Miracle-dz/UniFAR-FTUs huggingface dataset:
An unexplained sequestration of latrunculin A is required in neutrophils for inhibition of actin polymerization.

Latrunculin A (LatA) is a toxic natural product that causes disruption of the actin cytoskeleton in many eukaryotic cells at submicromolar concentrations. LatA has been found to bind G-actin with a dissociation constant of 0.2 microM, and more recently to bind profilin-G-actin and, weakly, thymosin beta4-G-actin. A number of investigators have used LatA as a G-actin sequestering agent. Thus, we studied neutrophil chemotaxis and its requisite conversion of G-actin to F-actin, supported by an extensive pool of G-actin, mainly bound to thymosin beta4. Calculations suggest that the affinity of LatA is insufficient to cause significant sequestration of this pool, and the pool's buffering action should protect neutrophils from depletion of productive G-actin species by submicromolar LatA. Nonetheless, we found that both chemoattractant stimulated migration and F-actin polymerization in neutrophils were inhibited by LatA at these concentrations. The latter effect was accompanied by sequestration of LatA and showed a cell density dependence that was consistent with G-actin sequestration. The apparent contradiction between the calculations and the experimental observations could be reconciled by assuming the presence of an accessory species, of unknown normal function, which forms a high affinity ternary complex with LatA and G-actin, thus causing the cells to concentrate LatA. Other models that could not be ruled out also invoke new actions of LatA, suggesting caution in the interpretation of its effects on cells.
Obesity-Related Pulmonary Arterial Hypertension in Rats Correlates with Increased Circulating Inflammatory Cytokines and Lipids and with Oxidant Damage in the Arterial Wall but not with Hypoxia

Obesity is causally linked to a number of comorbidities, including cardiovascular disease, diabetes, renal dysfunction, and cancer. Obesity has also been linked to pulmonary disorders, including pulmonary arterial hypertension (PAH). It was long believed that obesity-related PAH was the result of hypoventilation and hypoxia due to the increased mechanical load of excess body fat. However, in recent years it has been proposed that the metabolic and inflammatory disturbances of obesity may also play a role in the development of PAH. To determine whether PAH develops in obese rats in the absence of hypoxia, we assessed pulmonary hemodynamics and pulmonary artery (PA) structure in the diet-resistant/diet-induced obesity (DR/DIO) and Zucker lean/fatty rat models. We found that high-fat feeding (DR/DIO) or overfeeding (Zucker) elicited PA remodeling, neomuscularization of distal arterioles, and elevated PA pressure, accompanied by right ventricular (RV) hypertrophy. PA thickening and distal neomuscularization were also observed in DIO rats on a low-fat diet. No evidence of hypoventilation or chronic hypoxia was detected in either model, nor was there a correlation between blood glucose or insulin levels and PAH. However, circulating inflammatory cytokine levels were increased with high-fat feeding or calorie overload, and hyperlipidemia and oxidant damage in the PA wall correlated with PAH in the DR/DIO model. We conclude that hyperlipidemia and peripheral inflammation correlate with the development of PAH in obese subjects. Obesity-related inflammation may predispose to PAH even in the absence of hypoxia.
Use of home blood pressure measurements to diagnose "white coat hypertension' in general practice.

Mercury sphygmomanometers are the gold standard in blood pressure (BP) measurement. However, white coat hypertension can only be diagnosed by using either continuous ambulatory monitoring or home BP recording. Between 10% and 20% of patients under treatment for hypertension have white coat hypertension and most do not need medication. There have been no reports from general practice in the UK of the use of home recording which seems well suited to it. The aim of this study was to confirm the feasibility of carrying out validation procedures of a UA751 semi-automatic sphygmomanometer and to use it to diagnose white coat hypertension in one practice. Firstly, the validation consisted of tests based on the British Hypertension Societies (BHS) published methods. Simultaneous BP measurements were made with the UA751 and a mercury sphygmomanometer, using a t-tube, of 45 random normotensive and hypertensive patients. Validation readings were mercury instrument means 155/83 (s.d.s 25 and 11), UA751 means 156/85 (s.d.s 25 and 10). The proportion of acceptable differences between the readings placed the UA751 in the BHS Guidelines Grade 'B'. Secondly, to detect white coat hypertension, 52 consecutive new or poorly controlled hypertensive patients took a series of home BP readings. Five patients with white coat hypertension were found. We concluded that it is feasible to use the UA751 to diagnose white coat hypertension in general practice where most hypertensive patients are exclusively managed. Used for this specific purpose, it would be extremely cost effective, precluding many patients from unnecessary medication and saving substantial costs in drugs and other resources.
Regulation of PD‐1, PD‐L1, and PD‐L2 expression during normal and autoimmune responses

