Miracle-dz/UniFAR-FTUs huggingface dataset:
Multiple Membrane-associated Tryptophan Residues Contribute to the Transport Activity and Substrate Specificity of the Human Multidrug Resistance Protein, MRP1*

The multidrug resistance protein, MRP1, is a clinically important ATP-binding cassette transporter in which the three membrane-spanning domains (MSDs), which contain up to 17 transmembrane (TM) helices, and two nucleotide binding domains (NBDs) are configured MSD1-MSD2-NBD1-MSD3-NBD2. In tumor cells, MRP1 confers resistance to a broad spectrum of drugs, but in normal cells, it functions as a primary active transporter of organic anions such as leukotriene C4 and 17β-estradiol 17β-(d-glucuronide). We have previously shown that mutation of TM17-Trp1246 eliminates 17β-estradiol 17β-(d-glucuronide) transport and drug resistance conferred by MRP1 while leaving leukotriene C4 transport intact. By mutating the 11 remaining Trp residues that are in predicted TM segments of MRP1, we have now determined that five of them are also major determinants of MRP1 function. Ala substitution of three of these residues, Trp445 (TM8), Trp553 (TM10), and Trp1198 (TM16), eliminated or substantially reduced transport levels of five organic anion substrates of MRP1. In contrast, Ala substitutions of Trp361 (TM7) and Trp459(TM9) caused a more moderate and substrate-selective reduction in MRP1 function. More conservative substitutions (Tyr and Phe) of the Trp445, Trp553, and Trp1198 mutants resulted in substrate selective retention of transport in some cases (Trp445 and Trp1198) but not others (Trp553). Our findings suggest that the bulky polar aromatic indole side chain of each of these five Trp residues contributes significantly to the transport activity and substrate specificity of MRP1.
Consumer Behavior in Web-Based Commerce: An Empirical Study

Electronic commerce challenges companies to design electronic systems and interactions that retain customers and increase sales. This exploratory study examines the impact of consumer experience and attitudes on intention to return and unplanned purchases on-line. It also examines how certain consumer and Web site factors influence the on-line consumer experience. The study finds that perceived control and shopping enjoyment can increase the intention of new Web customers to return, but seemingly do not influence repeat customers to return. It also finds that a Web store that utilizes valueadded search mechanisms and presents a positively challenging experience can increase customers' shopping enjoyment. Further, the more often customers return to a Web store, the more their shopping enjoyment is determined by their product involvement. Customers with low need specificity (i.e., who do not know what they are looking for) are more likely to use value-added search mechanisms. Finally, neither perceived control nor shopping enjoyment has any significant impact on unplanned purchases.
Continuous Time Research and Development Investment and Innovation: Effects on Price and Dividend Paths

Here, I solve a general equilibrium, stochastic, dynamic control problem. In it, an agent who owns a productive asset decides how much of a non-storable good to consume and how much to invest in research and development. Combined, two features distinguish this from previous work. First, the agent maximizes lifetime expected utility (instead of profits or income). Second, the investment level affects the probability of a research and development innovation which would make future dividends jump. Dividend evolution is represented by a continuous time Poisson process with the jump probability depending on the investment level. In equilibrium, the agent chooses the investment level to give an optimal expected innovation rate. This results in endogenously chose, stationary growth rates in asset dividends and prices. These non-stationary price and dividend paths are of a type that Marsh and Merton (1986) predict will violate variance bounds tests such as Shiller's (1981). However, they are not subject to Shiller's (1986) criticism of Marsh and Merton, because they result from a general equilibrium with all agents behaving optimally and rationally.
Low Levels of Emotional Awareness Predict a Better Response to Dermatological Treatment in Patients with Psoriasis

