Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of tropomyosin internal deletion Δ23Tm on isometric tension and the cross‐bridge kinetics in bovine myocardium

Tropomyosin (Tm) spans seven actin monomers and contains seven quasi‐repeating, loosely similar regions, 1–7. Deletion of regions 2–3 decreases the in vitro sliding speed of synthetic filaments of actin‐Tm‐Troponin (Tn), and weakens Tm binding to the actin‐myosin subfragment 1 (S1) complex (acto‐S1). The thin filament was selectively removed from bovine myocardium by gelsolin, and the actin filament was reconstituted, followed by further reconstitution with Tm and Tn. In this reconstitution, full‐length Tm (control) was compared with Tm internal deletion mutant Δ23Tm, which lacks residues 47–123 (regions 2–3). The effects of phosphate, MgATP, MgADP and Ca2+ were studied in Tm‐reconstituted myocardium and Δ23Tm‐reconstituted myocardium at pH 7.00 and 25 °C. In Δ23Tm, both isometric tension and stiffness were about 40 % of the control. The Hill factor with Δ23Tm, deduced from the pCa‐tension plot, was 1.4 times that of the control, but the Ca2+ sensitivity was the same. Sinusoidal analysis indicated that the cross‐bridge number in force‐generating states was not decreased with Δ23Tm. We conclude that the thin filament cooperativity is increased with Δ23Tm, presumably because of the increased density of the Ca2+‐binding sites. We further conclude that tension per cross‐bridge is 40 % of control and stiffness per cross‐bridge is 40 % of control in Δ23Tm. These results are consistent with the idea that Tm modifies the actin‐myosin interface so as to increase the stereospecific interaction between moieties of actin and myosin. In Δ23Tm, the interface may not have a perfect stereospecific match so that the tension‐ and stiffness‐generating capacity is greatly diminished.
Effector and memory CD8+ T cells as seen in immunity to malaria

Summary: Transgenic (Tg) mice carrying a T‐cell receptor (TCR) specific for a CD8+ T‐cell epitope expressed in pre‐erythrocytic stages of Plasmodium yoelii has proven to be a valuable tool to advance our understanding of this anti‐parasite T‐cell response, as it occurs in vivo. The visualization of CD8+ T cells in vivo and ex vivo greatly facilitated research aimed at characterizing basic features of this T‐cell response such as the kinetics of differentiation and proliferation and the in vivo antigen presentation. Importantly, this research unveiled the existence of early self‐regulatory mechanisms controlling the magnitude of the CD8+ T‐cell response and also identified CD4+ T cells as critical elements in the development of memory populations. This review discusses our recent research using Tg mice and highlights our progress in understanding the CD8+ T‐cell‐mediated immunity against malaria liver stages.
Characterization of Intracellular Reverse Transcription Complexes of Human Immunodeficiency Virus Type 1

ABSTRACT To examine the early events of the life cycle of human immunodeficiency virus type 1 (HIV-1), we analyzed the intracellular complexes mediating reverse transcription isolated from acutely infected cells. Partial purification of the reverse transcription complexes (RTCs) by equilibrium density fractionation and velocity sedimentation indicated that two species of RTCs are formed but only one species is able to synthesize DNA. Most of the capsid, matrix, and reverse transcriptase (RT) proteins dissociate from the complex soon after cell infection, but Vpr remains associated with the RTC. The RTCs isolated 1, 4, and 7 h after infection are competent for reverse transcription in vitro, indicating that a small proportion of RT remains associated with them. HIV RTCs isolated early after infection have a sedimentation velocity of approximately 560S. Later, different species with a sedimentation velocity ranging from 350S to 100S appear. Nuclear-associated RTCs have a sedimentation velocity of 80S. Shortly after initiation of reverse transcription, the viral strong-stop DNA within the RTC is sensitive to nuclease digestion and becomes protected when reverse transcription is almost completed.
Influence of metoprolol and propranolol on hemodynamic effects induced by adrenaline and physical work.

