Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease

Abstract Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t 1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.
In vitro clinical‐grade generation of red blood cells from human umbilical cord blood CD34+ cells

BACKGROUND: There is no appropriate alternative source of red blood cells (RBCs) to relieve the worsening shortage of blood available for transfusion. Therefore, in vitro generation of clinically available RBCs from hematopoietic stem cells could be a promising new source to supplement the blood supply. However, there have been few studies about the generation of clinical‐grade RBCs by coculture on human mesenchymal stem cells (MSCs) and various cytokine supplements, even though the production of pure RBCs requires coculture on stromal cells and proper cytokine supplements.
A primitive ornithischian dinosaur from the Late Triassic of South Africa, and the early evolution and diversification of Ornithischia

Although the group played an important role in the evolution of Late Mesozoic terrestrial ecosystems, the early evolutionary history of the ornithischian dinosaurs remains poorly understood. Here, we report on a new primitive ornithischian, Eocursor parvus gen. et sp. nov., from the Late Triassic (? Norian) Lower Elliot Formation of South Africa. Eocursor is known from a single specimen comprising substantial cranial and postcranial material and represents the most complete Triassic member of Ornithischia, providing the earliest evidence for the acquisition of many key ornithischian postcranial characters, including an opisthopubic pelvis. A new phylogenetic analysis positions this taxon near the base of Ornithischia, as the sister taxon to the important and diverse clade Genasauria. The problematic clade Heterodontosauridae is also positioned basal to Genasauria, suggesting that an enlarged grasping manus may represent a plesiomorphic ornithischian condition. This analysis provides additional phylogenetic support for limited ornithischian diversity during the Late Triassic, and suggests that several major ornithischian clades may have originated later than generally believed. There are few morphological differences between Late Triassic and Early Jurassic ornithischians, supporting previous suggestions that the Early Jurassic ornithischian radiation may simply represent the filling of vacant ecological space following Late Triassic terrestrial extinctions.
Results from a Statics Concept Inventory and their Relationship to other Measures of Performance in Statics

Concept inventories have been proposed for an increasing number of subjects in engineering and other fields. Such an assessment tool has been developed for Engineering Statics. An assessment instrument like a concept inventory is of value, however, only if performance on it is an indicator of performance in the subject more generally. The relation between class examinations and inventory performance were reported recently for students at the home institution of inventory developer (Steif). In the present paper, the relation between class examinations and inventory performance for additional schools was analyzed. The inventory is found to be predictive of student performance at other institutions, and is relevant to a wider range of problems than earlier suspected
Laboratory and Field Performance of an Indoxacarb Bait Against German Cockroaches (Dictyoptera: Blattellidae)

Abstract Experimental indoxacarb powder and gel baits were evaluated in the laboratory, and a gel bait was evaluated in subsequent field studies against the German cockroach, Blattella germanica (L.). In continuous exposure tests, LT50 values were 1.90 and 1.10 d for 0.25 and 1% indoxacarb powder baits, respectively. However, 0.25% indoxacarb gel bait had an LT50 value of 0.68 d, similar to a 0.05% abamectin gel bait formulated with the same bait base. There was no difference in toxicity between fresh and 7-d-old gel bait deposits. A pyrethroid-resistant strain of German cockroaches was significantly resistant to both abamectin and indoxacarb gel baits. Gel bait contained ≈40% water, desiccated rapidly at 25–28°C and 30–45% RH, but did not rehydrate when held at 56.7% RH for 3 d. Powder indoxacarb baits contained <1% water and did not desiccate or gain water. Indoxacarb gel bait (0.25%) was relatively nonrepellent (≈30%) and had positive maximum performance index values (≈100) in Ebeling choice box experiments. In field experiments in cockroach-infested kitchens, the 0.25% indoxacarb gel bait significantly reduced visual counts of German cockroaches ≈74% at 3 d and >95% at 14 d. Indoxacarb baits are toxic, relatively nonrepellent, and can significantly reduce German cockroach populations.
Genetic and molecular analyses of spontaneous mutants of human rhinovirus 14 that are resistant to an antiviral compound

