Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical Characterization of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03–6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go–related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.
Impact d'un sevrage à l'alcool sur l'activité du réseau hippocampo-préfrontal au cours d'une épreuve de mémoire de travail : comparaison avec le stress chronique léger imprédictible

Notre etude a pour but de determiner l’implication de la corticosterone centrale sur l’activite du reseau hippocampe-cortex prefrontal (HPC-CPF) ainsi que son role dans l’emergence et le maintien d’alteration de la memoire de travail (MDT) durant l’alcoolisation chronique (12% durant 6 mois), ou bien apres un sevrage aigu (1semaine) ou prolonge (6 semaines). Les effets du sevrage ont egalement ete compares a ceux resultant d’un stress chronique leger impredictible (SCLI) modelisant la depression. Nos donnees montrent que le sevrage et le SCLI, mais non l’alcoolisation, induisent des troubles de MDT, un deficit d’activation de pCREB (CPF et HPC) ainsi qu’une augmentation excessive des taux de corticosterone specifiquement dans le CPF apres un sevrage. Sur le plan pharmacologique, l’inhibition de la synthese de la corticosterone restaure la MDT et l’activite de pCREB dans le CPF, chez les souris sevrees et SCLI. Nos resultats montrent egalement que l’augmentation de pCREB ou le blocage des recepteurs aux mineralocorticoides, dans le CPF, mais non dans l’HPC, restaure la MDT des souris sevrees. Ces resultats demontrent que la perturbation de taux de corticosterone dans le CPF joue un role cle dans l’emergence des troubles cognitifs et neuronaux apres un sevrage. Nous avons egalement montre qu’un traitement chronique au Diazepam attenue ces alterations transitoirement. Notre etude suggere que des composes agissant sur l'activite de l’axe corticotrope peuvent constituer des strategies alternatives pour prevenir l'emergence et le maintien des troubles cognitifs induits par le sevrage.
The Effects of Flaxseed on Menopausal Symptoms and Quality of Life

The purpose of this study was to analyze the effects of flaxseed on menopausal symptoms and quality of life throughout the menopausal period. The empirical research was conducted in an obstetrics and gynecology outpatient department of a university hospital and involved 140 menopausal women who were divided into 4 groups. The menopausal symptoms decreased and the quality of life increased among the women who used flaxseed for 3 months.
Quelques réflexions sur le diagnostic de la maladie d'Alzheimer

La maladie d’Alzheimer est definie par l’association de troubles cognitifs et comportementaux caracterisant un syndrome dementiel ; et par l’existence d’une perte neuronale, de plaques amyloides et de degenerescences neurofibrillaires a l’examen histologique du cerveau. Le diagnostic clinique de MA ne peut donc etre un diagnostic de certitude : il est probabiliste. Il repose sur une evaluation de l’efficience cognitive globale, de la memoire, des fonctions executives, des fonctions instrumentales, des troubles psycho-comportementaux et du retentissement des troubles sur la capacite a executer les activites de la vie quotidienne. Pour des raisons tenant autant au malade qu’a son entourage ou au medecin, la maladie d’Alzheimer est en France fortement sous diagnostiquee, et ce tout particulierement aux âges eleves. Quand il est porte, le diagnostic, en moyenne, est fait plus tardivement que dans les autres pays europeens ce qui constitue une perte de chance pour le patient. De nouveaux criteres diagnostiques ont ete recemment proposes qui permettent un diagnostique a la fois plus sur et plus precoce, au stade predementiel.
Three-dimensional dosimetry imaging of I-125 plaque for eye cancer treatment

Treatment of ocular cancers using eye plaque brachytherapy is now an established medical procedure. However, current QA for these eye plaques is quite rudimentary, limiting the opportunities for precise pretumour plaque customisation. This paper proposes and experimentally validates a new technique for imaging of eye plaque dose distributions using a high-resolution pixelated silicon detector. Results are presented demonstrating the 2D and 3D isodose surfaces produced using experimental data collected using this method.
Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro.