Background: Personality and emotional factors are thought to influence the onset of psoriasis, the occurrence of relapses, and the sensitivity of this condition to dermatological treatments. Objective:To explore the relationships between emotional disorders and emotional information processing in the one hand, and psoriasis severity and response to treatment on the other. Methods: We recruited 93 patients through an article in the local press. These patients attended three consultations. We evaluated psoriasis severity by Psoriasis Area and Severity Index (PASI) score and response to treatment by change in PASI score from baseline to the 3-month visit. We screened for comorbid mental disorders, using the Mini International Neuropsychiatric Interview. We used the Hospital Anxiety and Depression Scale to assess anxiety and depressive symptoms. Alexithymia (difficulty in identifying and expressing emotions) was evaluated with the 26-item version of the Toronto Alexithymia Scale (TAS-26) and the ability to integrate and differentiate emotions (emotional awareness) was assessed with the Lane and Schwartz Levels of Emotional Awareness Scale (LEAS). Results: Forty patients presented at least one psychiatric diagnosis and 33 were considered alexithymic (TAS ≧73). No psychological score was associated with baseline PASI score, which was higher in men and positively correlated with disease duration. Patients who considered their disease to be stress-reactive tended to have lower LEAS scores (p = 0.052). At the 3-month visit, PASI scores had significantly improved in the subset of patients (n = 67) presenting severe psoriasis at inclusion (PASI >2); emotional awareness and anxiety scores had also improved in these patients (p < 0.001), but dermatological and psychological changes were not statistically related. Dermatological improvement at 3 months with respect to baseline PASI was predicted by longer disease duration (>20 years) and lower baseline LEAS score (p = 0.044 and p = 0.021, respectively). Conclusion: This study demonstrates the value of assessing the ability of patients with psoriasis to process emotional information, as defined by emotional awareness. Patients with low LEAS scores appear to be more reactive to stress, but also to be more responsive to treatment, suggesting the activation of a particular stress physiology by negative affective states that are not experienced.
In Vivo Conversion of Cellular Prion Protein to Pathogenic Isoforms, as Monitored by Conformation-specific Antibodies*

The central event in prion disease is thought to be conformational conversion of the cellular isoform of prion protein (PrPC) to the insoluble isoform PrPSc. We generated polyclonal and monoclonal antibodies by immunizing PrPC-null mice with native PrPC. All seven monoclonal antibodies (mAbs) immunoprecipitated PrPC, but they immunoprecipitated PrPSc weakly or not at all, thereby indicating preferential reactivities to PrPC in solution. Immunoprecipitation using these mAbs revealed a marked loss of PrPC in brains at the terminal stage of illness. Histoblot analyses using these polyclonal antibodies in combination of pretreatment of blots dissociated PrPC and PrPSc in situ and consistently demonstrated the decrease of PrPC at regions where PrPScaccumulated. Interestingly, same mAbs showed immunohistochemical reactivities to abnormal isoforms. One group of mAbs showed reactivity to materials that accumulated in astrocytes, while the other group did so to amorphous plaques in neuropil. Epitope mapping indicated that single mAbs have reactivities to multiple epitopes, thus implying dual specificities. This suggests the importance of octarepeats as a part of PrPC-specific conformation. Our observations support the notion that loss of function of PrPC may partly underlie the pathogenesis of prion diseases. The conversion of PrPCto PrPSc may involve multiple steps at different sites.
Permeation enhancer strategies in transdermal drug delivery

Abstract Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.
Socioeconomic deprivation and mode-specific outcomes in patients with chronic heart failure

Objective To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF). Methods We prospectively observed 1802 patients with CHF and left ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year). Results A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005). Conclusions Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events.
NFBD1/MDC1 Associates with p53 and Regulates Its Function at the Crossroad between Cell Survival and Death in Response to DNA Damage*

