Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytochrome P450 3A Enzymes Catalyze the O6-Demethylation of Thebaine, a Key Step in Endogenous Mammalian Morphine Biosynthesis*

Background: Mammals synthesize endogenous morphine; the enzyme catalyzing thebaine O6-demethylation, a key late step, is uncharacterized. Results: Human cytochromes P450 (P450) 3A4 and 3A5 catalyzed thebaine O6-demethylation; the P450 3A-selective drug ketoconazole inhibited the reaction in human liver microsomes and rat brain homogenates. Conclusion: P450s 3A4 and 3A5 catalyze thebaine O6-demethylation in humans. Significance: Enzymes catalyzing all oxidations in the latter steps of mammalian morphine biosynthesis have been identified. Morphine, first characterized in opium from the poppy Papaver somniferum, is one of the strongest known analgesics. Endogenous morphine has been identified in several mammalian cells and tissues. The synthetic pathway of morphine in the opium poppy has been elucidated. The presence of common intermediates in plants and mammals suggests that biosynthesis occurs through similar pathways (beginning with the amino acid l-tyrosine), and the pathway has been completely delineated in plants. Some of the enzymes in the mammalian pathway have been identified and characterized. Two of the latter steps in the morphine biosynthesis pathway are demethylation of thebaine at the O3- and the O6-positions, the latter of which has been difficult to demonstrate. The plant enzymes responsible for both the O3-demethylation and the O6-demethylation are members of the FeII/α-ketoglutarate-dependent dioxygenase family. Previous studies showed that human cytochrome P450 (P450) 2D6 can catalyze thebaine O3-demethylation. We report that demethylation of thebaine at the O6-position is selectively catalyzed by human P450s 3A4 and 3A5, with the latter being more efficient, and rat P450 3A2. Our results do not support O6-demethylation of thebaine by an FeII/α-ketoglutarate-dependent dioxygenase. In rat brain microsomes, O6-demethylation was inhibited by ketoconazole, but not sulfaphenazole, suggesting that P450 3A enzymes are responsible for this activity in the brain. An alternate pathway to morphine, oripavine O6-demethylation, was not detected. The major enzymatic steps in mammalian morphine synthesis have now been identified.
[Mediastinitis following cardiac surgery. Patient insurance reports].

INTRODUCTION Mediastinitis in cardiac surgery is a well-known complication associated with high morbidity, invalidity, and mortality. Since the establishment by law of patients insurance in Denmark 1992, it has been possible to get compensation in some instances. MATERIALS AND METHODS During a period of 8 years (1996-2003) 30 cases of mediastinitis were reported to the Danish Patient Insurance Association (DPIA). The initial cardiac operations consisted of 28 coronary artery bypass graft operations (CABG), 1 CABG associated with substitution of the aortic valve, and 1 CABG with cryoablation because of atrial fibrillation. The median preoperative mortality risk (EuroSCORE) was 2 (0-6+). The treatment of mediastinitis consisted of open revision or closed rinsing-system and of vacuum assisted closure in the later part of the period. RESULTS Eighty percent of the patients had a transposition of thoracic muscle undertaken as a compensation for the lack of sternum. The median number of universal anaesthesias was 23 (3-32). The median admission time was 73 days (21-180), hospital mortality was 6.7%. A patient may receive compensation for an injury sustained during treatment if: 1) the best specialist would have acted differently, 2) the injury was caused by defect or malfunction of equipment, 3) the injury could have been prevented by using a different similar method of treatment, or 4) the patient had suffered more than is acceptable given the severity of the disease. Seventeen claims were approved (57%), the remainders were rejected. The criteria for acceptance according to the law of patient insurance are presented. In the actual period 511 cases of deep sternal infection after cardiac surgery were reported to the Danish Patient Registry. CONCLUSION The majority of mediastinitis cases were not reported to the DPIA. The parties involved (patients, patient advisors, general practitioners, and hospital departments) are asked to concentrate on the need of reporting these cases to the DPIA.
Subcellular Localization and Ubiquitin-conjugating Enzyme (E2) Interactions of Mammalian HECT Family Ubiquitin Protein Ligases*

