproven. Whether or not disease-modifying or preventive therapies become a reality, clinicians will be faced with AD patients who require treatment at all stages of illness for the indefinite future. Cholinergic and emerging noncholinergic medications will likely prevail as the standards of treatment for years to come.
AN ASSESSMENT OF THE RELATIONSHIP BETWEEN FOREIGN TRADE AND ECONOMIC PERFORMANCE: EMPIRICAL EVIDENCE FROM SOUTH AFRICA

The driving objective of the study was to estimate the impact of foreign trade on economic performance using the economy of South Africa as a test site. The study contributes to the empirical literature by testing for a long-run relationship between foreign trade and economic performance in South Africa by employing quarterly data stretching from the period 1995Q1 to 2015Q4. The method of vector autoregression (VAR) was employed. Variables included in the study consisted of real GDP, exports, openness of the economy and exchange rate. The study found cointegrating relationships among the variables investigated, and that export was found to contribute more towards economic performance compared to openness of the economy and exchange rates. When it came to Granger-causality analysis, the study found a number of unidirectional relationships between the pairs of variables examined in the model. For example, it was found that economic growth granger causes exports and also openness of the economy granger causes exports. The forecast error variance decomposition suggests that economic performance itself accounted for most of the innovations that ensued during the 10-period forecast horizon employed in the analysis. Policymakers could utilize the results of this study, when it comes to policy formulation and design for the economy of South Africa. The findings of the research could be used to improve upon economic policy for South Africa and other developing countries on a similar path. The study creates opportunities for further research endeavours concerning the issue under investigation so as to unveil more evidence on the nature of the relationship between foreign trade and economic performance in the economy of South Africa.
DC voltage limit compliance in voltage-source converter based multi-terminal HVDC

By adjusting V/sub ref/, the voltage reference setting of the DC voltage regulator or the power reference settings P/sub i//sup sp/ of the remaining converter stations, the steady-state DC bus voltages of the voltage-source converter based multi-terminal HVDC system can be made to comply with voltage limits. When any one of the converter stations is lost, over-voltage can destroy a converter station within a fraction of a second. As there is no time to reset the settings, the references must be determined in the very beginning to anticipate the accidental loss of a converter. The paper shows how the well-known voltage sensitivity method and the Lagrange multiplier method are adapted successfully to determine the reference settings for pre- and post-fault conditions.
'Gastro' of Mirpur Khas (Sindh) is resolved.

BACKGROUND Diarrhoeal disease is a common cause of major public health concern in many parts of the world including Pakistan. METHODS Eighteen stool samples were received from Civil Hospital Mirpur Khas (Sindh). All the specimens were processed for culture and antimicrobial susceptibility according to Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS Eight out of eighteen (44.4%) samples were positive for Vibrio cholerae. The isolates were gram negative rods, showed darting motility and were Oxidase positive. Contact with distilled water immobilized all these strains (Mdw). API 20NE was used for the biochemical identification and serological confirmation was done with 'difco' antisera. Kirby-Bauer disc diffusion method was performed for their respective susceptibility to various antibiotics. All these isolates were confirmed to be Vibrio cholerae O1 Biotype El Tor Serotype Ogawa. The isolates were generally sensitive to majority of the antibiotics but resistant to nalidixic acid except one strain. Six out of eight isolates were resistant to co-trimoxazole. CONCLUSION Cholera must be suspected in outbreaks of such kind of 'gastro'.
The m74 Gene Product of Murine Cytomegalovirus (MCMV) Is a Functional Homolog of Human CMV gO and Determines the Entry Pathway of MCMV

ABSTRACT The glycoprotein gO (UL74) of human cytomegalovirus (HCMV) forms a complex with gH/gL. Virus mutants with a deletion of gO show a defect in secondary envelopment with the consequence that virus spread is restricted to a cell-associated pathway. Here we report that the positional homolog of HCMV gO, m74 of mouse CMV (MCMV), codes for a glycosylated protein which also forms a complex with gH (M75). m74 knockout mutants of MCMV show the same spread phenotype as gO knockout mutants of HCMV, namely, a shift from supernatant-driven to cell-associated spread. We could show that this phenotype is due to a reduction of infectious virus particles in cell culture supernatants. m74 knockout mutants enter fibroblasts via an energy-dependent and pH-sensitive pathway, whereas in the presence of an intact m74 gene product, entry is neither energy dependent nor pH sensitive. This entry phenotype is shared by HCMV expressing or lacking gO. Our data indicate that the m74 and UL74 gene products both codetermine CMV spread and CMV entry into cells. We postulate that MCMV, like HCMV, expresses alternative gH/gL complexes which govern cell-to-cell spread of the virus.
Enabling user‐guided segmentation and tracking of surface‐labeled cells in time‐lapse image sets of living tissues