Abstract: The influence of intravenously administered metoprolol (10 mg), propranolol (5 and 10 mg) and saline on hemodynamic effects induced by adrenaline and physical work were studied in healthy volunteers. In the doses used the two β-blockers were approximately equipotent in reducing the heart rate and systolic blood pressure during exercise. Adrenaline induced an increase of the heart rate, systolic blood pressure and forearm blood flow, while the mean blood pressure, diastolic blood pressure and vascular resistance in the forearm decreased. The two β-blockers interacted differently with adrenaline. When adrenaline was infused after propranolol the mean and diastolic blood pressure increased as did also vascular resistance in the forearm. Adrenaline now had no significant effect on the forearm blood flow, while the heart rate decreased. After metoprolol, adrenaline still induced a decrease of the diastolic blood pressure and an increase of the forearm blood flow, but the effect of adrenaline on these variables seemed to be inhibited to a great extent. The decrease of the mean blood pressure after adrenaline was blocked by metoprolol, while the effect on the vascular resistance in the forearm and the heart rate was not significantly changed. The difference in interaction of the two β-blockers with adrenaline is interpreted as being caused by a much less pronounced effect of metoprolol on the adrenergic vascular β2-receptors compared to propranolol in the doses studied.
Interaction of Ketoconazole with Bovine Serum Albumin: Electrochemical, Spectroscopic and Molecular Modeling Studies

ABSTRACT The interaction of ketoconazole (KTZ) with bovine serum albumin (BSA) has been investigated by cyclic voltammetry, differential pulse voltammetry, UV-Vis absorption and fluorescence spectroscopy, viscosity measurements as well as molecular modeling methods. The measurements were performed in 0.1 mol L-1 phosphat buffer solution at pH = 7.4. Shifts in the peak potentials in cyclic Voltammetry, spectral changes in UV absorption and fluorescence titration, an increase in viscosity of BSA and the molecular modeling methods strongly support the electrostatic interaction between KTZ and BSA. The thermodynamic parameters ΔH, ΔG and ΔS at different temperatures were calculated, showing that the electrostatic interactions and hydrophobic interaction are the main forces for the binding of KTZ to BSA. The binding constant (Kb) determined by UV absorption and fluorescence measurements are very close to the value determined by cyclic Voltammetry assuming that the binding equilibrium is static. Moreover, from molecular modeling method, a docked structure with minimum energy was obtained in which KTZ was located in minor grooves of BSA.
Motor Actions in Retrieval of Valenced Information: A Motor Congruence Effect

To study the influence of overt behavior on the generation of valenced information participants were induced to perform either approach (arm flexion) or avoidance (arm extension) behaviors while generating the names of celebrities towards whom they had positive, negative, or neutral attitudes. Participants performing arm flexion generated more names of positively evaluated persons while participants performing arm extension tended to generate more names of negatively evaluated persons. Both self-perception and mood are discussed as potential bases for the obtained effect. In the light of our previous results, we suggest an alternative mechanism of compatibility between motor actions and information which implies that fewer cognitive resources are needed for “compatibility” than for “incompatibility. ”
Assessment of Effectiveness of Web-based Training on Demand

e-Learning is bringing training to the attention of upper management in a way that other learning technologies have never done. Web-based training will remain predominant to the design and delivery of workplace learning in the 21st century because of its advantages over traditional classroom-based training. A comprehensive framework that delineates the relationship between learner control and learning effectiveness in educational training is absent. This study therefore aims to fill this void. Unlike previous relevant research, this study compares learning effectiveness between two educational training delivery methodologies: traditional classroom-based training (TCT) and web-based training (WBT). Our framework focuses on learning effectiveness of web training in the context of the educational training programmes of two colleges' administration application systems. Based on the WBT literature, this study uses a model that investigates the relationship between learner control and learning effectiveness under five dimensions: learning performance, learner satisfaction, accumulation of learning experience, document navigation, and problem solving. To compare learning effectiveness between TCT and WBT we conducted a field experiment. Data were collected from two colleges that received training on their administration application systems. A total of 288 usable responses were analysed. The results allow five conclusions to be drawn: (1) learners receiving WBT achieved better learning performance than their counterparts receiving TCT; (2) learners receiving WBT reported higher levels of satisfaction than their counterparts with the traditional approach; (3) learners receiving WBT accumulated more learning experience than their counterparts with TCT; (4) WBT provided more integrated document navigation than the traditional format; (5) WBT offered faster problem solving mechanisms than TCT. The implications of this study are discussed and further research directions are proposed.
Neural immune modulation and immunotherapy assisted by focused ultrasound induced blood-brain barrier opening