In most instances, the transfer of ubiquitin to target proteins is catalyzed by the action of ubiquitin protein ligases (E3s). Full-length cDNAs encoding murine E6-associated protein (mE6-AP) as well as Nedd-4, a protein that is homologous to E6-AP in its C terminus, were cloned. Nedd-4 and mouse E6-AP are both enzymatically active E3s and function with members of the UbcH5 family of E2s. Mouse E6-AP, like its human counterpart, ubiquitinates p53 in the presence of human papilloma virus E6 protein, while Nedd-4 does not. Consistent with its role in p53 ubiquitination, mE6-AP was found both in the nucleus and cytosol, while Nedd-4 was found only in the cytosol. Binding studies implicate a 150-amino acid region that is 40% identical between mE6-AP and Nedd-4 as a binding site for the C-terminal portion of an E2 enzyme (UbcH5B). Nedd-4 was determined to have a second nonoverlapping E2 binding site that recognizes the first 67 amino acids of UbcH5B but not the more C-terminal portion of this E2. These findings provide the first demonstration of physical interactions between mammalian E2s and E3s and establish that these interactions occur independently of ubiquitin and an intact E3 catalytic domain. Furthermore, the presence of two E2 binding sites within Nedd-4 suggests models for ubiquitination involving multiple E2 enzymes associated with E3s.
Minimizing photobleaching during confocal microscopy of fluorescent probes bound to chromatin: role of anoxia and photon flux

Exposure to light can destroy the ability of a molecule to fluoresce. Such photobleaching limits the use of fluorescence and confocal microscopy in biological studies. Loss of fluorescence decreases the signal‐to‐noise ratio and so image resolution; it also prevents the acquisition of meaningful data late during repeated scanning (e.g. when collecting three‐dimensional images). The aim of this work was to investigate the role of oxygen in the photobleaching of fluorophores bound to DNA in fixed cells, and to explore whether anoxia could minimize such bleaching. Anoxia significantly reduced bleaching rates and changed the order of reaction of both propidium iodide (an intercalator) and chromomycin A3 (a minor‐groove binder) bound to DNA; it afforded the greatest protection at low photon fluxes. However, it had no effect on the bleaching of the green fluorescent protein (GFP) covalently attached to a histone and so bound to DNA, probably because the protein shielded the chromophore from oxygen. Bleaching of all three fluorophores depended on photon flux. Practical ways of minimizing bleaching were examined, and examples of three‐dimensional images of DNA marked by propidium and GFP (collected under standard and optimized conditions) are presented.
A fast nonlinear control technique for a grid-connected voltage source inverter with LCL filter used in renewable energy power conditioning systems

This paper presents a new controller scheme for a grid-connected voltage source inverter with an LCL filter based on the Control Lyapunov Function (CLF). Conventional Proportional Resonant (PR) controllers are not able to provide a fast transient response due to their limited bandwidth. Therefore, they have difficulties handling severe load transients. Additionally, they can only reject the disturbance created by the grid voltage to some extent. The proposed CLF-based controller is able to increase the bandwidth of the closed loop control system, while providing guaranteed stability and perfect disturbance rejection. Since the proposed controller is based on the system model, it is able to completely remove the disturbances caused by the grid voltage. The integral terms of the error are also incorporated into the Lyapunov function in order to account for parameter uncertainties in the system model. The performance of the proposed control scheme has been compared to the PR controller through experimental results. The experimental results demonstrate the superior performance of the proposed control scheme over the conventional PR controller.
Inequality Aversion and Marginal Income Taxation

