Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

Long-chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4, and UGT2B7. Bovine serum albumin (BSA) enhances these cytochrome P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here, we report the effects of BSA on CYP1A2-catalyzed phenacetin (PHEN) O-deethylation and lidocaine (LID) N-deethylation using HLM and Escherichia coli-expressed recombinant human CYP1A2 (rCYP1A2) as the enzyme sources. BSA (2% w/v) reduced (p < 0.05) the Km values of the high-affinity components of human liver microsomal PHEN and LID deethylation by approximately 70%, without affecting Vmax. The Km (or S50) values for PHEN and LID deethylation by rCYP1A2 were reduced to a similar extent. A fatty acid mixture, comprising 3 μM concentrations each of oleic acid and linoleic acid plus 1.5 μM arachidonic acid, doubled the Km value for PHEN O-deethylation by rCYP1A2. Inhibition was reversed by the addition of BSA. Ki values for the individual fatty acids ranged from 4.7 to 16.7 μM. Single-point in vitro-in vivo extrapolation (IV-IVE) based on the human liver microsomal kinetic parameters obtained in the presence, but not absence, of BSA predicted in vivo hepatic clearances of PHEN O-deethylation and LID N-deethylation that were comparable to values reported in humans, although in vivo intrinsic clearances were underpredicted. Prediction of the in vivo clearances of the CYP1A2 substrates observed here represents an improvement on other experimental systems used for IV-IVE.
Serum vitamin D in hypertensive patients versus healthy controls is there an association?

Background: Both vitamin D deficiency and hypertension are prevalent in the general population. Several observations indicate an association between vitamin D deficiency and high blood pressure. The present case-control study aimed to compare serum 25-hydroxyvitamin D (25-OHD) in hypertensive patients versus healthy controls. Methods: One hundred patients aged 30-60 years with hypertension (HTN) and 100 healthy controls without history of hypertention were compared regarding serum 25-OHD. Blood pressure was measured using standard method and the systolic and diastolic blood pressure more than140 mmHg and 90 mmHg respectively were considered as HTN. Patients and controls with coexistent morbidities, vitamin D supplementation were excluded. The serum levels of 25-OHD, PTH and calcium were measured after obtaining a written informed consent from the patients and taking their blood pressure under standard conditions. In statistical analysis, the two groups were compared using independent t test and chi-square test using SPSS Version 18. Results: The mean age of patients and controls was comparable (53.7±6.4 vs 52.3±7.54 years, P=0.17). Serum 25-OHD in HTN was significantly higher than controls (P=0.001). Conclusion: In the present study, serum 25-OHD level in hypertension was higher than controls. The results contradict with earlier studies indicating an association of HTN with vitamin D deficiency. This issue warrants further investigations in particular the follow-up of serum 25-OHD deficient and sufficient subjects with regard to the development of HTN.
Light Converts Endosymbiotic Fungus to Pathogen, Influencing Seedling Survival and Niche-Space Filling of a Common Tropical Tree, Iriartea deltoidea

Pathogens are hypothesized to play an important role in the maintenance of tropical forest plant species richness. Notably, species richness may be promoted by incomplete filling of niche space due interactions of host populations with their pathogens. A potentially important group of pathogens are endophytic fungi, which asymptomatically colonize plants and are diverse and abundant in tropical ecosystems. Endophytes may alter competitive abilities of host individuals and improve host fitness under stress, but may also become pathogenic. Little is known of the impacts of endophytes on niche-space filling of their hosts. Here we evaluate how a widespread fungal endophyte infecting a common tropical palm influences its recruitment and survival in natural ecosystems, and whether this impact is modulated by the abiotic environment, potentially constraining host niche-space filling. Iriartea deltoidea dominates many wet lowland Neotropical forests. Diplodia mutila is a common asymptomatic endophyte in mature plants; however, it causes disease in some seedlings. We investigated the effects of light availability on D. mutila disease expression. We found I. deltoidea seedlings to preferentially occur under shady conditions. Correspondingly, we also found that high light triggers endophyte pathogenicity, while low light favors endosymbiotic development, constraining recruitment of endophyte-infested seedlings to shaded understory by reducing seedling survival in direct light. Pathogenicity of D. mutila under high light is proposed to result from light-induced production of H2O2 by the fungus, triggering hypersensitivity, cell death, and tissue necrosis in the palm. This is the first study to demonstrate that endophytes respond to abiotic factors to influence plant distributions in natural ecosystems; and the first to identify light as a factor influencing where an endophyte is placed on the endosymbiont–pathogen continuum. Our findings show that pathogens can indeed constrain niche-space filling of otherwise successful tropical plant species, providing unoccupied niche space for other species.
Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN.