The central nervous system (CNS) has long been regarded as an immune-privileged site, with the blood-brain barrier (BBB) limiting the entering of systemic immune cells and components. Exposure of low-energy focused ultrasound (FUS) with the presence of microbubbles has been found to provide a temporary and targeted opening of the BBB without inflicting brain damage or inflammation, and is thus an attractive means of delivering CNS therapeutic agents and raising the potential for targeted CNS immunotherapy. Based on our recent studies on enhancing brain-tumor immune-related therapy via this mechanism,1 we summarize current approaches using FUS-induced BBB opening to promote immune regulation and project potential directions for FUS-induced CNS immunotherapy.
Appropriate levels of oxygen saturation for preterm infants

Although oxygen is probably the most common therapy delivered to small or sick newborns in the past 75 years, what constitutes appropriate oxygenation for these infants remains highly controversial. The lack of direct evidence, in the form of randomised trials, of the effects of different oxygen levels on meaningful, long‐term outcomes has fuelled this controversy and contributed to the significant variation in practice currently seen. Conclusions drawn from the existing evidence regarding oxygen saturation levels for preterm infants include that retinopathy of prematurity rates may be reduced if lower saturation ranges are targeted in the early weeks of life. There is, however, no recent, good quality, trial information that has directly addressed this question. Retinopathy outcomes may also be improved if oxygen saturation is targeted higher in a subset of preterm infants with more severe eye disease in the post‐acute phase. There is now direct evidence, from randomised trials, that routine higher oxygen saturation targeting in the chronic phase confers no short‐ or long‐term growth or development benefits. Evidence is now mounting regarding the adverse pulmonary sequelae associated with routine higher, and thus longer, oxygen exposure. Information regarding oxygen saturation levels and early mortality is inconclusive. The major unanswered question that requires urgent resolution is the important long‐term effects of targeting lower versus higher oxygen saturation ranges during the first days/weeks of a preterm infant's life. Such an important clinical question can only be answered rigorously and definitively using the randomised trial methodology.
Population based Heuristic Approaches for Grid Job Scheduling

strategies and approaches have been proposed to provide quality solutions for the grid job scheduling problem. Recently population based heuristics approaches are used widely to solve this problem. These approaches have demonstrated a surprising degree of effectiveness for handling combinatorial optimization problems. In this paper, the population based approaches for grid job scheduling have been studied. The focus was on investigating the criteria that help in the selection of the best scheduling algorithm for a certain type of grid and also shedding the light on how to improve the available population based approaches.
Mice Lacking α/β Subunits of GlcNAc-1-Phosphotransferase Exhibit Growth Retardation, Retinal Degeneration, and Secretory Cell Lesions

PURPOSE. Mucolipidosis II and III (ML II; ML III) are lysosomal storage diseases characterized by a deficiency in GlcNAc-1phosphotransferase. Patients with ML III have retinal disease, but in cases of the more clinically severe ML II, human ophthalmic studies are limited. In this study, retinal function and overall disease were assessed in mice lacking GNPTAB, the gene mutated in patients with ML II. METHODS. Mice deficient in GNPTAB were generated from Omnibank, a sequence-tagged gene-trap library of 270,000 mouse embryonic stem cell clones as part of a large-scale effort to knock out, phenotypically screen, and thereby validate pharmaceutically tractable genes for drug development. Routine diagnostics, expression analysis, histopathology, and ERG analyses were performed on mice lacking GNPTAB. In addition, measurements of serum lysosomal enzymes were performed. RESULTS. Severe retinal degeneration was observed in mice deficient in GNPTAB. Heterozygous mice were phenotypically normal and in situ hybridization showed expression across the neural retina. Compared to wild-type mice, the GNPTAB homozygous mice were smaller, had elevated levels of serum lysosomal enzymes, exhibited cartilage defects, and had cytoplasmic alterations in secretory cells of several exocrine glands. CONCLUSIONS. Mice deficient in GNPTAB exhibited severe retinal degeneration. Additional features observed in patients with ML II, a lysosomal storage disease, are also present in these mice. Understanding underlying mechanisms of this gene in the eye will increase its therapeutic potential for the treatment of retinal diseases. (Invest Ophthalmol Vis Sci. 2007;48: 5221‐5228) DOI:10.1167/iovs.07-0452
The Presence of Methicillin Resistant Staphylococcus aureus (MRSA) on Environmental Surfaces in Healthcare Facilities Pre- and Post-Cleaning

