Miracle-dz/UniFAR-FTUs huggingface dataset:
A gene–gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin

Objective The aim of this study was to determine the association between the renal clearance (CLrenal) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene–gene interactions between this SNP and (a) the promoter SNP g. -66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes. Methods Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied. Results When analyzed alone, the c.808 (G>T) affected neither the CLrenal nor the secretory clearance (CLsec) of metformin. However, both CLrenal and CLsec were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g. -66T>C: CLrenal: GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P=0.004), respectively and CLsec: GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P=0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g. -66T>C, both CLrenal and CLsec were found to be reduced (P<0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g. -66T>C reference genotype. Conclusion We report counteracting effects of the c.808 (G>T) and g. -66T>C on the renal elimination of metformin. When adjusted for the genetic variation g. -66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.
The implications of US punitive tariffs on Chinese tires for rubber exports from South-East Asia

In July 2015, the United States finalized the countervailing and anti-dumping tariff rates against tire imports from China. The tariff increases are substantial and irrevocable until 2020. We show that the US tariff hikes adversely affect the world tire trade, resulting in a weaker demand for natural rubber from South-East Asia. Using an economic simulation model, we find that the collateral damage to natural rubber export is about $48 million a year in Indonesia, $42 million a year in Thailand, $18 million a year in Malaysia, and $4 million a year in Vietnam.
Duty in a time of disaster: a concept analysis.

TOPIC The concept of "duty" is explored particularly as it applies to disaster nursing. PURPOSE To identify the contributing factors to a nurse's sense of duty and the resulting consequences of such. Nursing implications of duty in a time of disaster are also discussed. SOURCES OF INFORMATION Professional literature, electronic resources, and nursing textbooks were used. The analysis was done using Walker and Avant's (1995) process. CONCLUSION The concept of duty has always been prevalent in nursing. As long as nurses have a sense of duty to their communities, nurse administrators will also have a moral obligation to protect their staff, especially in a time of disaster when nurses are compelled by a heightened sense of duty.
Serum lipids, lipid-lowering drugs, and the risk of breast cancer.

BACKGROUND Experimental evidence suggests that statins protect against breast carcinogenesis by interrupting cell cycle progression and promoting apoptosis. Evidence in humans is limited and inconsistent. The relation between serum cholesterol levels and breast cancer risk is itself unclear; because cholesterol is the precursor to sex steroid hormones, higher levels could plausibly increase risk. METHODS The associations of statins, general lipid-lowering drugs, and reported cholesterol levels with breast cancer risk were assessed in the Nurses' Health Study, with 6 to 12 years of follow-up. A total of 79,994 women aged 42 to 69 years and free of cancer were followed prospectively for up to 12 years. Current statin use, including duration, was assessed retrospectively in 2000 in 75,828 women. Self-reported serum cholesterol level was assessed prospectively between 1990 and 2000 in 71,921 women. RESULTS Overall, we documented 3177 incident cases of invasive breast cancer. Compared with nonusers, current lipid-lowering drug users experienced similar breast cancer risk (multivariate relative risk [RR], 0.99; 95% confidence interval [CI], 0.86-1.13). Current use of statins also was not significantly associated with breast cancer risk (RR, 0.91; 95% CI, 0.76-1.08). Associations by duration of current use were similarly null. Self-reported serum cholesterol levels were not associated with breast cancer risk in postmenopausal women with levels of 240 mg/dL or higher (> or = 6.22 mmol/L) compared with less than 180 mg/dL (< 4.66 mmol/L) (RR, 1.04; 95% CI, 0.91-1.17). CONCLUSION Overall, these data suggest that serum cholesterol levels and the use of lipid-lowering drugs in general and of statins in particular are not substantially associated with breast cancer risk.
The Mechanistic Basis of Internal Conductance: A Theoretical Analysis of Mesophyll Cell Photosynthesis and CO2 Diffusion1[W][OA]