Spontaneous mutants of human rhinovirus 14 resistant to WIN 52084, an antiviral compound that inhibits attachment to cells, were isolated by selecting plaques that developed when wild-type virus was plated in the presence of high (2 micrograms/ml) or low (0.1 to 0.4 micrograms/ml) concentrations of the compound. Two classes of drug resistance were observed: a high-resistance (HR) class with a frequency of about 4 x 10(-5), and a low-resistance (LR) class with a 10- to 30-fold-higher frequency. The RNA genomes of 56 HR mutants and 13 LR mutants were sequenced in regions encoding the drug-binding site. The HR mutations mapped to only 2 of the 16 amino acid residues that form the walls of the drug-binding pocket. The side chains of these two residues point directly into the pocket and were invariably replaced by bulkier groups. These findings, and patterns of resistance to related WIN compounds, support the concept that HR mutations may hinder the entry or seating of drug within the binding pocket. In contrast, all of the LR mutations mapped to portions of the polypeptide chain near the canyon floor that move when the drug is inserted. Because several LR mutations partially reverse the attachment-inhibiting effect of WIN compounds, these mutants provide useful tools for studying the regions of the capsid structure involved in attachment. This paper shows that the method of escape mutant analysis, previously used to identify antibody binding sites on human rhinovirus 14, is also applicable to analysis of antiviral drug activity.
The role of Synaptobrevin1/VAMP1 in Ca2+‐triggered neurotransmitter release at the mouse neuromuscular junction

Non‐technical summary The neuromuscular junction (NMJ) is the synaptic connection between the nerve and the muscle. The neuromuscular synaptic transmission is highly reliable, as each nerve impulse results in the release of more neurotransmitter than is required for evoking an action potential in the muscle. This feature, often referred as the ‘safety factor’, ensures that a muscle contraction will occur in response to each nerve impulse under normal physiological conditions. Here we show that a small, integral membrane protein of synaptic vesicles, named synaptobrevin (Syb)/vesicle‐associated membrane protein (VAMP), is required for optimum synaptic transmission at the NMJ. A genetic mutation in Syb1/VAMP1 in mice causes marked reduction of neurotransmitter release at the NMJ, suggesting an important role for Syb1/VAMP1 in maintaining the ‘safety factor’ of the NMJ.
Potential of Renewable Energy Resources with an Emphasis on Solar Power in Iraq: An Outlook

This study presents an outlook on the renewable energies in Iraq, and the potential for deploying concentrated solar power technologies to support power generation in Iraq. Solar energy has not been sufficiently utilized at present in Iraq. However, this energy source can play an important role in energy production in Iraq, as the global solar radiation ranging from 2000 kWh/m2 to a 2500 kWh/m2 annual daily average. In addition, the study presents the limited current solar energy activities in Iraq. The attempts of the Iraqi government to utilize solar energy are also presented. Two approaches for utilizing concentrated solar power have been proposed, to support existing thermal power generation, with the possibility of being implemented as standalone plants or being integrated with thermal power plants. However, the cost analysis has shown that for 50 kW concentrated solar power in Iraq, the cost is around 0.23 US cent/kWh without integration with energy storage. Additionally, notable obstacles and barriers bounding the utilization of solar energy are also discussed. Finally, this study proposes initiatives that can be adopted by the Iraqi government to support the use of renewable energy resources in general, and solar energy in particular.
Response of normal infants to inhaled histamine.

The age at which nonspecific bronchial hyperresponsiveness (BHR) is first seen in humans is unknown, though both genetic and environmental factors have been implicated in its development. The current study aimed to establish whether BHR to histamine can be demonstrated in normal infants. Twelve infants, mean age of 7.8 months (range, 3 to 18 months), were studied. None had any history of a previous significant respiratory illness. Respiratory function was monitored using the maximal flow at function residual capacity (VmaxFRC) obtained with the forced expiratory flow-volume technique. Histamine was inhaled in doubling concentrations from 0.125 to 8 g.L-1. A greater than 30% fall in VmaxFRC was considered a response. All infants responded to histamine, the geometric mean concentration for their response being 1.4 g.L-1. Associated transient changes for the group were an increase in respiratory rate (p less than 0.02) and a fall in SaO2 (p less than 0.001). Forced expiratory flow-volume curves were concave in all infants after the last dose of histamine. We speculate that humans are born with "bronchial hyperresponsiveness" and that genetic or environmental factors determine which infants lose it thereafter.
Molecular Interactions between the Specialist Herbivore Manduca sexta (Lepidoptera, Sphingidae) and Its Natural Host Nicotiana attenuata. VII. Changes in the Plant's Proteome1[W]