This paper deals with tax policy responses to inequality aversion by examining the first-best Pareto-efficient marginal tax structure when people are inequality averse. In doing so, we distinguish between four different and widely used models of inequality aversion. The results show that empirically and experimentally quantified degrees of inequality aversion have potentially very strong implications for Pareto-efficient marginal income taxation. It also turns out that the exact type of inequality aversion (self-centered vs. non-self-centered), and the measures of inequality used, matter a great deal. For example, based on simulation results mimicking the disposable income distribution in the US in 2013, the preferences suggested by Fehr and Schmidt (1999) imply monotonically increasing marginal income taxes, with large negative marginal tax rates for low-income individuals and large positive marginal tax rates for high-income individuals. In contrast, the often considered similar model by Bolton and Ockenfels (2000) implies close to zero marginal income tax rates for all.
The Parent Firms’ Reverse Spillovers of China’s Production-Oriented OFDI Enterprises: Evidence from Chinese Manufacturing Enterprises

In recent years, the rise of Chinese investments follows the provisions of the “Going Out” strategy. Whether this local production foreign direct investment has a positive role in reverse spillovers to the parent company? Does the theme of the “Industry hollow” which has been caused great attention really existence? In this paper, we analyzed the reverse spillover of local production outward foreign direct investment (OFDI) using firm-level data from Chinese industrial enterprises in the period of 2000 to 2011. We will separately analyze the problem from productivity, exports and the scale of production. Combining with the method of propensity score matching and difference in difference estimator, we find that the productivity, the scale of production, and the export have all significantly improved no matter which data sample we use. In general, the local production of OFDI has a positive effect on the parent company; the Chinese government should encourage the enterprises to go out.
Automated breast ultrasound system (ABUS): reproducibility of mass localization, size measurement, and characterization on serial examinations

Background Automated breast ultrasound (ABUS) is gaining popularity for breast cancer detection and diagnosis with its high reproducibility. Consistent recognition of breast lesions on serial exams is critical, and high reproducibility for lesion characterization is expected with ABUS, but not well reported. Purpose To retrospectively evaluate the reproducibility of ABUS for mass localization, size measurement, and characterization. Material and Methods Bilateral whole breast US images were obtained twice using a commercially available ABUS within a mean interval of 1.3 days. In total, 24 patients were imaged before biopsy or surgery. There were 24 breast cancers and nine benign diagnoses. Two breast radiologists reviewed every paired three-dimensional dataset with regard to lesion visibility, reproducibility of documented location (clockface location, distance from nipple, and lesion depth), size of the lesions, and similarity for lesion characteristics. Lesion similarity was classified as being identical, similar, or different by consensus reading using the SomoVu workstation. Intraclass correlation coefficients (ICCs) and the Bland-Altman method were used to determine the amount of agreement between assessments of lesion location and size. Results Among 33 breast lesions, 31 lesions were depicted in both serial examinations. ICCs for the displayed lesion location (clock face location, distance from nipple), and the individual size of detected lesions were 0.994, 0.926, and 0.980, indicating excellent reliability. However, the ICC for lesion depth from the skin was 0.342 showing low reliability. For lesion similarity, 16 cancers and five benign lesions were classified as being identical, and six cancers and two benign lesions were classified as being similar. Two benign lesions were assessed to have different lesion characteristics and final assessment categories. Conclusion The ABUS provided reproducible images for mass localization, size measurement, and characterization, which may be useful for follow-up studies.
Impedance-based and eigenvalue based stability assessment compared in VSC-HVDC system

This paper presents the comparison between the impedance-based and eigenvalue-based stability analysis methods for a VSC-based HVDC system. In order to apply the impedance-based method, an impedance model for the VSCs is analytically derived and the derived model is validated by comparing the frequency responses of the analytical impedance and the impedance measured in a detailed switching model of the VSC-HVDC system. To determine the stability from the eigenvalue based method, an analytical state-space small-signal model is developed and the model is validated by time domain simulations. It is shown that both stability analysis methods can effectively determine the stability of the system. In the case of the impedance-based method, a low phase-margin in the Nyquist plot of impedance ratio indicates that the system can have harmonic oscillation; however the system still operates stably. A weakness of the impedance method is that the stability determined by this method is not a global stability assessment; and it is therefore necessary to investigate the stability at all possible sub/systems. On the other hand, the eigenvalue based method can determine the stability of the entire system; but it cannot predict harmonic oscillations caused by a PWM inverter operating in a stable point. A two terminal VSC-HVDC system has been developed analytically and the frequency domain stability analysis based on impedance and eigenvalues has been carried out. The theoretical analysis has been further validated by simulation and experiments.
Strawberry Intake, Lipids, C-Reactive Protein, and the Risk of Cardiovascular Disease in Women

