Miracle-dz/UniFAR-FTUs huggingface dataset:
Thiopurine Drugs Repositioned as Tyrosinase 2 Inhibitors 3

In this study, we repositioned thiopurine drugs used for the treatment of acute 12 leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two distinct and successive 13 oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) 14 and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule 15 inhibitors of tyrosinase for therapeutic, cosmetic, and agricultural purposes. Structure-based 16 virtual screening has predicted inhibitor candidates for mushroom tyrosinase from drugs 17 approved by the US Food and Drug Administration (FDA). Enzyme assays have confirmed the 18 thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor. Two other thiopurine drugs, 19 mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibitory activity; 20 mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a 21 poor inhibitor. The inhibitory constants of thioguanine and mercaptopurine were calculated as 22 52 and 16 μM, respectively, and the value of mercaptopurine was comparable to that of the 23 well-known inhibitor kojic acid (13 μM). The cell lysate and melanin content assay in B16F10 24 melanoma cells confirmed that the compounds inhibited mammalian tyrosinase. In particular, 25 50 μM thioguanine reduced the melanin content by 57% without cytotoxicity. Furthermore, 26 the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors. 27
Association of Intravascular Ultrasound- and Optical Coherence Tomography-Assessed Coronary Plaque Morphology With Periprocedural Myocardial Injury in Patients With Stable Angina Pectoris.

BACKGROUND Periprocedural myocardial injury (PMI) is not an uncommon complication and is related to adverse cardiac events after percutaneous coronary intervention (PCI). We investigated the predictors of PMI in patients with stable angina pectoris (SAP) on intravascular imaging. METHODSANDRESULTS We enrolled 193 SAP patients who underwent pre-PCI intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Clinical characteristics, lesion morphology, and long-term follow-up data were compared between patients with and without PMI, defined as post-PCI elevation of high-sensitivity cardiac troponin-T. PMI were observed in 79 patients (40.9%). Estimated glomerular filtration rate (odds ratio [OR], 0.973; 95% confidence interval [CI]: 0.950-0.996; P=0.020), ≥2 stents (OR, 3.100; 95% CI: 1.334-7.205; P=0.009), final myocardial blush grade 0-2 (OR, 4.077; 95% CI: 1.295-12.839; P=0.016), and IVUS-identified echo-attenuated plaque (EA; OR, 3.623; 95% CI: 1.700-7.721; P<0.001) and OCT-derived thin-cap fibroatheroma (OCT-TCFA; OR, 3.406; 95% CI: 1.307-8.872; P=0.012) were independent predictors of PMI on multivariate logistic regression analysis. A combination of EA and OCT-TCFA had an 82.4% positive predictive value for PMI. On Cox proportional hazards analysis, PMI was an independent predictor of adverse cardiac events during 1-year follow-up (hazard ratio, 2.984; 95% CI: 1.209-7.361; P=0.018). CONCLUSIONS Plaque morphology assessment using pre-PCI IVUS and OCT may be useful for predicting PMI in SAP patients.
Phthalate pathway of phenanthrene metabolism: formation of 2'-carboxybenzalpyruvate

The metabolism of phenanthrene by a gram-negative organism able to use this compound as a sole source of carbon and energy has been examined. 1-Hydroxy-2-naphthoic acid was oxidized by oxygen in a reaction catalyzed by a dioxygenase which was activated by ferrous ions. The stoichiometry of the oxidation and the UV spectrum of the product were consistent with the identification of the product as 2'-carboxybenzalpyruvate. This was confirmed by cleaving the product with a partially purified aldolase to yield 2-carboxybenzaldehyde and pyruvate. A number of enzymes for the metabolism of 1-hydroxy-2-naphthoic acid were induced by growth on phthalate or (less well) by growth on protocatechuate. The latter supported only a slow rate of growth, and this and poor induction may have been due to a slow rate of entry into the cell.
Exponentially Stretching Sheet in a Powell–Eyring Fluid: Numerical and Series Solutions

This work theoretically examines the flow and heat transfer characteristics due to an exponentially stretching sheet in a Powell-Eyring fluid. Governing partial differential equations are nondimensionalized and transformed into non-similar forms. Explicit analytic expressions of velocity and temperature functions are developed by homotopy analysis method (HAM). The Numerical solutions are obtained by using shooting method with fourth-order Runge-Kutta integration technique. The fields are influence appreciably with the variation of embedding parameters. We noticed that the velocity ratio has a dual behaviour on the momentum boundary layer. On the other hand the thermal boundary layer thins when the velocity ratio is increased. The results indicate a significant increase in the velocity and a decrease in thermal boundary layer thickness with an intensification in the viscoelastic effects.
‘Ein Deutsches Trauma?’: Zur Schamlosigkeit Deutscher Opferidentifikation