When Manduca sexta attacks Nicotiana attenuata, fatty acid-amino acid conjugates (FACs) in the larvae's oral secretions (OS) are introduced into feeding wounds. These FACs trigger a transcriptional response that is similar to the response induced by insect damage. Using two-dimensional gel electrophoresis, matrix-assisted laser desorption ionization-time of flight, and liquid chromatography-tandem mass spectrometry, we characterized the proteins in phenolic extracts and in a nuclear fraction of leaves elicited by larval attack, and/or in leaves wounded and treated with OS, FAC-free OS, and synthetic FACs. Phenolic extracts yielded approximately 600 protein spots, many of which were altered by elicitation, whereas nuclear protein fractions yielded approximately 100 spots, most of which were unchanged by elicitation. Reproducible elicitor-induced changes in 90 spots were characterized. In general, proteins that increased were involved in primary metabolism, defense, and transcriptional and translational regulation; those that decreased were involved in photosynthesis. Like the transcriptional defense responses, proteomic changes were strongly elicited by the FACs in OS. A semiquantitative reverse transcription-PCR approach based on peptide sequences was used to compare transcript and protein accumulation patterns for 17 candidate proteins. In six cases the patterns of elicited transcript accumulation were consistent with those of elicited protein accumulation. Functional analysis of one of the identified proteins involved in photosynthesis, RuBPCase activase, was accomplished by virus-induced gene silencing. Plants with decreased levels of RuBPCase activase protein had reduced photosynthetic rates and RuBPCase activity, and less biomass, responses consistent with those of herbivore-attacked plants. We conclude that the response of the plant's proteome to herbivore elicitation is complex, and integrated transcriptome-proteome-metabolome analysis is required to fully understand this ubiquitous ecological interaction.
Modulation of cerebral vascular tone by activated glia: involvement of nitric oxide

The ability of activated glia to affect cerebral vascular tone has been evaluated using an in vitro experimental system in which basilar arteries were incubated with glial cultures activated by treatment with lipopolysaccharide (LPS). Vascular tone was measured with an isometric myograph. Contraction in response to high KCl and serotonin was reduced in arteries co‐incubated for 24 h with LPS‐activated glia, whereas the response to acetylcholine was not modified. The reduced contraction was prevented when the nitric oxide synthase (NOS) inhibitor l‐N‐nitro‐arginine (L‐NNA) was added throughout the whole incubation time (activation of glial cells with LPS + co‐incubation of glial cells with cerebral arteries). Under these conditions, nitrite levels were drastically reduced. A reduced contraction to KCl was also observed after treatment of the cerebral vessel with sodium nitroprusside. In contrast, L‐NNA added to the vessel did not modify the response to contracting stimuli and the expression of endothelial NOS was not modified in cerebral arteries pre‐incubated with activated glia. These results suggest that activated glia, which finds an in vivo correlate in several neuropathological conditions, can contribute to changes of vascular tone by modifying the levels of nitric oxide (NO) to which the vessel is exposed.
Systematic review of whole body vibration exercises in the treatment of cerebral palsy: Brief report

Abstract Objective: Whole body vibration (WBV) is increasingly being used to improve balance and motor function and reduce the secondary complications associated with cerebral palsy (CP). The purpose of this study was to systematically appraise published research regarding the effects of static and/or dynamic exercise performed on a vibrating platform on gait, strength, spasticity and bone mineral density (BMD) within this population. Methods: Systematic searches of six electronic databases identified five studies that met our inclusion criteria (2 at Level II and 3 at Level III-2). Studies were analysed to determine: (a) participant characteristics; (b) optimal exercise and WBV treatment protocol; (c) effect on gait, strength, spasticity and BMD; and (d) the outcome measures used to evaluate effect. As data was not homogenous a meta-analysis was not possible. Results: Several design limitations were identified and intervention protocols are poorly described. The effects on strength, gait, spasticity and BMD in persons with CP remain inconclusive with weak evidence that WBV may improve selected muscle strength and gait parameters and that prolonged exposure may improve BMD; there is currently no evidence that WBV can reduce spasticity. Conclusions: The evidence for exercise performed on a vibrating platform on mobility, strength, spasticity and BMD in CP remains scant and further larger scale investigations with controlled parameters to better understand the effects of WBV exercises in this population is recommended.
Glutathione S-Transferase of the Malarial Parasite Plasmodium falciparum: Characterization of a Potential Drug Target

Abstract Glutathione Stransferases (GSTs), which occur abundantly in most organisms, are essentially involved in the intracellular detoxification of numerous substances including chemotherapeutic agents, and thus play a major role in the development of drug resistance. A gene encoding a protein with sequence identity of up to 37% with known GSTs was identified on chromosome 14 of the malarial parasite Plasmodium falciparum. It was amplified using gametocyte cDNA and expressed in Escherichia coli as a hexahistidyltagged protein of 26 kDa subunit size. The homodimeric enzyme (PfGST) was found to catalyse the glutathione (GSH)dependent modification of 1-chloro-2,4-dinitrobenzene and other typical GST substrates such as onitrophenyl acetate, ethacrynic acid, and cumene hydroperoxide. The Km value for GSH was 164±20 M. PfGST was inhibited by cibacron blue (Ki=0.5 M), Shexylglutathione (Ki=35 M), and protoporphyrin IX (Ki=10 M). Hemin, a most toxic compound for parasitised erythrocytes, was found to be an uncompetitive ligand of PfGST with a Ki of 6.5 M. Based on the activity of PfGST in extracts of P. falciparum, the enzyme represents 1 to 10% of cellular protein and might therefore serve as an efficient in vivo buffer for parasitotoxic hemin. Destabilising ligands of GST are thus expected to be synergistic with the antimalarial drug chloroquine, which itself was found to be a very weak inhibitor of PfGST (IC50 >200 M). Xray quality crystals of PfGST (25020050 m) will serve as starting point for structurebased drug design.
MR imaging findings of paravertebral gossypiboma.