Newer members of the B7‐CD28 superfamily include the receptor PD‐1 and its two ligands, PD‐L1 and PD‐L2. Here, we characterize the expression of PD‐1, PD‐L1, and PD‐L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non‐obese diabetic (NOD) mice and brain from mice with experimental autoimmune encephalomyelitis (EAE). In naive mice, proteiexpression of PD‐1, PD‐L1, and PD‐L2 was detected in the thymus, while PD‐1 and PD‐L1 were detected in the spleen. PD‐L1, but not PD‐L2, was also detected at low levels on cardiac endothelium, pancreatic islets, and syncyciotrophoblasts in the placenta. In pre‐diabetic NOD mice, PD‐1 and PD‐L1 were expressed on infiltrating cells in the pancreatic islets. Furthermore, PD‐L1 was markedly up‐regulated on islet cells. In brains from mice with EAE, PD‐1, PD‐L1, and PD‐L2 were expressed on infiltrating inflammatory cells, and PD‐L1 was up‐regulated on endothelium within EAE brain. The distinct expression patterns of PD‐L1 and PD‐L2 led us to compare their transcriptional regulation in STAT4–/–, STAT6–/–, or NF‐κB p50–/–p65+/– dendritic cells (DC). PD‐L2, but not PD‐L1, expression was dramatically reduced in p50–/–p65+/– DC. Thus, PD‐L1 and PD‐L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level.
A comparison of the effects of propofol and sevoflurane on the systemic toxicity of intravenous bupivacaine in rats.

UNLABELLED We compared the effects of propofol and sevoflurane on bupivacaine-induced central nervous system and cardiovascular toxicity in rats. Thirty-four male Sprague-Dawley rats were anesthetized with 70% N2O/30% O2 plus the 50% effective dose (ED50) of propofol (propofol group, n = 12); 70% N2O/30% O2 plus ED50 of sevoflurane (sevoflurane group, n = 11); or 70% N2O/30% O2 (control group, n = 11). Bupivacaine was infused at a constant rate of 2 mg x kg(-1) x min(-1) while electrocardiogram, electroencephalogram, and invasive arterial pressure were continuously monitored. The cumulative doses of bupivacaine that induced dysrhythmias, seizures, and 50% reduction of heart rate were larger in the propofol and sevoflurane groups than in the control group. The cumulative dose of bupivacaine that induced a 50% reduction in the mean arterial blood pressure was larger in the propofol group than in the sevoflurane and control groups. The margin of safety, assessed by the time between the onset of dysrhythmias and 50% reduction of mean arterial blood pressure, was wider in the propofol group than in the sevoflurane group. We conclude that propofol and sevoflurane attenuate bupivacaine-induced dysrhythmias and seizures and that propofol has a wider margin of safety than sevoflurane. IMPLICATIONS In anesthetized patients, dysrhythmias may be the only warning sign of intravascular injection of bupivacaine. Because propofol has a wider margin of safety than sevoflurane, life-threatening cardiovascular depression may be prevented by stopping the injection of bupivacaine at the onset of dysrhythmias during propofol anesthesia.
A Novel Developmental Role for Dopaminergic Signaling to Specify Hypothalamic Neurotransmitter Identity*

Hypothalamic neurons expressing histamine and orexin/hypocretin (hcrt) are necessary for normal regulation of wakefulness. In Parkinson's disease, the loss of dopaminergic neurons is associated with elevated histamine levels and disrupted sleep/wake cycles, but the mechanism is not understood. To characterize the role of dopamine in the development of histamine neurons, we inhibited the translation of the two non-allelic forms of tyrosine hydroxylase (th1 and th2) in zebrafish larvae. We found that dopamine levels were reduced in both th1 and th2 knockdown, but the serotonin level and number of serotonin neurons remained unchanged. Further, we demonstrated that th2 knockdown increased histamine neuron number and histamine levels, whereas increased dopaminergic signaling using the dopamine precursor l-DOPA (l-3,4-dihydroxyphenylalanine) or dopamine receptor agonists reduced the number of histaminergic neurons. Increases in the number of histaminergic neurons were paralleled by matching increases in the numbers of hcrt neurons, supporting observations that histamine regulates hcrt neuron development. Finally, we show that histaminergic neurons surround th2-expressing neurons in the hypothalamus, and we suggest that dopamine regulates the terminal differentiation of histamine neurons via paracrine actions or direct synaptic neurotransmission. These results reveal a role for dopaminergic signaling in the regulation of neurotransmitter identity and a potential mechanism contributing to sleep disturbances in Parkinson's disease.
Lipopolysaccharide potentiates platelet responses via toll-like receptor 4-stimulated Akt-Erk-PLA2 signalling