Der Artikel kritisiert anhand von Habbo Knochs Dissertation Die Tat als Bild und Aleida Assmanns Essay Ein deutsches Trauma eine Tendenz in der bundesdeutschen Wissenschaft, die Traumatisierung aufgrund der Vernichtung der europaischen Juden mit einer Traumatisierung der Deutschen durch Bilder von der Befreiung der Konzentrationslager gleichzusetzen. Die Kontinuitat deutscher Opferidentifikation ist in diesem Diskurs vollig vergessen und so fortgeschrieben. In einem ersten Teil wird deshalb anhand von popularen Bildern Erich Ohsers und A. Paul Webers von 1942/43 die Kontinuitat der Darstellung der Deutschen als Opfer nachgezeichnet, die sich in Schreckensbildern mit Leichenbergen materialisiert. Im zweiten Teil wird ein Begriff der Scham entwickelt, der an Primo Levis ‘Scham, ein Mensch zu sein’ anschliest. Dieser kritisiert Aleida Assmans Begriff einer deutschen Scham aufgrund eines Traumas durch die Betrachtung von Schreckensbildern.
Assorted Mutations in the Envelope Gene of Simian Immunodeficiency Virus Lead to Loss of Neutralization Resistance against Antibodies Representing a Broad Spectrum of Specificities

ABSTRACT Simian immunodeficiency virus (SIV) of macaques isolate SIVmac239 is highly resistant to neutralization by polyclonal antisera or monoclonal antibodies, a property that it shares with most primary isolates of human immunodeficiency virus type 1 (HIV-1). This resistance is important for the ability of the virus to persist at high levels in vivo. To explore the physical features of the viral envelope complex that contribute to the neutralization-resistant phenotype, we examined a panel of SIVmac239 derivatives for sensitivity to neutralization by a large collection of monoclonal antibodies (MAbs). These MAbs recognize both linear and conformational epitopes throughout the viral envelope proteins. The variant viruses included three derivatives of SIVmac239 with substitutions in specific N-linked glycosylation sites of gp120 and a fourth variant that lacked the100 amino acids that encompass the V1 and V2 loops. Also included in this study was SIVmac316, a variant of SIVmac239 with distributed mutations in env that confer significantly increased replicative capacity in tissue macrophages. These viruses were chosen to represent a broad range of neutralization sensitivities based on susceptibility to pooled, SIV-positive plasma. All three of these very different kinds of mutations (amino acid substitutions, elimination of N-glycan attachment sites, and a 100-amino-acid deletion spanning variable loops V1 and V2) dramatically increased sensitivity to neutralization by MAbs from multiple competition groups. Thus, the mutations did not simply expose localized epitopes but rather conferred global increases in neutralization sensitivity. The removal of specific N-glycan attachment sites from V1 and V2 led to increased sensitivity to neutralization by antibodies recognizing epitopes from both within and outside of the V1-V2 sequence. Surprisingly, while most of the mutations that gave rise to increased sensitivity were located in the N-terminal half of gp120 (surface subunit [SU]), the greatest increases in sensitivity were to MAbs recognizing the C-terminal half of gp120 or the ectodomain of gp41 (transmembrane subunit [TM]). This reagent set and information should now be useful for defining the physical, structural, thermodynamic, and kinetic factors that influence relative sensitivity to antibody-mediated neutralization.
Neu Differentiation Factor Inhibits EGF Binding

Neu differentiation factor (NDF, or heregulin) and epidermal growth factor (EGF) are structurally related proteins that bind to distinct members of the ErbB family of receptor tyrosine kinases. Here we show that NDF inhibits EGF binding in a cell type-specific manner. The inhibitory effect is distinct from previously characterized mechanisms that involve protein kinase C and receptor internalization because it occurred at 4°C and displayed reversibility. The extent of inhibition correlated with both receptor saturation and affinity of different NDF isoforms, and it was abolished upon overexpression of either EGF receptor or ErbB-2. Binding kinetics and equilibrium analyses indicated that NDF reduced the affinity, rather than the number, of EGF receptors, through an acceleration of the rate of ligand dissociation and deceleration of the association rate. On the basis of co-immunoprecipitation of EGF and NDF receptors, we attribute the inhibitory effect to the formation of receptor heterodimers. According to this model, EGF binding to NDF-occupied heterodimers is partially blocked. This model of negative trans-regulation within the ErbB family is relevant to other subgroups of receptor tyrosine kinases and may have physiological implications.
Multipath Translation Lexicon Induction via Bridge Languages