iii ACKNOWLEDGEMENTS iv LIST OF TABLES ix LIST OF FIGURES x CHAPTER 1 BACKGROUND 1 CHAPTER 2 INTRODUCTION 4 Emergence of Antimicrobial Resistant Bacteria 4 Methicillin Resistant Staphylococcus aureus (MRSA) 6 Epidemiology of MRSA 8 Impact of MRSA 11 MRSA in Long-Term Care Facilities 14 Treatment of MRSA Infections 14 Routes of Transmission 15 Environmental Decontamination 17 MRSA on Environmental Surfaces 18 Objectives 23 Research Questions and Hypotheses 24 CHAPTER 3 MATERIALS AND METHODS 26 Experimental Design 26 Quality Control Organisms and Culture Media 26 Sample Collection 27 Sample Processing 28 DNA Extraction and Purification 30
Proteasome-mediated Glucocorticoid Receptor Degradation Restricts Transcriptional Signaling by Glucocorticoids*

Ligand-dependent down-regulation of the glucocorticoid receptor (GR) has been shown to limit hormone responsiveness, but the mechanisms involved in this process are poorly understood. The glucocorticoid receptor is a phosphoprotein that upon ligand binding becomes hyperphosphorylated, and recent evidence indicates that phosphorylation status of the glucocorticoid receptor plays a prominent role in receptor protein turnover. Because phosphorylation is a key signal for ubiquitination and proteasomal catabolism of many proteins, we evaluated whether the ubiquitin-proteasomal pathway had a role in glucocorticoid receptor down-regulation and the subsequent transcriptional response to glucocorticoids. Pretreatment of COS-1 cells expressing mouse glucocorticoid receptor with the proteasome inhibitor MG-132 effectively blocks glucocorticoid receptor protein down-regulation by the glucocorticoid dexamethasone. Interestingly, both MG-132 and a second proteasome inhibitor β-lactone significantly enhanced hormone response of transfected mouse glucocorticoid receptor toward transcriptional activation of glucocorticoid receptor-mediated reporter gene expression. The transcriptional activity of the endogenous human glucocorticoid receptor in HeLa cells was also enhanced by MG-132. Direct evidence for ubiquitination of the glucocorticoid receptor was obtained by immunoprecipitation of cellular extracts from proteasome-impaired cells. Examination of the primary sequence of mouse, human, and rat glucocorticoid receptor has identified a candidate PEST degradation motif. Mutation of Lys-426 within this PEST element both abrogated ligand-dependent down-regulation of glucocorticoid receptor protein and simultaneously enhanced glucocorticoid receptor-induced transcriptional activation of gene expression. Unlike wild type GR, proteasomal inhibition failed to enhance significantly transcriptional activity of K426A mutant GR. Together these findings suggest a major role of the ubiquitin-proteasome pathway in regulating glucocorticoid receptor protein turnover, thereby providing a mechanism to terminate glucocorticoid responses.
A comparison of optical and manometric methods for the assay of human serum cholinesterase.

A method for the assay of human serum cholinesterase (pseudocholinesterase) is described in detail. The disappearance of benzoylcholine is measured by ultraviolet spectrophotometry. Minute amounts of serum and of the substrate are sufficient for a rapid and convenient test of good accuracy. The influence of temperature on the reaction rate is given particular attention, since temperature control is not as easily achieved in the spectrophotometer as for instance in a Warburg apparatus. Although the results of the spectrophotometric assay are fundamentally the same as those obtained by using a conventional gasometric method with acetylcholine as a substrate, small but significant differences between the two answers occur. These differences depend on the substrates and not on the methods as such. The ratio of hydrolysis rates of the two substrates, benzoylcholine and acetylcholine, varies slightly from person to person. If benzoylcholine is used in the Warburg apparatus, a concentration above the optimum mus.
Experimental myasthenia due to alpha‐bungarotoxin

