Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical relevance of pharmacokinetic and pharmacodynamic properties of edoxaban when treating patients with atrial fibrillation and heart failure

ABSTRACT Introduction: Atrial fibrillation (AF) is an independent risk factor for stroke. It is most prevalent in the elderly and frequently coexists with heart failure (HF). The joint occurrence of AF and HF further worsens prognosis. The prevention of thromboembolism is crucial in the management of AF. In recent years, new oral anticoagulants (NOACs) have been licensed for the prevention of stroke and systemic embolism in patients with AF. Areas covered: This article reviews the key published studies on the pharmacology, clinical efficacy and safety of edoxaban, the latest NOAC to receive approval for the AF indication. This potent and selective inhibitor of factor Xa shows predictable pharmacokinetic and pharmacodynamic profiles. Its efficacy and safety have been demonstrated in the pivotal, phase III, warfarin-controlled ENGAGE AF-TIMI 48 trial in 21,105 AF patients. Expert opinion: NOACs will likely improve the management of AF, with or without HF. Edoxaban has a favorable pharmacokinetic profile that supports its use in special patient populations, including patients aged ≥75 years, with HF, renal impairment, poor adherence, and on polypharmacy. Proven strategies of edoxaban dose-reduction for optimal use in the presence of moderate renal impairment, and/or use of strong P-gp inhibitors are available.
Mechanical transients initiated by photolysis of caged ATP within fibers of insect fibrillar flight muscle

Kinetics of the cross-bridge cycle in insect fibrillar flight muscle have been measured using laser pulse photolysis of caged ATP and caged inorganic phosphate (Pi) to produce rapid step increases in the concentration of ATP and Pi within single glycerol-extracted fibers. Rapid photochemical liberation of 100 microM-1 mM ATP from caged ATP within a fiber caused relaxation in the absence of Ca2+ and initiated an active contraction in the presence of approximately 30 microM Ca2+. The apparent second order rate constant for detachment of rigor cross- bridges by ATP was between 5 x 10(4) and 2 x 10(5) M-1s-1. This rate is not appreciably sensitive to the Ca2+ or Pi concentrations or to rigor tension level. The value is within an order of magnitude of the analogous reaction rate constant measured with isolated actin and insect myosin subfragment-1 (1986. J. Muscle Res. Cell Motil. 7:179- 192). In both the absence and presence of Ca2+ insect fibers showed evidence of transient cross-bridge reattachment after ATP-induced detachment from rigor, as found in corresponding experiments on rabbit psoas fibers. However, in contrast to results with rabbit fibers, tension traces of insect fibers starting at different rigor tensions did not converge to a common time course until late in the transients. This result suggests that the proportion of myosin cross-bridges that can reattach into force-generating states depends on stress or strain in the filament lattice. A steady 10-mM concentration of Pi markedly decreased the transient reattachment phase after caged ATP photolysis. Pi also decreased the amplitude of stretch activation after step stretches applied in the presence of Ca2+ and ATP. Photolysis of caged Pi during stretch activation abruptly terminated the development of tension. These results are consistent with a linkage between Pi release and the steps leading to force production in the cross-bridge cycle.
DARWIN: CMOS opamp Synthesis by Means of a Genetic Algorithm

DARWIN is a tool that is able to synthesize CMOS opamps, on the basis of a genetic algorithm. A randomly generated initial set of opamps evolves to a set in which the topologies as well as the transistor sizes of the opamps are adapted to the required performance specifications. Several design examples illustrate the behavior of DARWIN.
"Islands of Risk": subgroups of adolescents at risk for HIV.

OBJECTIVE To use cluster analysis to determine profiles of adolescents at risk for HIV. METHODS Adolescents 15-21 years old (N = 1153) with a history of unprotected sex were assessed in five domains of risk (unprotected sex, alcohol/marijuana use, other drug use, mental health crises, and arrest/school dropout) as well as demographic, contextual, and behavioral variables. RESULTS Cluster analysis revealed separate three-cluster solutions for males and females. Among males, clusters were characterized by (a) mental health crises and unprotected sex, (b) alcohol/marijuana use and unprotected sex, and (c) lower risk. Among females, clusters were distinguished by (a) unprotected sex, (b) substance use and mental health crises, and (c) lower risk. Cluster membership was associated with secondary variables related to sexual risk. CONCLUSIONS Even within populations of high-risk adolescents, subgroups exist for which specific risk factors co-occur, particularly unprotected sex, mental health crises, and substance use. These patterns suggest that effective HIV prevention interventions may need to target the association between mental health and/or substance abuse with sexual risk for some adolescents.
Domain Adaptation for Named Entity Recognition in Online Media with Word Embeddings

Content on the Internet is heterogeneous and arises from various domains like News, Entertainment, Finance and Technology. Understanding such content requires identifying named entities (persons, places and organizations) as one of the key steps. Traditionally Named Entity Recognition (NER) systems have been built using available annotated datasets (like CoNLL, MUC) and demonstrate excellent performance. However, these models fail to generalize onto other domains like Sports and Finance where conventions and language use can differ significantly. Furthermore, several domains do not have large amounts of annotated labeled data for training robust Named Entity Recognition models. A key step towards this challenge is to adapt models learned on domains where large amounts of annotated training data are available to domains with scarce annotated data. In this paper, we propose methods to effectively adapt models learned on one domain onto other domains using distributed word representations. First we analyze the linguistic variation present across domains to identify key linguistic insights that can boost performance across domains. We propose methods to capture domain specific semantics of word usage in addition to global semantics. We then demonstrate how to effectively use such domain specific knowledge to learn NER models that outperform previous baselines in the domain adaptation setting.
The Psychology of Creative Writing: The Tears of a Clown: Understanding Comedy Writers

Humor is an important part of the human condition. A world without laughter would be a world without a soul. Indeed, comedy serves many key purposes in life – reducing stress, defusing social tensions, revealing the absurdity of human behavior, and generally increasing the quality of life (Martin, 2007). One main vehicle by which funny thoughts are conveyed is through creative writing, which can blunt the edge of potentially controversial topics, evoke feelings of mirth in the reader, and contribute to increasing the audience’s health through laughter. Comedy writing takes many forms: stand-up comedy writing, sitcom writing, political satire writing as seen on The Daily Show, comedy screenwriting, comedy writing for Web sites like Cracked or The Onion, and literary fiction writing with a humorous bent. It varies from the attempts of a novice short story writer to the aesthetic achievements of Cervantes, Rabelais, and Shakespeare. Indeed, nearly any form of creative writing can be enhanced by humor. But behind every punch line is a person generating that line. What do we know about comedy writers? What are they like? Humor has been the subject of a great deal of speculation and, more recently, a rather impressive array of empirical research (Martin, 2007) on a variety of humor-related topics. For instance, research has examined the link between humor and psychological well-being (Kuiper & Martin, 1998; Martin & Lefcourt, 1983; Ruch, 1997), the link between humor and physical well-being (Cogan, Cogan, Waltz, & McCue, 1987; Lefcourt, Davidson-Katz, & Kueneman, 1990; Martin & Dobbin, 1988; McClelland & Cheriff, 1997), defining characteristics of funny jokes (Attardo, 1997; Koestler, 1964; Raskin, 1985; Wyer & Collins, 1992), social aspects of humor (Apter, 1982; Long & Graesser, 1988; Mulkay, 1988; Robinson & SmithLovin, 2001), the psychobiology of humor and laughter (Bachorowski, Smoski, & Owen, 2001; Coulson & Kutas, 2001; Goel & Dolan, 2001; Provine & Yong, 1991), the development of humor in children (Barnett, 1990; Johnson & Mervis, 1997; McGhee, 1980), the evolutionary emergence of the human capacity
Temporal regulation of murine cytomegalovirus transcription and mapping of viral RNA synthesized at immediate early times after infection

The replication of murine cytomegalovirus strain Smith in murine embryonic fibroblasts was investigated at immediate early, early, and late times after infection. Cloned subgenomic HindIII fragments of murine cytomegalovirus DNA served to define the regions of transcription. At immediate early times viral RNA classes ranging in size from 5.1 to 1.05 kilobases (kb) were transcribed mainly from the fragments HindIII-K and -L, whereas low levels of transcription were detected from the two termini HindIII-E and HindIII-N. A characteristic pattern of proteins could be translated from immediate early RNA in vitro. At early and late times after infection transcription from all HindIII fragments occurred, but different patterns of transcripts and proteins could be identified. Inhibitors of DNA synthesis induced differences in the late transcription pattern, located in the HindIII-F fragment. The coding region for abundant immediate early transcription could be located at between 0.769 and 0.817 map units. A plasmic clone containing the main part (0.769 to 0.815 map units) of this region was constructed. This region coded for six polyadenylated immediate early RNA species of 5.1, 2.75, 2.0, 1.75, 1.65, and 1.05 kb in size. Only the 1.75-kb RNA originated entirely from the HindIII-L fragment. The 5.1- and 2.75-kb RNA species were encoded by both the HindIII-L and HindIII-K fragments, and the 2.0-, 1.65-, and 1.05-kb RNA species were entirely transcribed within HindIII-K.
Simpler Evaluation of Predictions and Signature Stability for Gene Expression Data

Scientific advances are raising expectations that patient-tailored treatment will soon be available. The development of resulting clinical approaches needs to be based on well-designed experimental and observational procedures that provide data to which proper biostatistical analyses are applied. Gene expression microarray and related technology are rapidly evolving. It is providing extremely large gene expression profiles containing many thousands of measurements. Choosing a subset from these gene expression measurements to include in a gene expression signature is one of the many challenges needing to be met. Choice of this signature depends on many factors, including the selection of patients in the training set. So the reliability and reproducibility of the resultant prognostic gene signature needs to be evaluated, in such a way as to be relevant to the clinical setting. A relatively straightforward approach is based on cross validation, with separate selection of genes at each iteration to avoid selection bias. Within this approach we developed two different methods, one based on forward selection, the other on genes that were statistically significant in all training blocks of data. We demonstrate our approach to gene signature evaluation with a well-known breast cancer data set.
Efficient Routing in Suburban Ad-Hoc Networks (SAHN)

A suburban ad-hoc network (SAHN) is an economical, high-speed alternative for communities of cooperating users. The SAHN aims to provide broadband suburban area connectivity for local area networks with low costs using wireless technology. There exists a plethora of efficient routing solutions for ad-hoc networks. However, less attention has been paid towards optimizing these protocols for ad-hoc networks with a quasi-static topology. In this paper we outline an efficient routing algorithm, particulary for a suburban ad-hoc network, to make efficient use of network resources. Our primary comparison results are with respect to DSR and AODV.
The impact of DNA methylation technologies on drug toxicology

Introduction: Drug toxicology is central to drug development. Despite improvements in our understanding of molecular and cell biology, high attrition rates in drug development continue, speaking to the difficulties of developing unequivocal methods to predict the efficacy and safety of drugs. Areas covered: In this review, the authors provide a short overview of the ‘omics’ technologies that have been applied to drug toxicology, with an emphasis on a whole-genome DNA methylation analysis. Preliminary results from DNA methylation analysis technologies that may help in predicting response and efficacy of a drug are discussed. Expert opinion: Currently, we cannot fully contextualize the application of epigenetics to the field of drug toxicology, as there are still many challenges to overcome before DNA methylation-based biomarkers can be effectively used in drug development. Comprehensive whole-genome DNA methylation methods for a unbiased analysis based on either microarray or next-generation sequencing need to be evaluated in drug toxicology in an intensive and systematic manner. Additionally, robust analysis systems need to be developed to decode the large amounts of data generated by whole-genome DNA methylation analyses as well as protocol standardization for reproducibility to develop meaningful databases that can be applied to drug toxicology.
Sensorless observation of a very-high-speed permanent magnet synchronous machine

For optimally efficient control of a high-speed PM machine, continuous accurate information of the rotor position is necessary. At very high speeds, however, measurement of the rotor angle is difficult and/or expensive. This paper uses a solution of a sensorless observer based on a linear quadratic estimator combined with a phase locked loop. The sensorless observer is thoroughly analyzed and implemented for the use in a vector controller of high-speed permanent magnet synchronous machine for a micro-CHP application. The analysis contains robustness and stability analysis. The influence of delays in the control loop is accounted for in the observer. Measurements performed on a test setup show very good performance of the observer in tracking rotor speed and position. The sensorless vector controller show better output performance than the same controller relying on a Hall-sensor signal.
A selective culture system for generating terminal deoxynucleotidyl transferase-positive (TdT+) lymphoid precursor cells in vitro. I. Description of the culture system

A primary xenogeneic culture system has been devised that selectively generates undifferentiated TdT+ lymphoblasts from rat bone marrow under conditions that do not support the growth or maintenance of rat colony- forming unit-spleen (CFU-S) or granulocyte/macrophage colony-forming cells (GM-CFC). The culture system requires a mouse bone marrow feeder layer, and a serum supplement that has markedly reduced levels of cortisol. The growth of TdT+ cells can be significantly enhanced by the addition of mesodermalizing factors (e.g., fibroblast growth factor, guinea pig bone marrow extract) to the culture medium, and the serum supplement can be decreased by the addition of selenium, transferrin, and T3. The cultured TdT+ cells are antigenically "null" cells that further resemble their normal counterparts in bone marrow with respect to morphology, size, cortisone sensitivity, and pattern of TdT fluorescence. The TdT+ cells are generated with equal facility from bone marrow of normal and congenitally athymic rats, can be maintained in logarithmic growth for at least 10 mos by serial passage in vitro, and do not cause leukemia when infused into irradiated recipients. Although the lineage relationships of these immature lymphoid cells have not yet been established, our working hypothesis, based on preliminary evidence, is that the cultured TdT+ cells are primitive members of the T cell series.
Complex Structure of OspI and Ubc13: The Molecular Basis of Ubc13 Deamidation and Convergence of Bacterial and Host E2 Recognition

Ubc13 is an important ubiquitin-conjugating (E2) enzyme in the NF-κB signaling pathway. The Shigella effector OspI targets Ubc13 and deamidates Gln100 of Ubc13 to a glutamic acid residue, leading to the inhibition of host inflammatory responses. Here we report the crystal structure of the OspI-Ubc13 complex at 2.3 Å resolution. The structure reveals that OspI uses two differently charged regions to extensively interact with the α1 helix, L1 loop and L2 loop of Ubc13. The Gln100 residue is bound within the hydrophilic catalytic pocket of OspI. A comparison between Ubc13-bound and wild-type free OspI structures revealed that Ubc13 binding induces notable structural reassembly of the catalytic pocket, suggesting that substrate binding might be involved in the catalysis of OspI. The OspI-binding sites in Ubc13 largely overlap with the binding residues for host ubiquitin E3 ligases and a deubiquitinating enzyme, which suggests that the bacterial effector and host proteins exploit the same surface on Ubc13 for specific recognition. Biochemical results indicate that both of the differently charged regions in OspI are important for the interaction with Ubc13, and the specificity determinants in Ubc13 for OspI recognition reside in the distinct residues in the α1 helix and L2 region. Our study reveals the molecular basis of Ubc13 deamidation by OspI, as well as a convergence of E2 recognition by bacterial and host proteins.
New Fast and Accurate Jacobi SVD Algorithm. II

This paper presents new implementation of one–sided Jacobi SVD for triangular matrices and its use as the core routine in a new preconditioned Jacobi SVD algorithm, recently proposed by the authors. New pivot strategy exploits the triangular form and uses the fact that the input triangular matrix is the result of rank revealing QR factorization. If used in the preconditioned Jacobi SVD algorithm, it delivers superior performance leading to the currently fastest method for computing SVD decomposition with high relative accuracy. Furthermore, the efficiency of the new algorithm is comparable to the less accurate bidiagonalization based methods. The paper also discusses underflow issues in floating point implementation, and shows how to use perturbation theory to fix the imperfectness of machine arithmetic on some systems.
Recent developments in structural studies on acetylcholinesterase

This review focuses on several recent developments concerning structure–function relationships in vertebrate acetylcholinesterase. These include studies on high‐resolution structures of human acetylcholinesterase and its complexes; the first crystal structure of a snake venom acetylcholinesterase, in which open and closed states of the ‘back door’ are visualized; a powerful algorithm for redesigning proteins for enhanced expression in prokaryotic systems, as applied to human acetylcholinesterase, which has hitherto been an intractable target; in situ implementation of ‘click chemistry’ in crystalline acetylcholinesterase, which yields novel insights into the steric and dynamic changes involved in the reaction within the active‐site gorge; and a study that demonstrates the effect of crystallization conditions on ligand alignment within a protein complex, in this case the methylene blue–Torpedo californica acetylcholinesterase complex, which highlights the relevance of the precipitant employed to structure‐based drug design.
T cells and HIV‐induced T cell syncytia exhibit the same motility cycle

Ameboid cells ranging in complexity from Dictyostelsum amebas to human polymorphonuclear leu kocytes (PMNs) translocate in a cyclical fashion. Using computer‐assisted motion analysis, we have analyzed the motility of human lymphocytes of the immortal SupTl cell line and of a peripheral blood mononuclear cell popu lation highly enriched for CD4‐positive cells (CD4‐enriched PBMCs) on four substrates—plastic, dehydrated rat tail collagen, hydrated rat tail collagen, and bovine aortic en dothelium. In addition, we have analyzed the motility on these substrates of syncytia induced by human immuno deficiency virus (HIV) in cultures of both cell types. It is demonstrated that both SupTl cells and CD4‐enriched PBMCs exhibit a motility cycle with a period of 1.6 min that is independent of substrate, independent of average cell velocity, and similar to the periods of translocating Dictyostelium amebas and PMNs. More surprisingly, it is demonstrated that HIV‐induced SupTl and PBMG syn cytia with volumes 10 to 100 times those of single cells ex hibit the same motility cycle as their single‐cell progeni tors. These observations support the generality of the motility cycle in animal cells and, for the first time, demonstrate that the cycic is independent of cell size. J. Lcukoc. BioL 57; 643–650; 1995.
The Metabolic Role of the Legume Endosperm: A Noninvasive Imaging Study1[W][OA]

Although essential for normal seed development in the legumes, the metabolic role of the endosperm remains uncertain. We designed noninvasive nuclear magnetic resonance tools for the in vivo study of key metabolites in the transient liquid endosperm of intact pea (Pisum sativum) seeds. The steady-state levels of sucrose, glutamine, and alanine could be monitored and their distribution within the embryo sac visualized. Seed structure was digitalized as a three-dimensional model, providing volume information for distinct seed organs. The nuclear magnetic resonance method, combined with laser microdissection, isotope labeling, in situ hybridization, and electron microscopy, was used to contrast the wild-type endosperm with that of a mutant in which embryo growth is retarded. Expression of sequences encoding amino acid and sucrose transporters was up-regulated earlier in the endosperm than in the embryo, and this activity led to the accumulation of soluble metabolites in the endosperm vacuole. The endosperm provides a temporary source of nutrition, permits space for embryo growth, and acts as a buffer between the maternal organism and its offspring. The concentration of sucrose in the endosperm vacuole is developmentally controlled, while the total amount accumulated depends on the growth of the embryo. The endosperm concentration of glutamine is a limiting factor for protein storage. The properties of the endosperm ensure that the young embryo develops within a homeostatic environment, necessary to sustain embryogenesis. We argue for a degree of metabolite-mediated control exerted by the endosperm on the growth of, and assimilate storage by, the embryo.