Photosynthesis is limited by the conductance of carbon dioxide (CO2) from intercellular spaces to the sites of carboxylation. Although the concept of internal conductance (gi) has been known for over 50 years, shortcomings in the theoretical description of this process may have resulted in a limited understanding of the underlying mechanisms. To tackle this issue, we developed a three-dimensional reaction-diffusion model of photosynthesis in a typical C3 mesophyll cell that includes all major components of the CO2 diffusion pathway and associated reactions. Using this novel systems model, we systematically and quantitatively examined the mechanisms underlying gi. Our results identify the resistances of the cell wall and chloroplast envelope as the most significant limitations to photosynthesis. In addition, the concentration of carbonic anhydrase in the stroma may also be limiting for the photosynthetic rate. Our analysis demonstrated that higher levels of photorespiration increase the apparent resistance to CO2 diffusion, an effect that has thus far been ignored when determining gi. Finally, we show that outward bicarbonate leakage through the chloroplast envelope could contribute to the observed decrease in gi under elevated CO2. Our analysis suggests that physiological and anatomical features associated with gi have been evolutionarily fine-tuned to benefit CO2 diffusion and photosynthesis. The model presented here provides a novel theoretical framework to further analyze the mechanisms underlying diffusion processes in the mesophyll.
Gene therapy for monogenic disorders of the bone marrow

Ex‐vivo gene transfer of autologous haematopoietic stem cells in patients with monogenic diseases of the bone marrow has emerged as a new therapeutic approach, mainly in patients lacking a suitable donor for transplant. The encouraging results of initial clinical trials of gene therapy for primary immunodeficiencies were tempered by the occurrence of genotoxicity in a number of patients. Over the last decade, safer viral vectors have been developed to overcome the risk of insertional mutagenesis and have led to impressive clinical outcomes with considerably improved safety. We review the efforts in specific immunodeficiencies including adenosine deaminase deficiency, X‐linked severe combined immunodeficiency, chronic granulomatous disease and Wiskott Aldrich syndrome. Major recent progress has also been made in haemoglobinopathies, such as beta‐thalassaemia, sickle cell disease and Fanconi anaemia, and also specific lysosomal storage diseases, which, although not strictly bone marrow specific conditions, have been effectively treated by bone marrow‐based treatment. The success of these recent studies and the advent of new technologies, such as gene editing, suggest that gene therapy could become a more generally applied treatment modality for a number of haematopoietic disorders.
Comparison of the airborne survival of calf rotavirus and poliovirus type 1 (Sabin) aerosolized as a mixture

A mixture of a cell culture-adapted strain (C-486) of calf rotavirus and poliovirus type 1 (Sabin) was prepared in tryptose phosphate broth containing 0.1% uranine (physical tracer) and antifoam at a final concentration of 0.001%. By using a six-jet Collison nebulizer, the mixture was aerosolized into a 300-liter stainless-steel rotating (4 rpm) drum. The temperature of the air inside the drum was kept at 20 +/- 1 degrees C, and the virus aerosols were held at the following three levels of relative humidity (RH): low (30 +/- 5%), medium (50 +/- 5%), and high (80 +/- 5%). An all-glass impinger, containing 10.0 ml of tryptose phosphate broth with antifoam, was used to collect samples of air from the drum. Both viruses were propagated and quantitated in MA-104 cells. The calf rotavirus was found to survive well at mid-range RH, where 60% of the infectious virus could be detected even after 24 h of virus aerosolization. At the low RH, the half-life of the infectious rotavirus was ca. 14 h. On the other hand, no infectious poliovirus could be recovered from the drum air at the low and medium RH. At the high RH, more than 50% of the infectious rotavirus became undetectable within 90 min of aerosolization. In contrast to this, the half-life of the poliovirus at the high RH was about 10 h. These data, based on the aerosolization of virus mixtures, therefore suggest that there is a pronounced difference in the way RH influences the airborne survival of these two types of viruses held under identical experimental conditions.
Influence of Cabergoline on Motor Excitability in Patients With Restless Legs Syndrome

Summary: To investigate whether the increased urge to move the legs in restless legs syndrome (RLS) corresponds to an electrophysiological phenomenon and whether motor excitability or behavior is influenced by the treatment with a dopamine agonist. We examined 10 patients who had RLS with transcranial magnetic stimulation (TMS) before and during treatment with the dopamine agonist cabergoline. Results were compared with data obtained from healthy subjects. Inhibitory mechanisms were explored by measurement of the cortical silent period (cSP). Recordings were obtained from the right anterior tibial muscle. Clinical severity of RLS was rated using the International Restless Legs Syndrome Study Group Rating Scale (IRLSSGRS). During therapy with cabergoline, all patients reported a significant improvement of RLS symptoms. Before medication, patients showed a significant shortening of cSP compared with healthy subjects. After 14 days of treatment with cabergoline, cSP normalized in RLS patients; 90 days after the start of daily cabergoline, cSP tended to shorten again, whereas RLS symptoms further improved. There was no correlation between cSP duration and IRLSSGRS results. There were no differences in patient and control motor thresholds. These thresholds remained unchanged during treatment with cabergoline. RLS patients have a disturbance of inhibitory neurons that can temporarily be reversed with a dopamine agonist. However, the cSP does not correlate with the clinical symptoms.
Vaccination with a co‐expression DNA plasmid containing GAD65 fragment gene and IL‐10 gene induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes

The non‐obese diabetic (NOD) mouse is a commonly used animal model for studying type 1 diabetes (T1D). The aims of our study were to explore the diabetes‐preventive effect in NOD mice and the potential mechanisms of an optimized co‐expression DNA vaccine containing GAD65 fragment gene with the IL‐10 gene (SGAD65190‐315/IL‐10).
Hazards Induced by Breach of Liquid Rocket Fuel Tanks: Conditions and Risks of Cryogenic Liquid Hydrogen-Oxygen Mixture Explosions

We analyze the data of purposeful rupture experiments with LOx and LH2 tanks, the Hydrogen-Oxygen Vertical Impact (HOVI) tests that were performed to clarify the ignition mechanisms, the explosive power of cryogenic H2/Ox mixtures under different conditions, and to elucidate the puzzling source of the initial formation of flames near the intertank section during the Challenger disaster. We carry out a physics-based analysis of general explosions scenarios for cryogenic gaseous H2/Ox mixtures and determine their realizability conditions, using the well-established simplified models from the detonation and deflagration theory. We study the features of aerosol H2/Ox mixture combustion and show, in particular, that aerosols intensify the deflagration flames and can induce detonation for any ignition mechanism. We propose a cavitation-induced mechanism of self-ignition of cryogenic H2/Ox mixtures that may be realized when gaseous H2 and Ox flows are mixed with a liquid Ox turbulent stream, as occurred in all HOVI tests. We present an overview of the HOVI tests to make conclusion on the risk of strong explosions in possible liquid rocket incidents and provide a semi-quantitative interpretation of the HOVI data based on aerosol combustion. We uncover the most dangerous situations and discuss the foreseeable risks which can arise in space missions and lead to tragic outcomes. Our analysis relates to only unconfined mixtures that are likely to arise as a result of liquid propellant space vehicle incidents.
Evaluation of Lapatinib and Topotecan Combination Therapy: Tissue Culture, Murine Xenograft, and Phase I Clinical Trial Data

Purpose: Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial. Experimental Design: The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial. Results: Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m2 topotecan i.v. on days 1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization. Conclusions: The lapatinib/topotecan combination is well tolerated and warrants further study.
In Good Times But Not in Bad: The Role of Managerial Discretion in Moderating the Stakeholder Management and Financial Performance Relationship

We examine the role of managers in controlling the positive impact of stakeholder management (SM) on firm financial performance (FP) in the long term. We develop and test competing hypotheses on whether managers act as “good citizens” or engage in “self-dealing” when allowed greater discretion. We test our assertions using dynamic panel data analysis of a sample of 806 U.S. public firms operating in 34 industries over 5 years (2005–2009). Our results indicate a nuanced influence of managerial discretion contexts on the SM-FP relationship. We infer that given more latitude in decision making, as long as the “going is good” managers act as good citizens, but otherwise they revert to managerial self-dealing. In light of our results, firms designing governance mechanisms to encourage managers to balance the needs of both shareholders and stakeholders must remain cognizant of contextual contingencies.
Effect of Fluconazole on Indinavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Patients

ABSTRACT To evaluate a potential pharmacokinetic interaction of coadministration of fluconazole, and indinavir, a human immunodeficiency virus (HIV) protease inhibitor, 13 patients were enrolled in a multiple-dose, three-period, placebo-controlled, crossover study. Patients were randomly assigned to receive indinavir at 1,000 mg every 8 h for 713 days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The pharmacokinetics of both drugs were measured on day 8 of each treatment period. The peak concentration in plasma (Cmax) and the time to reach Cmax were obtained by inspection, and the area under curve (AUC) was calculated for indinavir and fluconazole for each treatment period in which the respective drugs were administered. There was a marginally (P = 0.08) statistically significant decrease in the AUC from 0 to 8 h (AUC0–8) for indinavir when it was administered with fluconazole. However, the magnitudes of the decreases inCmax and the concentration at 8 h postdosing (C8) were not as great as the decrease in AUC0–8. Although the 90% confidence interval for the geometric mean ratio was within the hypothesized limits, the clinical significance is not clear. Indinavir coadministration with fluconazole had no statistically (P > 0.5) or clinically significant effect on the Cmax andC8 of indinavir. Fluconazole coadministration with indinavir had no statistically or clinically significant effect on the pharmacokinetics of fluconazole. One patient was discontinued because of mild to moderate abdominal pain and diarrhea while on indinavir and fluconazole in combination. No serious adverse experience according to the results of laboratory tests was noted. Total bilirubin levels in serum were mildly increased in most patients treated with indinavir. This was not clinically significant and was not affected by the coadministration of fluconazole. Although the values of the pharmacokinetic parameters for indinavir decrease in the presence of fluconazole, indinavir and fluconazole can be administered concomitantly to HIV-infected patients without adjustment of the dose of either drug, and both drugs are generally well tolerated.
Atypical mechanism of conduction in potassium channels