BACKGROUND Topotecan [(S)-9-dimethylaminomethyl(10-hydroxy-camptothecin), NSC 609699, SK&F 104864A], a semisynthetic analogue of the natural product camptothecin, is a cell cycle-specific drug that exerts antineoplastic activity through inhibition of topoisomerase I. Currently, topotecan is undergoing phase I and early phase II clinical trials. The dose-limiting toxicity for topotecan is myelosuppression. PURPOSE Our purpose was to determine plasma concentrations and exposure times necessary for optimal clinical activity and tumor types that may be responsive in phase II clinical studies of topotecan. METHODS A soft-agar cloning system assay was used to determine the in vitro effects of topotecan against cells from biopsy specimens of colorectal, breast, lung, ovarian, renal cell, and gastric cancers and cancers of unknown primary origin. We studied 141 freshly explanted tumor specimens, using 1-hour exposure to topotecan, and 80 were studied using continuous exposure. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in controls. RESULTS With 1-hour exposure, in vitro responses were seen in 10% and 25% of assessable tumor specimens at final topotecan concentrations of 1.0 and 10.0 micrograms/mL, respectively. With continuous exposures at concentrations of 0.1 and 1.0 micrograms/mL, in vitro response rates were 34% and 76%, respectively. Specific activity was seen against colorectal, breast, non-small-cell lung, ovarian, and renal cell cancers, with responses observed in 27%, 25%, 32%, 39%, and 83%, respectively, of assessable tumor specimens after continuous exposure to 0.1 micrograms/mL topotecan. A subset of tumor specimens resistant to doxorubicin or fluorouracil was sensitive to topotecan, and the difference in sensitivity was statistically significant. In addition, some of the tumor specimens resistant to cyclophosphamide and etoposide were also sensitive to topotecan. CONCLUSIONS Topotecan appears to be active in vitro against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. If plasma levels of 0.1 micrograms/mL can be achieved for prolonged periods of time in ongoing clinical trials, topotecan should have substantial clinical activity. IMPLICATIONS Further clinical development of topotecan is warranted.
Dual Income Taxes: A Nordic Tax System

This paper discusses the principles and practices of dual income taxation in the Nordic countries. The first part of the paper explains the rationale and the historical background for the introduction of the dual income tax and describes the current Nordic tax practices. The second part of the paper focuses on the problems of taxing income from small businesses and the issue of corporate-personal tax integration under the dual income tax, considering alternative ways of dealing with these challenges. In the third and final part of the paper, I briefly discuss whether introducing a dual income tax could be relevant for New Zealand.
Reactivation of retinopathy of prematurity after bevacizumab injection.

OBJECTIVE To report late reactivation and progression of retinopathy of prematurity (ROP) after intravitreal bevacizumab monotherapy. METHODS Retrospective review of 9 patients (17 eyes) with recurrence of ROP after initial treatment with intravitreal bevacizumab monotherapy. Data collected included (1) location and stage of ROP activity, (2) number and timing of treatments, and (3) structural outcomes. RESULTS Mean age at treatment-requiring recurrence was 49.3 weeks (SD, 9.1 weeks; minimum, 37 weeks; maximum, 69 weeks) postmenstrual age (PMA). The mean time between initial treatment and treatment-requiring recurrence was 14.4 weeks, with a minimum of 4 and maximum of 35 weeks. Fives eyes progressed to retinal detachment (4 eyes stage 5, 1 eye stage 4a). Age at retinal detachment ranged from 49 to 69 weeks PMA with a median of 55 weeks PMA and mean of 58.4 weeks PMA. No eye that received laser treatment for recurrence progressed to retinal detachment. CONCLUSIONS Although intravitreal bevacizumab treatment is effective in inducing regression of ROP, the effect may be transient. Recurrence can occur later in the course than with conventional laser therapy. Late retinal detachment can occur despite early regression. Longterm favorable structural outcome may require extended observation and retreatment. Laser may be a useful treatment for recurrences.
A brief questionnaire on metacognition: Psychometric properties

Objectives: Existing questionnaires on personal views of one's own cognitive functioning are either unduly long, restrict their focus on memory, and/or capture complaints rather than the general status quo. A brief 9-item questionnaire was developed, assessing metacognition with two subscales covering metamemory and metaconcentration. Methods: The questionnaire was tested in a sample of healthy women (n = 228) aged 70–93 years, during two face-to-face interviews with an interval of 6 months. Results: Subscales were confirmed to have factorial validity. While objective cognitive test performance did not predict self-reported everyday functioning, metamemory and metaconcentration accounted for a substantial amount of its variance. The newly developed instrument was shown to be predominantly characterized by latent trait variance components. Conclusion: The presented questionnaire is advantageous for the assessment of metacognition as it is brief and easily applicable. Since metacognition is highly relevant for sustained independence in old age, the questionnaire is suitable to capture important determining factors in research on aging phenomena and processes.
CELL-FREE PEPTIDE SYNTHESIS DEPENDENT UPON SYNTHETIC OLIGODEOXYNUCLEOTIDES.