Lipopolysaccharide (LPS) from the cell envelope of Gram-negative bacteria is a principal cause of the symptoms of sepsis. LPS has been reported to modulate the function of platelets although the underlying mechanisms of LPS action in these cells remain unclear. Platelets express the Toll-like receptor 4 (TLR4) which serves as a receptor for LPS, although the potential role of TLR4 and associated cell signalling in controlling platelet responses to LPS has not been extensively explored. In this study, we therefore investigated the actions of LPS prepared from different strains of Escherichia coli on platelet function, the underlying signalling mechanisms, and the potential role of TLR4 in orchestrating these. We report that LPS increased the aggregation of washed platelets stimulated by thromboxane (U46619) or GPVI collagen receptor agonists, effects that were prevented by a TLR4 antagonist. Associated with this, LPS enhanced fibrinogen binding, P-selectin exposure and reactive oxygen species (ROS) release. Increase of ROS was found to be important for the actions of LPS on platelets, since these were inhibited in the presence of superoxide dismutase or catalase. The effects of LPS were associated with phosphorylation of Akt, ERK1/2 and PLA2 in stimulated platelets, and inhibitors of PI3-kinase, Akt and ERK1/2 reduced significantly LPS enhanced platelet function and associated ROS production. Furthermore, inhibition of platelet cyclooxygenase or the thromboxane receptor, revealed an important role for thromboxane A2. We therefore conclude that LPS increases human platelet activation through a TLR4-PI3K-Akt-ERK1/2-PLA2 -dependent pathway that is dependent on ROS and TXA2 formation.
Dual-loop controller for LLC resonant converters using an average equivalent circuit

LLC resonant converters are widely employed in industrial applications due to their high efficiency and power density. The design of closed-loop controllers for these converters is particularly challenging due to its non-linear behaviour and many different operating modes. The traditional linear techniques that are usually employed for this application require complex analysis or the use of empirical methods to obtain the small signal transfer functions of the system. This paper proposes a method to design a dual-loop controller using a simplified average model of the LLC resonant converter at resonant frequency. It is shown that the resonant condition represents the worst-case scenario from the control point of view, and that can be used as a reference point for designing the compensators. The theoretical analysis is validated by simulation and experimental results using a 150 W LLC resonant converter prototype.
Predicting Childhood Obesity Prevention Behaviors Using Social Cognitive Theory: Children in China

Four commonly suggested public health strategies to combat childhood obesity are limiting television viewing, encouraging daily physical activity, increasing fruit and vegetable intake, and increasing water consumption. This study examined the extent to which selected social cognitive theory constructs can predict these four behaviors in upper elementary Chinese children. A 55-item valid and reliable scale was administered to 282 fifth-graders. Minutes of physical activity was predicted by self-efficacy to exercise and number of times taught at school (R2 = 0.198). Hours of TV watching was predicted by self-efficacy of watching less than two hours of TV (R2 = 0.155). Glasses of water consumed was predicted by self-efficacy for drinking water, gender, and number of times taught about physical activity at school (R2 = 0.100). Servings of fruits and vegetables consumed was predicted by self-efficacy of eating fruits and vegetables (R2 = 0.197). Social cognitive theory offers a useful framework for designing primary prevention interventions to reduce childhood obesity.
Serum Cytokine Levels, Cigarette Smoking and Airway Responsiveness among Pregnant Women