BACKGROUND Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood. METHODS Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) -Cre or myogenin (MYOG) -Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)- Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided. RESULTS Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN ( f/f ) vs FLCN ( f/f ) /CKM-Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < . 001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney. CONCLUSION FLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation.
Variation of the Intercellular Space in the Esophageal Epithelium in Response to Hydrochloridric Acid Infusion in Patients with Erosive Esophagitis

ABSTRACT: The purpose of this study was to compare esophageal infusion with 0.1 N hydrochloridric acid (HCl) to esophageal infusion with saline in patients presenting with typical gastroesophageal reflux symptoms and erosive esophagitis. METHODS: Upper gastrointestinal endoscopy was performed on 44 prospective subjects, 29 of whom were included in the study. Eighteen patients presented with normal esophagi (Control Group “C”), nine of whom were infused with HCl and nine with saline. Eleven patients presented with erosive esophagitis (Lesion Group “L”), five of whom were infused with HCl and six with saline. Biopsies of the esophageal mucosa were collected before and after infusions. RESULTS: No statistically significant difference was found between the two types of infusions in terms of the dilation of the intercellular space of the esophageal epithelium, regardless of the status of the patient. CONCLUSIONS: Response to HCl infusion cannot be used as a marker for gastroesophageal reflux disease.
The influence of homework on the educational experiences of sixth grade students from low socio-economic backgrounds: A phenomenological study

The purpose of this transcendental phenomenological study was to describe the influence homework has on the educational experiences of sixth grade students from low socio-economic backgrounds at a middle school in a rural county located in the western region of North Carolina. Eight sixth grade students provided a visual narrative pertaining to homework, and participated in individual and focus group interviews. The major themes to emerge were (a) motivation: teacher policies and practices, (b) family interaction: time and attention, (c) self-efficacy: emotional aspect, and (d) educational effects: shortand long-term. Recommendations for future research include replication of the study in urban areas, the inclusion of seventh and eighth grade students, and increasing the number of male participants.
Use of periconceptional folic acid supplements in Victoria and New South Wales, Australia

Objectives:To determine the proportion of women who took folate supplementation prior to conception and in the first three months of pregnancy and/or increased folate dietary intake; to determine how folate supplementation varied with socio‐demographic factors; and to describe the ways women had seen or heard about folate prior to pregnancy.
An investigation of professional ballet dancers experiences of flow and motivations perspectives

This study investigates professional ballet dancers’ experiences of flow: an extraordinary state of consciousness, reached by the dancers when fully immersed in their performance, which allows them to function at the limit of their physical and mental abilities, enhancing levels of achievement. Dancers’ flow experiences and motivational tendencies were analysed by quantitative and qualitative methods in order to test the theoretical relationship between intrinsic motivation and flow, to understand the performers’ subjective experiences of this optimal psychological state, and to identify factors that may help or hinder the achievement of flow in ballet settings. Fifty-four elite professional ballet dancers completed questionnaires measuring motivation and flow, and four participants were interviewed on their subjective experiences. The results demonstrated that intrinsic motivation was only weakly associated with the occurrence of this optimal state. The most self-determined form of extrinsic motivation, integrated regulation, was the most effective form of motivation associated with the frequency and intensity of the dancers’ experience of flow. Clear Goals, concentration on the task at hand, and autotelic experience were the most endorsed dimensions of flow, while challenge-skills balance, unambiguous feedback, sense of control and autotelic experience were the most representative characteristics of the interviewees’ optimal experience. Confidence was found to be the most influential psychological facilitator or inhibitor of their optimal experience. Lights, setting, floor, props, costumes, and musical conductor, were unique environmental and social inhibitors specific to the ballet world.
A Mortar Finite Element Method Using Dual Spaces for the Lagrange Multiplier