This paper presents a method for inducing translation lexicons based on transduction models of cognate pairs via bridge languages. Bilingual lexicons within languages families are induced using probabilistic string edit distance models. Translation lexicons for arbitrary distant language pairs are then generated by a combination of these intra-family translation models and one or more cross-family on-line dictionaries. Up to 95% exact match accuracy is achieved on the target vocabulary (30-68% of inter-family test pairs). Thus substantial portions of translation lexicons can be generated accurately for languages where no bilingual dictionary or parallel corpora may exist.
Altered platelet plug formation in hyperthyroidism and hypothyroidism.

OBJECTIVE Patients with thyroid diseases have abnormalities of blood coagulation including an alteration of von Willebrand factor (vWF) levels. Because vWF plays an important role in primary hemostasis, we hypothesized that heightened and decreased vWF levels in hyper- and hypothyroidism enhance and decrease platelet plug formation, respectively. METHODS We followed a cohort of 120 patients with overt hyperthyroidism, patients with subclinical and overt hypothyroidism, and euthyroid controls. vWF and in vitro platelet plug formation as collagen-epinephrine-induced closure time (CEPI-CT) were measured at baseline and during therapy with thiamazole or T(4). RESULTS Baseline vWF levels were higher in patients with hyperthyroidism and lower in patients with overt hypothyroidism than in controls (P < 0.01). High vWF antigen levels were associated with increased baseline platelet plug formation in patients with hyperthyroidism as compared with controls [114 sec (95% confidence interval, 105-122 sec) vs. 130 sec (120-140 sec), P = 0.01]. After 8 wk of therapy with thiamazole, serum concentrations of T(4) and vWF levels decreased to normal values (P < 0.01 vs. baseline), and CEPI-CT was prolonged as compared with baseline (P < 0.01). During therapy with T(4), vWF levels increased (P < 0.05 vs. baseline) and CEPI-CT was shortened as compared with baseline (P < 0.01). CONCLUSION Hyperthyroidism-induced vWF elevation is associated with enhanced platelet function and therefore shortened CEPI-CT values. These changes may contribute to the higher risk for cardiovascular disease in patients with hyperthyroidism. Platelet plug formation decreases during therapy with thiamazole. Furthermore, CEPI-CT appears to be sensitive to detect acquired von Willebrand disease associated with overt hypothyroidism.
First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial.

PURPOSE Erlotinib prolonged survival of unselected patients with advanced non-small-cell lung cancer (NSCLC) who were not eligible for further chemotherapy, and two phase II studies suggested it might be an alternative to first-line chemotherapy. A randomized phase III trial was designed to test whether first-line erlotinib followed at progression by cisplatin-gemcitabine was not inferior in terms of survival to the standard inverse sequence. PATIENTS AND METHODS Patients with stage IIIB (with pleural effusion or supraclavicular nodes) to IV NSCLC and performance status of 0 to 1 were eligible. With a 95% CI upper limit of 1.25 for the hazard ratio (HR) for death, 80% power, a one-sided α = . 025, and two interim analyses, a sample size of 900 patients was planned. RESULTS At the first planned interim analysis with half the events, the inferiority boundary was crossed, and the Independent Data Monitoring Committee recommended early termination of the study. Seven hundred sixty patients (median age, 62 years; range, 27 to 81 years) had been randomly assigned. Baseline characteristics were balanced between study arms. As of June 1, 2011, median follow-up was 24.3 months, and 536 deaths were recorded (263 in the standard treatment arm and 273 in the experimental arm). Median survival was 11.6 months (95% CI, 10.2 to 13.3 months) in the standard arm and 8.7 months (95% CI, 7.4 to 10.5 months) in the experimental arm. Adjusted HR of death in the experimental arm was 1.24 (95% CI, 1.04 to 1.47). There was no heterogeneity across sex, smoking habit, histotype, and epidermal growth factor receptor (EGFR) mutation. CONCLUSION In unselected patients with advanced NSCLC, first-line erlotinib followed at progression by cisplatin-gemcitabine was significantly inferior in terms of overall survival compared with the standard sequence of first-line chemotherapy followed by erlotinib.
Extinction retention predicts improvement in social anxiety symptoms following exposure therapy