Objective: There is indirect evidence suggesting that strawberries, containing several key nutrients, may be associated with the risk of cardiovascular disease (CVD). In the Women’s Health Study, we examined strawberry intake for both its prospective association with CVD risk in 38,176 women and its cross-sectional association with lipids and C-reactive protein (CRP) in a subset of 26,966 women. Methods: Strawberry intake was assessed from a baseline semiquantitative food frequency questionnaire, along with other self-reported lifestyle, clinical and dietary factors. Participants returned baseline bloods which were assayed for lipids and CRP. We computed the relative risks (RRs) for total CVD (1,004 cases) (including confirmed myocardial infarction, stroke, revascularization, and cardiovascular death) occurring during 10.9 years of follow-up. Results: At baseline, 25.6%, 41.9%, 24.8%, and 7.7% of women reported corresponding strawberry intake of none, 1–3 servings/month, 1 serving/week, and ≥2 servings/week. For total CVD, the multivariate RRs (95% confidence intervals) for increasing categories of strawberry intake were 1.00 (ref), 1.01 (0.85–1.19), 0.95 (0.77–1.17), and 1.27 (0.94–1.72) (P, trend = 0.06). We found a similar lack of an association for individual cardiovascular endpoints and comparing mean levels of lipids and CRP by category of strawberry intake. However, women consuming ≥2 servings/week versus none had a borderline significant, multivariate 14% lower likelihood of an elevated CRP of ≥3 mg/L. Conclusions: Strawberry intake was unassociated with the risk of incident CVD, lipids, or CRP in middle-aged and older women, though higher strawberry intake may slightly reduce the likelihood of having elevated CRP levels. Additional epidemiologic data are needed to clarify any role of strawberries in CVD prevention.
Specific and Rapid Enumeration of Viable but Nonculturable and Viable-Culturable Gram-Negative Bacteria by Using Flow Cytometry

ABSTRACT An issue of critical concern in microbiology is the ability to detect viable but nonculturable (VBNC) and viable-culturable (VC) cells by methods other than existing approaches. Culture methods are selective and underestimate the real population, and other options (direct viable count and the double-staining method using epifluorescence microscopy and inhibitory substance-influenced molecular methods) are also biased and time-consuming. A rapid approach that reduces selectivity, decreases bias from sample storage and incubation, and reduces assay time is needed. Flow cytometry is a sensitive analytical technique that can rapidly monitor physiological states of bacteria. This report outlines a method to optimize staining protocols and the flow cytometer (FCM) instrument settings for the enumeration of VBNC and VC bacterial cells within 70 min. Experiments were performed using the FCM to quantify VBNC and VC Escherichia coli O157:H7, Pseudomonas aeruginosa, Pseudomonas syringae, and Salmonella enterica serovar Typhimurium cells after staining with different fluorescent probes: SYTO 9, SYTO 13, SYTO 17, SYTO 40, and propidium iodide (PI). The FCM data were compared with those for specific standard nutrient agar to enumerate the number of cells in different states. By comparing results from cultures at late log phase, 1 to 64% of cells were nonculturable, 40 to 98% were culturable, and 0.7 to 4.5% had damaged cell membranes and were therefore theoretically dead. Data obtained using four different Gram-negative bacteria exposed to heat and stained with PI also illustrate the usefulness of the approach for the rapid and unbiased detection of dead versus live organisms.
Effect of Food and Food Composition on Alcohol Elimination Rates in Healthy Men and Women