13 Molecular nitrogen inhibits production of hydrogen gas from thiosulfate [Losada, M. , M. Nozaki, and D. I. Arnon, in Light and Life (Baltimore: Johns Hopkins Press, 1961), p. 570]. 14 Roberts, R. B. , D. B. Cowie, P. H. Abelson, E. I. Bolton, and R. J. Britten, in Studies of Biosynthesis in E. coli, Carnegie Inst. Wash. Publ. 607, 1957. '5 Sadler, W. R. , and R. Y. Stanier, these PROCEEDINGS, 46, 1328 (1960). 16 Schatz, A. , J. Gen. Microbiol. , 6, 329 (1952). 17 Baalsrud, K. , and K. S. Baalsrud, in Phosphorus Metabolism (Baltimore: Johns Hopkins Press, 1952), vol. 2, p. 544; Arch. Mikrobwol. , 20, 34 (1954). 18 Clayton, R. K. , Ann. Rev. Plant Physiol. , 14, 159 (1963). 19 Frenkel, A. W. , in Light and Life (Baltimore: Johns Hopkins Press, 1961), p. 587. 20 Larsen, H. , J. Biol. Chem., 193, 167 (1951). 21 Gaffron, H. , in Plant Physiology (New York: Academic Press, 1960), vol. 1B, pp. 3-277. 22 Franck, J., in Handbuch der Pflanzenphysiologie (Berlin: Springer-Verlag, 1960), vol. 5, pp. 689-735.
Modeling of electric vehicles dynamics with Multi-Bond Graphs

The construction of a model that represents the behavior of an Electric Vehicle is studied in detail. The contribution of this work is twofold. On one hand an efficient and compact way to model dynamical systems is introduced. On the other hand, the power interchange between the electrical and mechanical sub-models allows a deep understanding of the dynamics involved in electrically driven vehicles. The approach used to model the mechanical parts (chassis, suspension, wheels) and the induction motors is the Multi-Bond Graph based in models discussed in recent literature. Then these models are integrated in order to form the complete model that simulates the whole system dynamics. Simulation results are aimed to illustrate the electromechanical interaction (ABS, regenerative braking, etc) as well as the evolution of certain variables during a risky situation. Conclusions are obtained based on these results.
Revising the Brand Evolution Stage Model-a Case Study of an Asian IT Company

The Goodyear (1996) brand evolution stage model suggests a possible brand evolution process. It comprises six stages, namely unbranded goods, brand as reference, brand as personality, brand as icon, brand as company, and brand as policy. However, the Goodyear model is just a general and conceptual model. This study responds to the call of McEnally and de Chernatony (1999) for substantial empirical study of the Goodyear brand evolution stage conceptual model. This study considered the case of an Asian IT company, Trend Micro. The results of this case study indicate that there are three brand evolution stages existing in the companies in the IT industry context. The author’s revised brand evolution stage model proposed that the sequence of the brand evolution stage model in the IT industry context is brand as identity, brand as reference, and brand as company. For the IT companies, the author revises the brand evolution stage model and suggests that the brand as company stage immediately follows the brand as reference stage and the IT companies may not experience the brand as personality and brand as icon stages.
Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by genomic expansions of CTG or CCTG repeats. When transcribed, these mutations give rise to repeat expansion RNAs that form nuclear inclusions and compromise the function of myonuclei. Here, we have used in situ hybridization and immunofluorescence to compare DM1 and DM2 and search for proteins that associate with the RNA nuclear (ribonuclear) inclusions. Although muscle disease is generally more severe in DM1, the ribonuclear inclusions were 8‐ to 13‐fold more intense in DM2, implying greater amounts of repeat expansion RNA. Expression of repeat expansion RNA in myoblasts has been implicated in the pathogenesis of congenital DM1. However, we found that repeat expansion RNA is also expressed in myoblasts in DM2, a disorder that has not been associated with a congenital phenotype. Of 10 putative CUG binding proteins tested for colocalization with mutant RNA, only proteins in the muscleblind family were recruited into ribonuclear inclusions. Previous studies have shown activation of the protein kinase, PKR, by expanded CUG repeats in vitro. However, breeding experiments utilizing PKR knockout mice indicate that this kinase is not required for disease pathogenesis in a transgenic mouse model of DM1. We conclude that ribonuclear inclusions are a key feature of the muscle pathology in DM and that sequestration of muscleblind proteins may have a direct role in the disease process. Ann Neurol 2003;54:760–768
Incidencia y circulación del virus dengue en el estado Zulia, Venezuela (2009-2010)