BACKGROUND AND PURPOSE "Gossypiboma" is a term used to describe a mass within the body that comprises a cotton matrix surrounded by a foreign-body reaction, which is extremely rare after spinal surgery. The purpose of this study was to describe the clinical and MR imaging features of gossypibomas in the paravertebral area of 7 patients. MATERIALS AND METHODS Between October 1999 and December 2005, 7 cases of paravertebral gossypibomas were confirmed pathologically at 2 institutions. The clinical features were reviewed retrospectively. We recorded MR imaging features and differential MR imaging-based diagnoses. RESULTS All patients were symptomatic; the most frequent symptom was nonspecific back or neck pain. None of the patients presented with signs of infection or required surgery urgently. In 3 of the 7 patients, gossypiboma was included in the preoperative differential imaging diagnosis. In all patients, the gossypiboma was located in the vicinity of the initial site of surgery. Typically, gossypibomas were visible in T2-weighted images as a mass with a hyperintense center and hypointense rim and exhibited strong peripheral enhancement in contrast-enhanced images. Retained surgical gauze was removed surgically from 4 patients; in the remaining patients, the surgical specimens contained suture threads. CONCLUSION Gossypiboma should be included in the differential diagnosis of the paravertebral mass when a mass with a hyperintense center and peripheral hypointense rim on T2-weighted images and strong peripheral rim enhancement on contrast-enhanced T1-weighted MR images is seen in postoperative patients.
Bone Plug Versus Suture-Only Fixation of Meniscal Grafts

Background: Meniscus allograft transplantation (MAT) is primarily undertaken to relieve the symptoms associated with meniscal deficiencies. However, its ability to restore normal knee joint contact mechanics under physiological loads is still unclear. Purpose: To quantify the dynamic contact mechanics associated with 2 commonly used fixation techniques in MAT of the medial compartment: transosseous suture fixation via bone plugs and suture-only fixation at the horns. Study Design: Controlled laboratory study. Methods: Physiological loads to mimic gait were applied across 7 human cadaveric knees on a simulator. A sensor placed on the medial tibial plateau recorded dynamic contact stresses under the following conditions: (1) intact meniscus, (2) MAT using transosseous suture fixation via bone plugs at the anterior and posterior horns, (3) MAT using suture-only fixation, and (4) total medial meniscectomy. A “remove-replace” procedure was performed to place the same autograft for both MAT conditions to minimize the variability in graft size, geometry, and material property and to isolate the effects of the fixation technique. Contact stress, contact area, and weighted center of contact stress (WCoCS) were quantified on the medial plateau throughout the stance phase. Results: Knee joint contact mechanics were sensitive to the meniscal condition primarily during the first half of the gait cycle. After meniscectomy, the mean peak contact stress increased from 4.2 ± 1.2 MPa to 6.2 ± 1.0 MPa (P = .04), and the mean contact area decreased from 546 ± 132 mm2 to 192 ± 122 mm2 (P = .01) compared with the intact meniscus during early stance (14% of the gait cycle). After MAT, the mean contact stress significantly decreased with bone plug fixation (5.0 ± 0.7 MPa) but not with suture-only fixation (5.9 ± 0.7 MPa). Both fixation techniques partially restored the contact area, but bone plug fixation restored it closer to the intact condition. The location of WCoCS in the central cartilage region (not covered by the meniscus) shifted peripherally throughout the stance phase. Bone plug fixation exhibited correction to this peripheral offset, but suture-only fixation did not. Conclusion: Under dynamic loading, transosseous fixation at the meniscal horns provides superior load distribution at the involved knee compartment after meniscal transplantation compared with suture-only fixation. Particular attention should be directed to the ability of medial MAT to function during the early stance phase. Clinical Relevance: Transosseous fixation via bone plugs provides superior load distribution of a transplanted meniscal allograft compared with suture fixation alone at time zero.
Asymmetric Variance Premium, Skewness Premium, and the Cross-Section of Stock Returns

We find a positive relationship between the individual stocks’ asymmetric variance premia, defined as the difference between the risk-neutral and physical expected variance asymmetries, and the future stock returns. The high-minus-low hedge portfolio earns the excess return of 72 basis points per month, the characteristicadjusted return of 66 basis points per month, and the industry-adjusted return of 79 basis points per month. They are all economically substantial and statistically highly significant. We show that asymmetric variance premium is closely related to skewness premium. Such a positive relationship can not be explained by risk-based asset pricing models. We find that the predictive power of asymmetric variance premium is information-driven and reflects trading activity of informed traders who place more transactions on options.