The mortar finite element method allows the coupling of different discretization schemes and triangulations across subregion boundaries. In the original mortar approach the matching at the interface is realized by enforcing an orthogonality relation between the jump and a modified trace space which serves as a space of Lagrange multipliers. In this paper, this Lagrange multiplier space is replaced by a dual space without losing the optimality of the method. The advantage of this new approach is that the matching condition is much easier to realize. In particular, all the basis functions of the new method are supported in a few elements. The mortar map can be represented by a diagonal matrix; in the standard mortar method a linear system of equations must be solved. The problem is considered in a positive definite nonconforming variational as well as an equivalent saddle-point formulation.
Low-distance Surface Codes under Realistic Quantum Noise

We study the performance of distance-three surface code layouts under realistic multi-parameter noise models. We first calculate their thresholds under depolarizing noise. We then compare a Pauli-twirl approximation of amplitude and phase damping to amplitude and phase damping. We find the approximate channel results in a pessimistic estimate of the logical error rate, indicating the realistic threshold may be higher than previously estimated. From Monte-Carlo simulations, we identify experimental parameters for which these layouts admit reliable computation. Due to its low resource cost and superior performance, we conclude that the 17-qubit layout should be targeted in early experimental implementations of the surface code. We find that architectures with gate times in the 5-40 ns range and T1 times of at least 1-2 us range will exhibit improved logical error rates with a 17-qubit surface code encoding.
Plasma Total Homocysteine Levels and Methylenetetrahydrofolate Reductase Gene Polymorphism in Patients with Type 2 Diabetes Mellitus

Background: Thrombotic episodes account for approximately 80% of deaths in type 2 diabetic patients. Hyperhomocysteinaemia is a well recognized independent risk factor for atherosclerosis and thromboembolism. Increased homocysteine levels may occur due to a number of factors including inherited gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T. Here, we evaluate plas- ma total homocysteine (tHcy) levels and frequency of the MTHFR C677T gene polymorphism in asymptomatic healthy volunteers and type 2 diabetic patients with hypertension but without nephropathy. We have also investigated the relationship between tHcy levels and the presence of MTHFR C677T gene polymorphism. Methods: Plasma tHcy levels and MTHFR C677T genotype were investigated in a total of 53 subjects. These included asymptomatic healthy volunteers (n = 16), patients with type 2 diabetes (n = 7), subjects with hypertension (n = 12) and patients with both type 2 diabetes and hypertension (n = 18). Renal function, serum lipids and other metabolites were also assessed. Results: There was no significant difference in tHcy levels between the groups studied. The frequency of MTHFR C677T gene polymorphism observed was similar to that obtained for the general Brazilian population. In patients with type 2 diabetes and hypertension but without impaired renal function, we observed no meaningful correlation between increased tHcy levels and the presence of MTHFR C677T gene polymorphism. Conclusions: Type 2 diabetics who are homozygous or heterozygous for the MTHFR C677T gene polymorphism showed normal tHcy levels. Our results further suggest that diabetes without an associated adverse risk profile is not an independent correlate of increased tHcy levels.
Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A

ABSTRACT In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2–16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3× /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0–48.0] and 11.0 [0–55.0], respectively) compared with baseline (16.0 [0–56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A.
Use of Questionnaire-Based Measures in the Assessment of Listening Difficulties in School-Aged Children