El Estado Zulia historicamente ha sido afectado por epidemias de Dengue. Esta enfermedad afecta diferentes regiones del continente, cuyo agente etiologico tiene antecedente de circulacion en la zona debido, entre otras causas, a la proliferacion de su vector principal Aedes aegypti. El objetivo de este estudio fue determinar la incidencia y circulacion del virus dengue en el Estado Zulia-Venezuela, desde enero 2009 a diciembre 2010. A un total de 8.279 sueros de pacientes con clinica de infeccion por virus dengue, se les determinaron anticuerpos IgM (n=8.279) e IgG anti-dengue (n=196) por Elisa de captura, el aislamiento viral se realizo en cultivo de celulas C6/36 y la identificacion por Inmunofluorescencia Indirecta. El estudio arrojo 70,32% de seropositividad (5.822/8.279), homogeneamente distribuida entre los grupos, con mayor gravedad en los adolescentes, adultos jovenes y tercera edad con circulacion de los serotipos DENV-3 y 4. Se encontro una frecuencia mayor (p
Differentially Private Variance Reduced Stochastic Gradient Descent

In this paper, we propose a differentially private stochastic variance reduced gradient algorithm, called DP-SVRG. To privatize SVRG algorithm, we randomize the gradient computation process by injecting random noise.There are two main challenges in this approach: (i) high variance of stochastic gradient updates, and (ii) low per-iteration privacy budget. To cope with these challenges, we employ two advanced techniques recently introduced in the literature. First, we apply control variate technique to stochastic gradient update, shown to effective inreducing the variance. Second, we use the tight composition theorem of zero-concentrated differential privacy (zCDP) toeffectively bound the cumulative privacy cost.To show the effectiveness of the proposed algorithm, we conduct empirical evaluations on a set of real datasets and compare our algorithm with existing approaches.
Genetic variation at the estrogen receptor α locus in relation to venous thromboembolism risk among postmenopausal women

Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Blood 2002; 100: 3229–32. 4 Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 541–4. 5 Rost S, FreginA, Ivaskevicius V, ConzelmannE,HortnagelK, PelzHJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537–41. 6 Harrington DJ, Underwood S, Morse C, Shearer MJ, Tuddenham EG, Mumford AD. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thromb Haemost 2005; 93: 23–6. 7 Kereveur A, Leclercq M, Trossaert M, Dupeyron JP, Parent F, Horellou MH, Conard J, Bachmann F, Samama MM. Vitamin K metabolism in a patient resistant to vitamin K antagonists.Haemostasis 1997; 27: 168–73.
Emergency Preparedness for Home Healthcare Providers

Unfortunately, disasters occur. We cannot always know the effects ahead of time, but we do know that lives can be lost, property damaged, and public health and home care agencies may not be able to provide the normal standard of care. Studies have shown that disaster preparedness content is limited in U.S. nursing programs (Weiner et al., 2005). Given the magnitude of recent natural disasters, such as the Japanese earthquake and tsunami in 2011, these findings are alarming. The increasing demands on healthcare providers in response to emergencies force home healthcare clinicians to identify their roles and responsibilities in emergency preparedness. This article discusses 1 model of disaster response and the role of the home healthcare provider at each stage. It further guides home healthcare nurses in creating a personal and professional plan, enabling them to understand how to minimize the impact of disasters and address the needs of their patients and those close to them.
Hardware design on an FPGA chip of impedance force control for interaction between a human operator and a robot arm

This paper presents the development of interface hardware for interaction between robot arms called the ROBOKER and human arms. Hardware design of impedance force control scheme along with the robust position control method on a single FPGA chip by the hardware description language is presented. Force induced by a human operator is transformed into a position command for the robot arm to move so that it mimics handshaking between a robot arm and a human operator. To achieve better interaction of feeling, position commands are filtered by the impedance function. Experimental results confirm the functionality of the designed hardware implementation. Successful experiments are demonstrated.
Decentralized hybrid control of multi-agent systems

This work introduces a decentralized hybrid control scheme for a class of nonlinear control of multi-agent systems with dynamical connections. The idea behind this approach is to adapt hybrid control laws to improve the convergence rate and connectedness of the multi-agent system. The consensus property is established by means of the common Lyapunov function approach, and a numerical example is provided to exhibit the effectiveness of the proposed scheme.