Neuromuscular transmission was studied electrophysiologically in rabbits intoxicated by α-bungarotoxin, a specific inhibitor of acetylcholine receptor. The findings consisted of a slight reduction in amplitude of single evoked muscle action potential, a decrement in amplitude of successive evoked muscle action potentials, post-tetanic potentiation and exhaustion, edrophonium reversal, and no change of muscle action potentials evoked by direct stimulation of the muscle. These were similar to characteristic electrophysiologic phenomena seen in 40 patients with myasthenia gravis. The receptor abnormality may be responsible for the underlying defect of myasthenia.
PLASMA CHOLINE: ITS TURNOVER AND EXCHANGE WITH BRAIN CHOLINE 1

—The kinetics of plasma choline (Ch) and the uptake of plasma Ch into the brain were studied by means of intravenous infusion of [2H4]Ch at various rates into anaesthetized and conscious rats. [2H4]Ch levels in both arterial and venous plasma at steady state were linearly related to the infusion rate; however, unlabelled Ch levels were independent of infusion rate. [2H4]Ch levels were higher in the arterial plasma than in the venous plasma, while unlabelled Ch levels were higher in the venous plasma than in the arterial plasma. It was concluded that Ch is being generated in the brain and is released into the venous effluent. The supply of Ch to the plasma is not decreased if the plasma Ch level is increased. The clearance and turnover of Ch in the compartment of its initial distribution are 75 ml kg‐1 min‐1 and 716 nmol kg‐1 min‐1, respectively. The uptake of plasma Ch into the brain is not saturated even at very high levels of plasma Ch.
Aberrant expression of the LHX4 LIM‐homeobox gene caused by t(1;14)(q25;q32) in chronic myelogenous leukemia in biphenotypic blast crisis

Chromosomal aberrations observed in addition to the Philadelphia chromosome in chronic myelogenous leukemia (CML) are likely to be involved in disease progression to the blast crisis. We describe here a t(1;14)(q25;q32) as an additional chromosomal aberration in a patient with CML in biphenotypic blast crisis. By use of long‐distance inverse polymerase chain reaction (PCR), we cloned the chromosomal breakpoint and revealed that the immunoglobulin heavy chain gene is fused near its Eμ enhancer region to the 5′ region of the LHX4 LIM‐homeobox gene, whose expression is restricted to the central nervous system. By use of quantitative real‐time reverse‐transcription PCR, we found that the LHX4 mRNA is expressed at high levels in the patient's leukemic cells and in an acute lymphoblastic leukemia (ALL) cell line. The aberrant expression of the LHX4 gene by the t(1;14)(q25;q32) has very recently been reported in a case of ALL, thus, representing a rare, but recurrent genetic abnormality of possible importance in leukemogenesis. © 2003 Wiley‐Liss, Inc.
Negative-balance isolated pelvic perfusion in patients with incurable symptomatic rectal cancer: results and drug dose correlation to adverse events

Background Drug leakage and lack of a drug-removal system have prevented clinical application of isolated pelvic perfusion (IPP). These barriers were overcome with negative-balance IPP (NIPP) in experimental pig models. Here, a phase 1 clinical study of NIPP was performed in patients with incurable symptomatic rectal cancer. Purpose To establish a safe regimen of high-dose regional chemotherapy with NIPP using cisplatin in patients with incurable rectal cancer. Material and Methods Between June 2004 and January 2007, NIPP therapy was performed for 23 patients (11 women, 12 men; mean age, 58 years). NIPP was routinely performed twice over a 4-week interval. Dose-limiting toxicities (DLTs) were defined using a 5 + 3 design, and cisplatin doses were escalated from 170 mg/m2, with a fixed 5-fluorouracil dose of 1000 mg/m2. The grade of adverse events (AEs) at the first and second sessions of NIPP therapy, pharmacokinetics, and antitumor response were evaluated. Results No DLTs were observed during the first session of NIPP. However, at the second session, two patients experienced the DLT of neuropathy after administration of 200 mg/m2 cisplatin. Therefore, 190 mg/m2 cisplatin was indicated as the maximum tolerated dose (MTD). The plasma pelvic-to-systemic exposure ratio was 18.4 based on the maximum concentration and 19.0 based on the concentration-time curve. Solid tumor responses included complete response in two patients, partial response in five patients, stable disease in 15 patients, and progressive disease in one patient. Conclusion NIPP may offer the safe delivery of high-dose regional chemotherapy (MTD of 190 mg/m2 cisplatin) with negligible AEs and effective control of tumor growth in patients with incurable rectal cancer.