To study the process of morphogenesis, one often needs to collect and segment time‐lapse images of living tissues to accurately track changing cellular morphology. This task typically involves segmenting and tracking tens to hundreds of individual cells over hundreds of image frames, a scale that would certainly benefit from automated routines; however, any automated routine would need to reliably handle a large number of sporadic, and yet typical problems (e.g., illumination inconsistency, photobleaching, rapid cell motions, and drift of focus or of cells moving through the imaging plane). Here, we present a segmentation and cell tracking approach based on the premise that users know their data best–interpreting and using image features that are not accounted for in any a priori algorithm design. We have developed a program, SeedWater Segmenter, that combines a parameter‐less and fast automated watershed algorithm with a suite of manual intervention tools that enables users with little to no specialized knowledge of image processing to efficiently segment images with near‐perfect accuracy based on simple user interactions. © 2012 International Society for Advancement of Cytometry
Dietary calcium source influences body composition, glucose metabolism and hormone levels in a mouse model of postmenopausal obesity.

BACKGROUND The prevalence of obesity has risen dramatically, with postmenopausal women particularly prone to increased adiposity. Epidemiologic data suggest that dietary calcium, particularly from dairy products, can decrease weight gain. The aim of this study was to evaluate effects of different calcium sources in a mouse model of postmenopausal obesity. MATERIALS AND METHODS Ovariectomized C57BL/6 mice were randomized to either low-fat (LF) or high-fat (HF) diets containing either calcium phosphate from non-fat dried milk and whey mineral concentrate (dairy) or calcium carbonate (supplement). RESULTS Dairy, but not supplement, decreased weight gain and percent body fat in HF mice, with no effect on food consumption. Dairy improved insulin resistance and glucose tolerance, while supplement increased bone mineral density in LF mice. Dairy had no effect on bone. CONCLUSION The beneficial effects of dietary calcium on body weight and bone health after menopause may be significantly influenced by other dietary components.
Forecasting volatility using GARCH models

The purpose of these research is to forecast volatility using diﬀerent GARCH (General autoregressive conditional heteroeskedasticity) models in order to test which model has best forecasting ability. The focus of this research is the US market. The data is composed by NASDAQ-100 quotations from 1986 to 2016. The study considers three estimation periods for the GARCH family models: 500 days, 1000 days and 2000 days in order to minimize structure changes that might be present in the data. A series of Mincer-Zarnowitz regressions were completed in order to assess the performance of each GARCH model. Afterwards, the SPA test from Hansen and Lunde (2005) is used in order to detect which is the best model. The empirical results show that the GARCH models produce similar results in what comes to forecasting next day conditional volatility, with the possible exception of the IGARCH model. There is also reason to believe that the GJR model does not provide good estimations of volatility when the rolling window used in the estimation of the models is 1000 days.
Quantifying the effects of migration and mutation on adaptation and demography in spatially heterogeneous environments

How do mutation and gene flow influence population persistence, niche expansion and local adaptation in spatially heterogeneous environments? In this article, we analyse a demographic and evolutionary model of adaptation to an environment containing two habitats in equal frequencies, and we bridge the gap between different theoretical frameworks. Qualitatively, our model yields four qualitative types of outcomes: (i) global extinction of the population, (ii) adaptation to one habitat only, but also adaptation to both habitats with, (iii) specialized phenotypes or (iv) with generalized phenotypes, and we determine the conditions under which each equilibrium is reached. We derive new analytical approximations for the local densities and the distributions of traits in each habitat under a migration–selection–mutation balance, compute the equilibrium values of the means, variances and asymmetries of the local distributions of phenotypes, and contrast the effects of migration and mutation on the evolutionary outcome. We then check our analytical results by solving our model numerically, and also assess their robustness in the presence of demographic stochasticity. Although increased migration results in a decrease in local adaptation, mutation in our model does not influence the values of the local mean traits. Yet, both migration and mutation can have dramatic effects on population size and even lead to metapopulation extinction when selection is strong. Niche expansion, the ability for the population to adapt to both habitats, can also be prevented by small migration rates and a reduced evolutionary potential characterized by rare mutation events of small effects; however, niche expansion is otherwise the most likely outcome. Although our results are derived under the assumption of clonal reproduction, we finally show and discuss the links between our model and previous quantitative genetics models.
Phenolics: A Comparison of Diverse Analytical Methods

A variety of phenolic assays were used to evaluate the phenolic content of Californian red and white wines. Conventional methods (Folin-Ciocalteu, RP-HPLC, NP-HPLC, and dimethylaminocinnamaldehyde [DAC] assays) and relatively new methods (tannin and polymeric pigment assay, cyclic voltammetry, and antioxidant assay) were compared. The total phenol contents measured using the Folin-Ciocalteu, RP-HPLC, and cyclic voltammetry methods were strongly correlated (p 0.90). Considering assays measuring the monomeric phenols, the flavan-3-ol content measured using the DAC, RP-HPLC, and NP-HPLC methods were correlated (p 0.9, p 0.90). The identity of the substances quantified in the pigmented tannin assays need clarification.