Objectives: In this study, the authors assessed the potential utility of a recently developed questionnaire (Evaluation of Children’s Listening and Processing Skills [ECLiPS]) for supporting the clinical assessment of children referred for auditory processing disorder (APD). Design: A total of 49 children (35 referred for APD assessment and 14 from mainstream schools) were assessed for auditory processing (AP) abilities, cognitive abilities, and symptoms of listening difficulty. Four questionnaires were used to capture the symptoms of listening difficulty from the perspective of parents (ECLiPS and Fisher’s auditory problem checklist), teachers (Teacher’s Evaluation of Auditory Performance), and children, that is, self-report (Listening Inventory for Education). Correlation analyses tested for convergence between the questionnaires and both cognitive and AP measures. Discriminant analyses were performed to determine the best combination of tests for discriminating between typically developing children and children referred for APD. Results: All questionnaires were sensitive to the presence of difficulty, that is, children referred for assessment had significantly more symptoms of listening difficulty than typically developing children. There was, however, no evidence of more listening difficulty in children meeting the diagnostic criteria for APD. Some AP tests were significantly correlated with ECLiPS factors measuring related abilities providing evidence for construct validity. All questionnaires correlated to a greater or lesser extent with the cognitive measures in the study. Discriminant analysis suggested that the best discrimination between groups was achieved using a combination of ECLiPS factors, together with nonverbal Intelligence Quotient (cognitive) and AP measures (i.e., dichotic digits test and frequency pattern test). Conclusions: The ECLiPS was particularly sensitive to cognitive difficulties, an important aspect of many children referred for APD, as well as correlating with some AP measures. It can potentially support the preliminary assessment of children referred for APD.
Dopamine D1 and D3 receptors oppositely regulate NMDA‐ and cocaine‐induced MAPK signaling via NMDA receptor phosphorylation

Development of drug addiction involves complex molecular changes in the CNS. The mitogen‐activated protein kinase (MAPK) signaling pathway plays a key role in mediating neuronal activation induced by dopamine, glutamate, and drugs of abuse. We previously showed that dopamine D1 and D3 receptors play different roles in regulating cocaine‐induced MAPK activation. Although there are functional and physical interactions between dopamine and glutamate receptors, little is known regarding the involvement of D1 and D3 receptors in modulating glutamate‐induced MAPK activation and underlying mechanisms. In this study, we show that D1 and D3 receptors play opposite roles in regulating N‐methyl‐d‐aspartate (NMDA) ‐induced activation of extracellular signal‐regulated kinase (ERK) in the caudate putamen (CPu). D3 receptors also inhibit NMDA‐induced activation of the c‐Jun N‐terminal kinase and p38 kinase in the CPu. NMDA‐induced activation of the NMDA‐receptor R1 subunit (NR1), Ca2+/calmodulin‐dependent protein kinase II and the cAMP‐response element binding protein (CREB), and cocaine‐induced CREB activation in the CPu are also oppositely regulated by dopamine D1 and D3 receptors. Finally, the blockade of NMDA‐receptor reduces cocaine‐induced ERK activation, and inhibits phosphorylation of NR1, Ca2+/calmodulin‐dependent protein kinase II, and CREB, while inhibiting ERK activation attenuates cocaine‐induced CREB phosphorylation in the CPu. These results suggest that dopamine D1 and D3 receptors oppositely regulate NMDA‐ and cocaine‐induced MAPK signaling via phosphorylation of NR1.
Fatty Acid Export from the Chloroplast. Molecular Characterization of a Major Plastidial Acyl-Coenzyme A Synthetase from Arabidopsis1

Acyl-coenzyme A (CoA) synthetases (ACSs, EC 6.2.1.3) catalyze the formation of fatty acyl-CoAs from free fatty acid, ATP, and CoA. Essentially all de novo fatty acid synthesis occurs in the plastid. Fatty acids destined for membrane glycerolipid and triacylglycerol synthesis in the endoplasmic reticulum must be first activated to acyl-CoAs via an ACS. Within a family of nine ACS genes from Arabidopsis, we identified a chloroplast isoform,LACS9. LACS9 is highly expressed in developing seeds and young rosette leaves. Both in vitro chloroplast import assays and transient expression of a green fluorescent protein fusion indicated that the LACS9 protein is localized in the plastid envelope. A T-DNA knockout mutant (lacs9-1) was identified by reverse genetics and these mutant plants were indistinguishable from wild type in growth and appearance. Analysis of leaf lipids provided no evidence for compromised export of acyl groups from chloroplasts. However, direct assays demonstrated thatlacs9-1 plants contained only 10% of the chloroplast long-chain ACS activity found for wild type. The residual long-chain ACS activity in mutant chloroplasts was comparable with calculated rates of fatty acid synthesis. Although another isozyme contributes to the activation of fatty acids during their export from the chloroplast, LACS9 is a major chloroplast ACS.