Background: Several researchers have argued that basic research on extinction learning can guide efforts to enhance the efficacy of exposure‐based therapy. At the basis of this translational research paradigm is the assumption that extinction retention is important to the outcome of exposure‐based therapy. This study is the first to examine the relationship between extinction retention, which comprises the amount of fear reduction that is retained between two exposure sessions and improvement in anxiety symptoms following exposure treatment. Methods: Adults (N=90), participating in two separate studies, who received three sessions of repeated exposure to public speaking provided ratings of peak fear during exposure treatment and completed the Liebowitz Social Anxiety ScaleSelf—Report version, LSAS‐SR, Baker et al. [2002: Behav Res Ther 40:701–715] at baseline, posttreatment, and follow‐up. Results: After controlling for within‐session extinction, extinction retention accounted for significant variance in the improvement of LSAS‐SR scores over time. Conclusions: Our findings suggest that the consolidation of extinction learning into long‐term memory is associated with improvements in fear and avoidance related to social situations following exposure therapy. Implications for exposure therapy augmentation studies are discussed. Depression and Anxiety, 2009. ©2008 Wiley‐Less, Inc.
Gray Matter Growth Is Accompanied by Increasing Blood Flow and Decreasing Apparent Diffusion Coefficient during Childhood

BACKGROUND AND PURPOSE: Normal values of gray matter volume, cerebral blood flow, and water diffusion have not been established for healthy children. We sought to determine reference values for age-dependent changes of these parameters in healthy children. MATERIALS AND METHODS: We retrospectively reviewed MR imaging data from 100 healthy children. Using an atlas-based approach, age-related normal values for regional CBF, apparent diffusion coefficient, and volume were determined for the cerebral cortex, hippocampus, thalamus, caudate, putamen, globus pallidus, amygdala, and nucleus accumbens. RESULTS: All gray matter structures grew rapidly before the age of 10 years and then plateaued or slightly declined thereafter. The ADC of all structures decreased with age, with the most rapid changes occurring prior to the age of 5 years. With the exception of the globus pallidus, CBF increased rather linearly with age. CONCLUSIONS: Normal brain gray matter is characterized by rapid early volume growth and increasing CBF with concomitantly decreasing ADC. The extracted reference data that combine CBF and ADC parameters during brain growth may provide a useful resource when assessing pathologic changes in children.
Serum 25-hydroxyvitamin D concentrations and cardiometabolic risk factors in adolescents and young adults

Abstract Evidence associating serum 25-hydroxyvitamin D (25(OH)D) concentrations and cardiometabolic risk factors is inconsistent and studies have largely been conducted in adult populations. We examined the prospective associations between serum 25(OH)D concentrations and cardiometabolic risk factors from adolescence to young adulthood in the West Australian Pregnancy Cohort (Raine) Study. Serum 25(OH)D concentrations, BMI, homoeostasis model assessment for insulin resistance (HOMA-IR), TAG, HDL-cholesterol and systolic blood pressure (SBP) were measured at the 17-year (n 1015) and 20-year (n 1117) follow-ups. Hierarchical linear mixed models with maximum likelihood estimation were used to investigate associations between serum 25(OH)D concentrations and cardiometabolic risk factors, accounting for potential confounders. In males and females, respectively, mean serum 25(OH)D concentrations were 73·6 (sd 28·2) and 75·4 (sd 25·9) nmol/l at 17 years and 70·0 (sd 24·2) and 74·3 (sd 26·2) nmol/l at 20 years. Deseasonalised serum 25(OH)D3 concentrations were inversely associated with BMI (coefficient −0·01; 95 % CI −0·03, −0·003; P=0·014). No change over time was detected in the association for males; for females, the inverse association was stronger at 20 years compared with 17 years. Serum 25(OH)D concentrations were inversely associated with log-HOMA-IR (coefficient −0·002; 95 % CI −0·003, −0·001; P<0·001) and positively associated with log-TAG in females (coefficient 0·002; 95 % CI 0·0008, 0·004; P=0·003). These associations did not vary over time. There were no significant associations between serum 25(OH)D concentrations and HDL-cholesterol or SBP. Clinical trials in those with insufficient vitamin D status may be warranted to determine any beneficial effect of vitamin D supplementation on insulin resistance, while monitoring for any deleterious effect on TAG.
Hydroxyurea in Children with Sickle Cell Disease: Impact on Splenic Function and Compliance with Therapy