Several studies have evaluated the effect of food on alcohol pharmacokinetics; however, most studies have used oral alcohol administration, which cannot separate the influence of food on absorption from its influence on alcohol elimination. Alcohol clamping uses intravenous alcohol and provides a direct measure of the alcohol elimination rate (AER). Two studies, using alcohol clamping at 50 mg%, were conducted to investigate the effect of food and food composition on AER (g/h) in healthymenand women. In the first study, 20 subjects underwent two clamping sessions, one after a 12‐hour fast and another 1 hour after consuming a 530‐calorie breakfast. In the second study, 8 subjects underwent four clamping sessions: one after a 12‐hour fast and, in each of three “fed” sessions, 1 hour after a 550‐calorie high‐fat, high‐protein, or high‐carbohydrate breakfast. Comparison of AERs from the first study showed an average 25% increase following food compared to that following fasting. Men showed significantly higher AERs compared to women; however, the food effect was similar in both genders. In the second study, the AER showed a significant average 45% increase following the meal, regardless of composition, compared with that following fasting. These findings indicate that food intake results in increased alcohol elimination rates. The increase was similar for meals of different compositions, suggesting that the food effect is not due to specific interactions with meal constituents. Probable mechanisms for the increased alcohol elimination include food‐induced increases in hepatic blood flow and in the activity of alcohol‐metabolizing enzymes.
Avoidance of Soccer Injuries with Preseason Conditioning

The effect of a preseason conditioning program was studied to evaluate its influence on the occurrence and severity of soccer injuries. Three hundred female soccer players (ages 14 to 18 years) were studied over a 1-year period. Forty-two of these players participated in a 7-week training program before the start of the season. The type, mechanism, and severity of the injury, when the injury occurred, the number of games or practices missed, and type of shoe worn were recorded. All injuries occurred in the lower extremities, with 61.2% occurring at the knee and ankle. Student's t-test evaluations revealed that the trained group experienced a significantly lower incidence of injury than the untrained group (P 0.0085). Although not statistically significant, the trained group also had a lower percentage (2.4%) of anterior cruciate ligament injuries compared with the untrained group (3.1%). These results suggest that this type of conditioning has a significant influence on lowering the incidence of injury in female adolescent soccer players.
Evaluating the Effectiveness of Environmental Policy. An Analysis of Conceptual and Methodological Issues

Problems of implementation and effectiveness have recently been subject to growing interest in the field of policy evaluation, in particular at the EU level. The literature as well as the praxis in this field have also highlighted a number of problems, which can be divided into three categories. The first type are conceptual problems; one example can be found in the definition of the concept of effectiveness. The second type are the methodology-based problems, such as the causality question. Finally, important empirical obstacles exist, mostly related to the (non-) existence of input and output indicators and the quality of data. In our paper we will analyse these problems and their consequences for the field of environmental policy evaluation. The findings of the paper are based on the first results of the work of the Centre of Expertise for Environmental Policy Sciences (CEEPS), funded by the Flemish government for a period of five years (2002-2007).
SCIENCE TEACHERS’ TRUTHFUL NARRATIVES ON INTEREST IN CURRICULUM

The teacher’s entire personality including his or her specific interests in different parts of the curriculum and in teaching in general is present in the classroom. The way the teacher teaches the curriculum is thus coloured by the teacher’s personality and personal interest besides being entangled in all other aspects of the actual school context’s complexity. A way to address the individual teacher’s perception of the complexity of teaching is by redeeming truthfulness as a central virtue in education. The application of truthfulness opens given contextualised and subjective narratives and makes it possible to nuance the interests implied in them. Truthfulness has been used to expose how the interests of ten Danish primary and lower secondary school science teachers are personal and situated. The teachers react to the technical interest of the national curriculum makers to control science teaching by pursuing their own practical interest in making their own school working day possible to relate to with their personality intact. They rephrase the national curriculum from their personal standpoint in order to live out their emancipatory interest in improving the children’s understanding of themselves and in order to help themselves and their colleagues in their teaching. The results suggest that learning and knowing to be in science teaching presupposes an interest in the specific part of science teaching in question. Being and knowing furthermore requires experience in exactly being in science teaching as illustrated by the contextual and detailed way the teachers give their narratives. The analysis seems to indicate that if science teacher research wants to understand science teachers’ more subjective and personal aspects of teaching science it could be beneficial to address the evidence in science teachers’ narratives and actions of truthfulness and dedicated human interest.