Potassium channels can conduct passively K+ ions with rates of up to ≈108 ions per second at physiological conditions, and they are selective to these species by a factor of 104 over Na+ ions. Ion conduction has been proposed to involve transitions between 2 main states, with 2 or 3 K+ ions occupying the selectivity filter separated by an intervening water molecule. The largest free energy barrier of such a process was reported to be of the order of 2–3 kcal mol−1. Here, we present an alternative mechanism for conduction of K+ in potassium channels where site vacancies are involved, and we propose that coexistence of several ion permeation mechanisms is energetically possible. Conduction can be described as a more anarchic phenomenon than previously characterized by the concerted translocations of K+–water–K+.
Backward in high heels: A critical discourse analysis of major news magazines covering Hillary Clinton's 2008 campaign

This critical discourse analysis looked at newsmagazine coverage of Hillary Clinton’s 2008 campaign for the Democratic nomination. The research sought to understand if there was any difference in the language used to write about Clinton and Barack Obama, and if the content focus of the articles differed between the two candidates. Using framing and feminist theory, the research showed that much of the reporting on Clinton was sexist, but uses coded sexism rather than overt showings. This is important to understand because coded sexism is much more likely to survive without being identified as sexist. Journalists should understand the power of their words and how they can inadvertently cast subjects in a certain light. Coded words used to describe Clinton were certainly present in the reporting and could ultimately affect readers’ perception of Clinton and other female politicians.
Stimulation of Dorsolateral Prefrontal Cortex Enhances Adaptive Cognitive Control: A High-Definition Transcranial Direct Current Stimulation Study

Conflict adaptation is a hallmark effect of adaptive cognitive control and refers to the adjustment of control to the level of previously experienced conflict. Conflict monitoring theory assumes that the dorsolateral prefrontal cortex (DLPFC) is causally involved in this adjustment. However, to date, evidence in humans is predominantly correlational, and heterogeneous with respect to the lateralization of control in the DLPFC. We used high-definition transcranial direct current stimulation (HD-tDCS), which allows for more focal current delivery than conventional tDCS, to clarify the causal involvement of the DLPFC in conflict adaptation. Specifically, we investigated the regional specificity and lateralization of potential beneficial stimulation effects on conflict adaptation during a visual flanker task. One hundred twenty healthy participants were assigned to four HD-tDCS conditions: left or right DLPFC or left or right primary motor cortex (M1). Each group underwent both active and sham HD-tDCS in crossover, double-blind designs. We obtained a sizeable conflict adaptation effect (measured as the modulation of the flanker effect as a function of previous response conflict) in all groups and conditions. However, this effect was larger under active HD-tDCS than under sham stimulation in both DLPFC groups. In contrast, active stimulation had no effect on conflict adaptation in the M1 groups. In sum, the present results indicate that the DLPFC plays a causal role in adaptive cognitive control, but that the involvement of DLPFC in control is not restricted to the left or right hemisphere. Moreover, our study confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner. SIGNIFICANCE STATEMENT Conflict adaptation is a hallmark effect of adaptive cognitive control. While animal studies have suggested causal involvement of the DLPFC in this phenomenon, such evidence is currently lacking in humans. The present study used high-definition transcranial direct current stimulation (HD-tDCS) to demonstrate that the DLPFC is causally involved in conflict adaptation in humans. Our study confirms a central claim of conflict monitoring theory, which up to now has predominantly relied on correlational studies. Our results further indicate an equal involvement of the left and right DLPFC in adaptive control, whereas stimulation of a control region—the primary motor cortex—had no effect on adaptive control. The study thus confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner.