Miracle-dz/UniFAR-FTUs huggingface dataset:
2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), an Orally Available and Long-Acting Prostacyclin Receptor Agonist Prodrug

Prostacyclin (PGI2) and its analogs are useful for the treatment of various vascular disorders, but their half-lives are too short for widespread clinical application. To overcome this drawback, we have synthesized a novel diphenylpyrazine derivative, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), a prodrug of the active form {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269). NS-304 is an orally available and potent agonist for the PGI2 receptor (IP receptor). The inhibition constant (Ki) of MRE-269 for the human IP receptor was 20 nM; in contrast, the Ki values for other prostanoid receptors were >2.6 μM. MRE-269 was therefore a highly selective agonist for the IP receptor. The plasma concentrations of MRE-269 remained near peak levels for more than 8 h after oral administration of NS-304 to rats and dogs, and NS-304 increased femoral skin blood flow in rats in a long-lasting manner without affecting the hemodynamics. These findings indicate that NS-304 acts as a long-acting IP receptor agonist in vivo. The continuous vasodilation evoked by NS-304 was not attenuated by repeated treatment, indicating that NS-304 is unlikely to cause severe desensitization of the IP receptor in rats. Moreover, a microdose pharmacokinetic study in which NS-304 was orally administered to healthy male volunteers showed conversion of NS-304 to MRE-269 and a long plasma elimination half-life for MRE-269 (7.9 h). In conclusion, NS-304 is an orally available and long-acting IP receptor agonist prodrug, and its active form, MRE-269, is highly selective for the IP receptor. Therefore, NS-304 is a promising drug candidate for various vascular diseases, especially pulmonary arterial hypertension and arteriosclerosis obliterans.
Isolation, identification of Staphylococcus aureus from bovine milk and its antibiotics susceptibility

The isolation, identification of Staphylococcus aureus from bovine milk and its antibiotic susceptibility was studied. One milliliter of each freshly drawn milk sample was inoculated into 9 ml of sterile peptone water and incubated overnight. A loop full of peptone water broth was streaked on blood agar base enriched with sheep blood using the quadrant streaking method for each quarter. Blood agar plates were incubated aerobically at 37°C for 24 h. S. aureus was identified by the tube coagulase test. Antimicrobial sensitivity test was conducted on S. aureus isolates using 18 antibiotics. From the study 43.75% had subclinical mastitis, while none was tested positive for clinical mastitis. None of the S. aureus isolates was fully sensitive to all the agents; 3 (42.86%) isolates were resistant to 10 agents, followed by 2 (28.57%) isolates which were resistant to 4 agents. Key words: Milk, antibiotics, Staphylococcus aureus, mastitis, cow.
Analysis of categorical data by linear models.

Assume there are ni. , i = 1, 2, *--, s, samples from s multinomial distributions each having r categories of response. Then define any u functions of the unknown true cell probabilities {7rij: i = 1, 2, * , s; j = 1, 2, * , r, where E jrij l 1 } that have derivatives up to the second order with respect to 7rij, and for which the matrix of first derivatives is of rank u. A general noniterative procedure is described for fitting these functions to a linear model, for testing the goodness-of-fit of the model, and for testing hypotheses about the parameters in the linear model. The special cases of linear functions and logarithmic functions of the 7rin are developed in detail, and some examples of how the general approach can be used to analyze various types of categorical data are presented.
Composition of Dirac structures and control of port-Hamiltonian systems

Key feature of Dirac structures (as opposed to Poisson or symplectic structures) is the fact that the standard composition of two Dirac structures is again a Dirac structure. In particular this implies that any power-conserving interconnection of port-Hamiltonian systems is a port-Hamiltonian system itself. This constitutes a fundamental property in the port-Hamiltonian approach to modeling, simulation and control of complex physical systems. Furthermore, the composed Dirac structure directly determines the algebraic constraints of the interconnected system, as well as its Casimir functions. Especially the Casimirs are of prime importance in the set-point regulation of port-Hamiltonian systems. It is therefore of importance to characterize the set of achievable Dirac structures when a given plant port-Hamiltonian system is intercon-nected with an arbitrary controller port-Hamiltonian system. The set of achievable Dirac structures in a restricted sense has been recently characterized in [1, 2]. Here we extend this theorem to the present situation occurring in the interconnection of a plant and controller Hamiltonian system. Furthermore, wegive an insightful procedure for the construction of the controller Dirac structure. This procedure works for the general case of (non-closed) Dirac structures on manifolds. In this way we also fully characterize the set of achievable Casimir functions of the interconnected ("closed-loop") system. This yields a fundamental limitation to the design of stabilizing controllers for underactuated mechanical systems by interconnection with a port-Hamiltonian controller.
The Perception-Production Link in L2 Phonology

In a first or second language (L2), it is thought that in order to accurately produce a sound, one must be able to accurately distinguish that same sound in reception. This intuitive connection, called the perception-production link, also enjoys theoretical support from Flege’s (1995) Speech Learning Model and empirical support from a considerable number of experimental studies. However, reports of perception without production and production without perception present a challenge to the perception-production link. In this brief review, the perception-production link is explained and evidence supporting and challenging the link is summarized. Additionally, empirical research on the link is critically reviewed to highlight issues with research design and interpretation. Finally, the perception-production link’s current status in L2 research is discussed and directions for future research are presented.
Determination of three‐dimensional ventricular strain distributions in gene‐targeted mice using tagged MRI

A model‐based method for calculating three‐dimensional (3D) cardiac wall strain distributions in the mouse has been developed and tested in a genetically engineered mouse model of dilated cardiomyopathy. Data from MR tagging and harmonic phase (HARP) tracking were used to measure material point displacements, and 3D Lagrangian strains were calculated throughout the entire left ventricle (LV) with a deformable parametric model. A mouse model where cardiomyocytes are specifically made deficient in vinculin (VclKO) were compared to wild‐type (WT) littermates. 3D strain analysis revealed differences in LV wall mechanics between WT and VclKO mice at 8 weeks of age when systolic function had just begun to decline. Most notably, end‐systolic radial strain and torsional shear were reduced in VclKO hearts which contributed to regional mechanical dysfunction. This study demonstrates the feasibility of using MRI tagging methods to detect alterations in 3D myocardial strain distributions in genetically engineered mouse models of cardiovascular disease. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.
Tenascin-R Restricts Posttraumatic Remodeling of Motoneuron Innervation and Functional Recovery after Spinal Cord Injury in Adult Mice

Tenascin-R (TNR) is an extracellular glycoprotein in the CNS implicated in neural development and plasticity. Its repellent properties for growing axons in a choice situation with a conducive substrate in vitro have indicated that TNR may impede regeneration in the adult mammalian CNS. Here we tested whether constitutive lack of TNR has beneficial impacts on recovery from spinal cord injury in adult mice. Using the Basso, Beattie, Bresnahan (BBB) locomotor rating scale, we found that open-field locomotion in TNR-deficient (TNR−/−) mice recovered better that in wild-type (TNR+/+) littermates after compression of the thoracic spinal cord. We also designed, validated, and applied a motion analysis approach allowing numerical assessment of motor functions. We found, in agreement with the BBB score, that functions requiring low levels of supraspinal control such as plantar stepping improved more in TNR−/− mice. This was not the case for motor tasks demanding precision such as ladder climbing. Morphological analyses revealed no evidence that improved recovery of some functions in the mutant mice were attributable to enhanced tissue sparing or axonal regrowth. Estimates of perisomatic puncta revealed reduced innervation by cholinergic and GABAergic terminals around motoneurons in intact TNR−/− compared with TNR+/+ mice. Relative to nonlesioned animals, spinal cord repair was associated with increase in GABAergic and decrease of glutamatergic puncta in TNR−/− but not in TNR+/+ mice. Our results suggest that TNR restricts functional recovery by limiting posttraumatic remodeling of synapses around motoneuronal cell bodies where TNR is normally expressed in perineuronal nets.
Number in Kambaata

This paper analyses the expression of number; more precisely, it investigates on which parts of speech and by which linguistic means number is grammatically encoded in Kambaata (Cushitic, Ethiopia). Number is marked, to different degrees, on common nouns, proper nouns and pronouns. Traces of number agreement are found on modifiers and verbs. The core of this paper deals with number marking on common nouns, especially the interaction of number marking with the lexical semantics of certain noun classes. A comparison with the grammatical categories of case and gender shows that number is a grammatical category between inflection and derivation.
Rodent models in Down syndrome research: impact and future opportunities

ABSTRACT Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets. Summary: Mouse models have boosted therapeutic options for Down syndrome, and improved models are being developed to better understand the pathophysiology of this genetic condition.
A generic, context sensitive analysis framework for object oriented programs

Abstract interpreters rely on the existence of a nxpoint algorithm that calculates a least upper bound approximation of the semantics of the program. Usually, that algorithm is described in terms of the particular language in study and therefore it is not directly applicable to programs written in a different source language. In this paper we introduce a generic, block-based, and uniform representation of the program control flow graph and a language-independent nxpoint algorithm that can be applied to a variety of languages and, in particular, Java. Two major characteristics of our approach are accuracy (obtained through a topdown, context sensitive approach) and reasonable efficiency (achieved by means of memoization and dependency tracking techniques). We have also implemented the proposed framework and show some initial experimental results for standard benchmarks, which further support the feasibility of the solution adopted.
Should Benzodiazepines and Anticonvulsants Be Used During Electroconvulsive Therapy?: A Case Study and Literature Review

Objective This study aims to investigate the clinical effects of benzodiazepines or anticonvulsant use during a course of electroconvulsive therapy (ECT). Method A case report study of a patient who received ECT with and without concomitant flurazepam and pregabalin is presented. The literature on the use of benzodiazepines and anticonvulsants during ECT is reviewed. Results A woman with treatment resistant depression received a course of ECT while taking flurazepam and pregabalin, but seizures were of short duration and symptomatic improvement was minimal. After discontinuation of flurazepam and pregabalin, a course of right unilateral ultrabrief ECT was associated with adequate seizures and remission of depression and suicidal ideation. Our literature review suggests that benzodiazepines decrease seizure duration, but most evidence shows no association with increased seizure threshold. One prospective RCT and 3 large retrospective studies found that benzodiazepines compromise the efficacy of unilateral but not bilateral ECT. Regarding anticonvulsants, several studies had varied and contradictory results on their effect on seizure duration and seizure threshold. Of the 2 large retrospective studies and 3 RCTs, only 1 retrospective study showed that anticonvulsants decrease the efficacy of ECT. Conclusions Judicious assessment of all medications used in combination with ECT is recommended. Overall, published studies suggest that benzodiazepines and anticonvulsants impact the clinical outcomes of ECT less than what would be expected given their pharmacologic effects. However, there are significant gaps in the literature, including a lack of study on suprathreshold stimulation of right unilateral ECT and the possibility of a greater effect with higher medication doses.
Ultrabroadband 2D electronic spectroscopy as a tool for direct visualization of pathways of energy flow

Two-dimensional electronic spectroscopy (2DES) has emerged as an incisive tool for mapping out energy relaxation pathways in complex molecular systems by determining correlation maps between the excitation and emission frequencies. Its enhanced spectral as well as temporal resolution offer new insights into coupling and energy transfer between closely-spaced energy states, which are often hidden in a one-dimensional transient spectrum. However, a major drawback of the current 2DES technique is that the spectral window of detection is directly limited to the laser bandwidth used, which leads to an incomplete visualization of the full energy landscape of the system. As a solution to this limitation, we present an ultrabroadband 2DES apparatus utilizing a 8-fs, 185-nm bandwidth supercontinuum that covers the entire visible region. We demonstrate the utility of our setup by measuring the 2D spectra of laser dyes absorbing at different regions of the laser spectrum, and the major light-harvesting complex of spinach.
Performance Optimization of Virtual Keyboards

Text entry has been a bottleneck of nontraditional computing devices. One of the promising methods is the virtual keyboard for touch screens. Correcting previous estimates on virtual keyboard efficiency in the literature, we estimated the potential performance of the existing Qwerty, FITALY, and OPTI designs of virtual keyboards to be in the neighborhood of 28, 36, and 38 words per minute (wpm), respectively. This article presents 2 quantitative design techniques to search for virtual keyboard layouts. The first technique simulated the dynamics of a keyboard with digraph springs between keys, which produced a Hooke keyboard with 41.6 wpm movement efficiency. The second technique used a Metropolis random walk algorithm guided by a "Fitts-digraph energy" objective function that quantifies the movement efficiency of a virtual keyboard. This method produced various Metropolis keyboards with different shapes and structures with approximately 42.5 wpm movement efficiency, which was 50% higher than Qwerty and 10% higher than OPTI. With a small reduction (41.16 wpm) of movement efficiency, we introduced 2 more design objectives that produced the ATOMIK layout. One was alphabetical tuning that placed the keys with a tendency from A to Z so a novice user could more easily locate the keys. The other was word connectivity enhancement so the most frequent words were easier to find, remember, and type.
Clothing flammability and skin burn injury in normal and micro-gravity

As space exploration has advanced, time spent in space has increased. With the building of the International Space Station and plans for exploration missions to the Moon and Mars, astronauts will be staying in space for longer periods of time. With these increased stays in space comes an increase in fire safety concerns. One area of fire safety interest is flammability. While current flammability test procedures are in place, they are all performed on the ground and may not be representative of flammability in microgravity. In addition to this, limited research into the severity of skin burn injury in a microgravity environment has been performed. An apparatus was designed to be flown on a low gravity parabolic aircraft flight to assess the flammability of cotton and 50% cotton/50% polyester fabrics and the resulting skin burn injury that would occur if these fabrics were to ignite. The apparatus, modelled after a Canadian General Standards Board standard flammability test, was also used on the ground for experiments in 1-g. Variables examined in the tests include gravity level, fabric type, air gap size, oxygen concentration, apparatus orientation, ignition source, and method used to secure the specimen. Flame spread rates, heat fluxes, and skin burn predictions determined from test results were compared. Results from test in 1-g indicated that the orientation of the apparatus had a large effect on flame spread rate, heat flux and predicted skin burn times. Flame spread rates and heat fluxes were highest when the fabric was held in the vertical orientation, which resulted in the lowest predicted times to produce skin burns. Flame spread rates and heat fluxes were considerably lower in microgravity than in 1-g, which resulted in higher predicted times to produce skin burns.
Modeling depression in Parkinson disease

Objective: To construct a model for depression in Parkinson disease (PD) and to study the relative contribution of PD-specific and nonspecific risk factors to this model. Methods: Structural equation modeling of direct and indirect associations of risk factors with the latent depression outcome using a cross-sectional dataset of 342 patients with PD. Results: A model with acceptable fit was generated that explained 41% of the variance in depression. In the final model, 3 PD-specific variables (increased disease duration, more severe motor symptoms, the use of levodopa) and 6 nonspecific variables (female sex, history of anxiety and/or depression, family history of depression, worse functioning on activities of daily living, and worse cognitive status) were maintained and significantly associated with depression. Nonspecific risk factors had a 3-times-higher influence in the model than PD-specific risk factors. Conclusion: In this cross-sectional study, we showed that nonspecific factors may be more prominent markers of depression than PD-specific factors. Accordingly, research on depression in PD should focus not only on factors associated with or specific for PD, but should also examine a wider scope of factors including general risk factors for depression, not specific for PD.
A Generalized Secondary Frost Heave Model

A generalized model for secondary frost heave is developed based on the one-dimensional model of O'Neill and Miller. Secondary frost heave arises during freezing owing to cryostatic suction effects that can increase the upward water permeation to facilitate ice-lens growth and increased heave. Nondi-mensionalization and scaling are used to simplify the model equations and to identify a dimensionless group whose magnitude characterizes the nature of secondary frost heave in different soils. Computational problems encountered by O'Neill and Miller are avoided by recognizing the boundary layer nature of the water permeation and by reducing the frozen fringe, wherein freezing and ice-lens growth occur, to a moving planar boundary across which jump boundary conditions are prescribed. This generalized model can predict the frost heave behavior of different soils. Its predictions for the initiation time, spacing, and thickness of sequential ice lenses agree with the results of qualitative observations. This mode.
A Regulatory CD4+ T Cell Subset in the BB Rat Model of Autoimmune Diabetes Expresses Neither CD25 Nor Foxp31

Biobreeding (BB) rats model type 1 autoimmune diabetes (T1D). BB diabetes-prone (BBDP) rats develop T1D spontaneously. BB diabetes-resistant (BBDR) rats develop T1D after immunological perturbations that include regulatory T cell (Treg) depletion plus administration of low doses of a TLR ligand, polyinosinic-polycytidylic acid. Using both models, we analyzed CD4+CD25+ and CD4+CD45RC− candidate rat Treg populations. In BBDR and control Wistar Furth rats, CD25+ T cells comprised 5–8% of CD4+ T cells. In vitro, rat CD4+CD25+ T cells were hyporesponsive and suppressed T cell proliferation in the absence of TGF-β and IL-10, suggesting that they are natural Tregs. In contrast, CD4+CD45RC− T cells proliferated in vitro in response to mitogen and were not suppressive. Adoptive transfer of purified CD4+CD25+ BBDR T cells to prediabetic BBDP rats prevented diabetes in 80% of recipients. Surprisingly, CD4+CD45RC−CD25− T cells were equally protective. Quantitative studies in an adoptive cotransfer model confirmed the protective capability of both cell populations, but the latter was less potent on a per cell basis. The disease-suppressing CD4+CD45RC−CD25− population expressed PD-1 but not Foxp3, which was confined to CD4+CD25+ cells. We conclude that CD4+CD25+ cells in the BBDR rat act in vitro and in vivo as natural Tregs. In addition, another population that is CD4+CD45RC−CD25− also participates in the regulation of autoimmune diabetes.
Biogenesis of inner membrane proteins in Escherichia coli

For a long time, it was generally assumed that the biogenesis of inner membrane proteins in Escherichia coli occurs spontaneously, and that only the translocation of large periplasmic domains requires the aid of a protein machinery, the Sec translocon. However, evidence obtained in recent years indicates that most, if not all, inner membrane proteins require the assistance of protein factors to reach their native conformation in the membrane. Here, we review and discuss recent advances in our understanding of the biogenesis of inner membrane proteins in E. coli.