Purpose: Hydroxyurea therapy reduces clinical complications in sickle cell disease. While evaluating the clinical and laboratory responses to hydroxyurea in children with sickle cell disease, we concurrently objectively monitored, for the first time during such treatment, compliance with therapy. Because most deaths in affected children are related to infection, we also evaluated the impact of hydroxyurea on splenic function, estimated by the percentage of red cells containing endocytic vacuoles (“pitted” cells) over 1 year of therapy. Patients and Methods: Seventeen children with a history of ⩾3 hospital admissions in the previous year, aged (mean ± standard error of mean) 12.3 ± 1.2 years, were treated with hydroxyurea. Clinical and laboratory assessments monitored efficacy and toxicity. Compliance was monitored using computerized pill bottles containing cap microprocessors which monitor the frequency of bottle openings. Results: Over 18.5 ± 2.1 months, compliance with hydroxyurea (as determined by percent of the perscribed drug actually taken) was 96 ± 2%, resulting in increases in mean fetal hemoglobin from 7.7 ± 1.6% to 16.7 ± 1.8% (p <0.005). In 11 patients who reached maximum tolerated doses, an increase to 18.8 ± 2.5% (p = 0.0001) was observed. Pitted red cell counts did not change. Annual rates of vaso-occlusive crisis (p = 0.0105), acute chest syndrome (p = 0.0417), transfusions administered (p = 0.0168), and days in hospital (p = 0.0017) all decreased significantly. Conclusions: Hydroxyurea in children is associated with sustained excellent compliance and monitoring this compliance is uncomplicated. Splenic function in most hydroxyurea-treated children did not change over 1 year of therapy.
Gaze-related activity of putative inhibitory burst neurons in the head-free cat.

1. Previous studies in the cat have demonstrated that output neurons of the superior collicular as well as brain stem omnipause neurons have discharges that are best correlated, not with the trajectory of the eye in the head but, with the trajectory of the visual axis in space (gaze = eye-in-head + head-in-space) during rapid orienting coordinated eye and head movements. In this study, we describe the gaze-related activity of cat premotor "inhibitory burst neurons" (IBNs) identified on the basis of their position relative to the abducens nucleus. 2. The firing behavior of IBNs was studied during 1) saccades made with the head stationary, 2) active orienting combined eye-head gaze shifts, and 3) passive movements of the head on the body. IBN discharges were well correlated with the duration and amplitude of saccades made when the head was stationary. In both head-free paradigms, the behavior of cat IBNs differed from that of previously described primate "saccade bursters". The duration of their burst was better correlated with gaze than saccade duration, and the total number of spikes in a burst was well correlated with gaze amplitude and generally poorly correlated with saccade amplitude. The behavior of cat IBNs also differed from that of previously described primate "gaze bursters". The slope of the relationship between the total number of spikes and gaze amplitude observed during head-free gaze shifts was significantly lower than that observed during head-fixed saccades. 3. These studies suggest that cat IBNs do not fit into the categories of gaze-bursters or saccade-bursters that have been described in primate studies. (ABSTRACT TRUNCATED AT 250 WORDS)
Efficacité du Pentathlon en équipe auprès d’élèves provenant de différents milieux socio-économiques

Cet article s’interesse a l’efficacite du Pentathlon en equipe, un programme cree pour promouvoir la pratique d’activites physiques chez les jeunes. Pendant six semaines, le programme a ete implante aupres de 104 jeunes dans des ecoles primaires de la region de Quebec appartenant a trois milieux socio-economiques differents et des groupes controles ont servi de comparatifs pour l’etude. Les resultats demontrent que la majorite des jeunes (77%) a ete active pendant l’implantation du Pentathlon en equipe, independamment de leur genre ou leur milieu socio-economique d’origine. Ces resultats sont superieurs a ceux des enquetes sur l’activite physique des jeunes. Ils offrent donc des perspectives interessantes pour le developpement des strategies d’intervention qui visent une gestion autonome de la pratique d’activites physiques par les jeunes.