NFBD1/MDC1, which belongs to the BRCT superfamily, has an anti-apoptotic activity and contributes to the early cellular responses to DNA damage. Here we found that NFBD1 protects cells from apoptotic cell death by inhibiting phosphorylation of p53 at Ser-15 under steady state as well as early phase of DNA damage, thereby blocking its transcriptional and pro-apoptotic activities. During late phase of DNA damage, a remarkable reduction of NFBD1 was observed in dying but not in surviving A549 cells bearing wild-type p53. Small interference RNA-mediated knockdown of the endogenous NFBD1 resulted in an increase in sensitivity to adriamycin in A549 cells but not in p53-deficient H1299 cells. Immunoprecipitation and luciferase reporter analyses demonstrated that NFBD1 binds to the NH2-terminal region of p53 and strongly inhibits its transcriptional activity. Additionally, BRCT domains, which can interact with p53, reduced the adriamycin-induced phosphorylation levels of p53 at Ser-15 and also suppressed the transcriptional activity of p53. Thus, our present findings strongly suggest that NFBD1 plays an important role in the decision of cell survival and death after DNA damage through the regulation of p53.
The hydrogenation of unsaturated fatty acids by five bacterial isolates from the sheep rumen, including a new species.

Five strictly anaerobic bacteria able to hydrogenate unsaturated fatty acids were isolated from sheep rumen. One was characterized as Ruminococcus albus, two as Eubacterium spp. and two as Fusocillus spp. , one of which is named as a new species. The Fusocillus organisms were able to hydrogenate oleic acid and linoleic acid to stearic acid, and linolenic acid to cis-octadec-15-enoic acid. The R. albus and the two Eubacteria did not hydrogenate oleic acid but converted linoleic and linolenic acids to a mixture of octadecenoic acids; trans-octadec-II-enoic acid predominated but several isomeric cis and trans octadecenoic acids were produced together with isomers of non-conjugated octadecadienoic acids. The intermediate and final products of hydrogenation by each organism were compatible with the results from mixed rumen bacteria.
Brussel Spatio-Temporally Consistent Color and Structure Optimization for Multiview Video Color

When compared to conventional 2D video, multiview video can significantly enhance the visual 3D experience in 3D applications by offering horizontal parallax. However, when processing images originating from different views, it is common that the colors between the different cameras are not well calibrated. To solve this problem, a novel energy function-based color correction method for multiview camera setups is proposed to enforce that colors are as close as possible to those in the reference image but also that the overall structural information is well preserved. The proposed system introduces a spatiotemporal correspondence matching method to ensure that each pixel in the input image gets bijectively mapped to a reference pixel. By combining this mapping with the original structural information, we construct a global optimization algorithm in a Laplacian matrix formulation and solve it using a sparse matrix solver. We further introduce a novel forward-reverse objective evaluation model to overcome the problem of lack of ground truth in this field. The visual comparisons are shown to outperform state-of-the-art multiview color correction methods, while the objective evaluation reports PSNR gains of up to 1.34 dB and SSIM gains of up to 3.2% respectively.
Beyond the Baseline: Establishing the Value in Mobile Phone Based Poverty Estimates

Within the remit of `Data for Development' there have been a number of promising recent works that investigate the use of mobile phone Call Detail Records (CDRs) to estimate the spatial distribution of poverty or socio-economic status. The methods being developed have the potential to offer immense value to organisations and agencies who currently struggle to identify the poorest parts of a country, due to the lack of reliable and up to date survey data in certain parts of the world. However, the results of this research have thus far only been presented in isolation rather than in comparison to any alternative approach or benchmark. Consequently, the true practical value of these methods remains unknown. Here, we seek to allay this shortcoming, by proposing two baseline poverty estimators grounded on concrete usage scenarios: one that exploits correlation with population density only, to be used when no poverty data exists at all; and one that also exploits spatial autocorrelation, to be used when poverty data has been collected for a few regions within a country. We then compare the predictive performance of these baseline models with models that also include features derived from CDRs, so to establish their real added value. We present extensive analysis of the performance of all these models on data acquired for two developing countries -- Senegal and Ivory Coast. Our results reveal that CDR-based models do provide more accurate estimates in most cases; however, the improvement is modest and more significant when estimating (extreme) poverty intensity rates rather than mean wealth.
Restriction and modification systems.

BIOLOGY OF RESTRICTION AND MODIFICATION . Restriction and modification enzymes . Occurrence of R-M systems . Restriction and modification of viruses . Cloning restriction and modification genes . CHARACTERISTICS OF R-M SySTEMS . Type I systems . Type II systems . Type lIs systems . Type III systems . f! ::���:f�':rZ:::;i�g . ;;�;��;::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: Regulation of expression . CONTRASTS AND COMPARISONS AMONG R-M SYSTEMS . Type I systems . Type II systems . Type II endonucleases . Methyltransferases . DiSCUSSION .
Ill-Defined Benefits: The Uncertain Present and Brighter Future of Employee Pensions in Canada

Attempts to shore up the classic single-employer, defined-benefit pension plan are the wrong response to Canada’s occupational pension problems. While tax and regulatory changes can help, Canadians need a new approach to retirement income that will pool risks, control costs, and avoid the agency problems that have put many pension promises at risk.
A Discrete-Continuous Model for Analyzing the Ownership and Usage of Electric Vehicles Using Stated Preference Data

This paper develops a discrete-continuous model to examine the ownership and usage of electric vehicles in the household. The impact of the ownership and usage of ordinary vehicles is taken into consideration. 5766 stated preference data concerning purchasing electric vehicles in the Chukyo region in Japan are utilized as the research sample. The monthly mileages of ordinary and electric vehicles are measured by a Tobit model, respectively. The ordinary vehicle ownership is measured by an ordered probit model, while the electric vehicle ownership is measured by a binary probit model. Gibbs sampler algorithm is used to estimate four jointed equations. The result shows that there is a substitution effect between two types of vehicles in the ownership and usage. The price, capacity, range and charging rate in the gas station impact both the ownership and usage of electric vehicles. Meanwhile, charging time does not affect either the ownership or usage.
Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations

Abstract Objectives: To assess further the relation in Intersalt of 24 hour urinary sodium to blood pressure of individuals and populations, and the difference in blood pressure from young adulthood into middle age. Design: Standardised cross sectional study within and across populations. Setting: 52 population samples in 32 countries. Subjects: 10 074 men and women aged 20-59. Main outcome measures: Association of sodium and blood pressure from within population and cross population multiple linear regression analyses with multivariate correction for regression dilution bias. Relation of sample median daily urinary sodium excretion to difference in blood pressure with age. Results: In within population analyses (n=10 074), individual 24 hour urinary sodium excretion higher by 100 mmol (for example, 170 v 70 mmol) was associated with systolic/diastolic blood pressure higher on average by 3/0 to 6/3 mm Hg (with and without body mass in analyses). Associations were larger at ages 40-59. In cross population analyses (n=52), sample median 24 hour sodium excretion higher by 100 mmol was associated with median systolic/diastolic pressure higher on average by 5-7/2-4 mm Hg, and estimated mean difference in systolic/diastolic pressure at age 55 compared with age 25 greater by 10-11/6 mm Hg. Conclusions: The strong, positive association of urinary sodium with systolic pressure of individuals concurs with Intersalt cross population findings and results of other studies. Higher urinary sodium is also associated with substantially greater differences in blood pressure in middle age compared with young adulthood. These results support recommendations for reduction of high salt intake in populations for prevention and control of adverse blood pressure levels. Key messages The within population findings were previously underestimated because of incomplete correction for the regression dilution problem Revised estimates of the within population association of sodium to blood pressure in Intersalt are concordant with the cross population findings for 52 samples Estimates of the effect of median sodium excretion higher by 100 mmol/day over a 30 year period (age 55 minus age 25) were a greater difference of 10-11 mm Hg in systolic blood pressure and 6 mm Hg in diastolic blood pressure These results lend further support to recommendations for mass reduction of high salt intake for the prevention and control of adverse blood pressure levels and high blood pressure in populations
Intestinal and Hepatic Expression of Cytochrome P450s and mdr1a in Rats with Indomethacin-Induced Small Intestinal Ulcers

Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.