Background: Five to twenty percent of healthy, nonasthmatic individuals exhibit airway hyperreactivity. Because cytokines are important intermediates in airway responses, we investigated the relationship between serum cytokines and airway responsiveness in a well-characterized population of pregnant women. Methods: We analyzed serum levels of interleukin-4 (IL-4), IL-5, IL-6, interferon-γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in frozen sera from 240 pregnant nonasthmatic subjects from a previous study of airway responsiveness and preterm labor for their relationship to methacholine challenge test results. Results: Serum IFN-γ and GM-CSF levels were significantly related to levels of methacholine airway responsiveness among nonasthmatics in this population. Nonasthmatics with PD20 <8 µmol (the highest level of airway responsiveness) had the highest mean serum levels of IFN-γ and GM-CSF, those with 8 ≤ PD20 ≤ 50 µmol had intermediate levels, and those with PD20 >50 µmol had the lowest levels. Both serum IFN-γ and GM-CSF levels were also significantly related to the log dose-response slope for methacholine responsiveness. These relationships were confirmed in a multiple linear regression analysis controlling for age, ethnic background, and cigarette smoking. Current smoking was uniformly associated with decreased cytokine levels. Conclusion: IFN-γ, GM-CSF, and other cytokines may be useful serum markers in population studies of airway responsiveness.
Initiation of Embryo Implantation and Maintenance of Early Pregnancy in the Rat by Chlordecone (Kepone)

Abstract The effect of chlordecone (Kepone), an insecticide/fungicide with reproductive toxicity, on the early stages of pregnancy in the rat was studied. Intraperitoneal injection of chlordecone into adult virgin female Holtzman strain rats before mating, in doses as high as 80 mg/kg, did not prevent fertilization, early development of the embryo to the blastocyst stage, transport of the embryo through the oviduct, or its implantation into the uterus. However, a single dose of 60 or 80 mg/kg, but not 20 or 40 mg/kg, before mating significantly reduced the concentration of progesterone in the serum of rats undergoing normal embryo implantation 5 days later. A dose of 80 mg/kg of chlordecone reduced progesterone levels in the serum by more than 50% within 48 hr in ovariectomized rats with Silastic tubing implants containing crystalline progesterone. This dose of chlordecone induced deciduomata formation in progesterone-primed ovariectomized rats to the same extent as 1 μg of estradiol benzoate. The minimal effective single dose of chlordecone to initiate implantation of blastocysts in the uteri of hypophysectomized progesterone-primed rats, and to maintain embryo development for at least 5 days, was 50 mg/kg. Daily doses of 20 mg/kg for 3 or 5 days were effective at initiating implantation but did not maintain pregnancy. The latter treatment, however, did not prevent initiation of implantation or embryo development induced by subsequent administration of estrone. The results are consistent with the view that chlordecone is a weak estrogen that has both nongenomic and genomic estrogenic actions.
Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation

ABSTRACT Originally, itraconazole for parenteral administration was licensed in a 40% hydroxypropyl-beta-cyclodextrin (HPBCD) solution for intravenous administration. A novel formulation, the NanoCrystal formulation (NCF), was prepared. NCF consists of drug particles of approximately 200 to 300 nm. The pharmacokinetics of itraconazole and its hydroxy metabolite in healthy subjects were evaluated after single and multiple doses of itraconazole as NCF. In the single-ascending-dose (SAD) study, itraconazole doses were planned to range from 50 to 500 mg, while in the multiple-ascending-dose (MAD) study, itraconazole doses of 100, 200, and 300 mg as NCF were studied, as was one dose level (200 mg) as an HBPCD solution. Samples were collected in heparinized tubes at various time points and were analyzed by high-performance liquid chromatography to allow full pharmacokinetic analysis both after the first dose and on day 7. The results of both the SAD and the MAD studies indicated that there was a dose dependency in the half-life of itraconazole from the novel formulation, increasing from 44 h (100 mg) to more than 150 h (300 mg) once steady state was achieved. Similar dose-dependent effects were observed for the hydroxy metabolite. The areas under the concentration-time curves for itraconazole and hydroxyitraconazole were also dose dependent. The pharmacokinetic profiles after 200-mg doses of itraconazole as NCF and HPBCD formulations were comparable with respect to the terminal half-life, both after a single dose and at steady state. NCF may provide an alternative to the HPBCD solution for the further optimization of antifungal treatment with itraconazole.
Psychophysique de la lecture en basse vision : simulation de scotome, modélisation et développement d'aides visuelles

Cette these s'inscrit dans le cadre d'analyses psychophysiques de la vision avec scotome central, pathologie perturbant les performances visuelles des patients et entrainant le developpement d'une ou plusieurs zones peripheriques de fixation (PRL). Son but est de mieux comprendre les phenomenes perceptifs et oculomoteurs qui limitent les capacites des patients a extraire l'information visuelle necessaire a la lecture d'un texte. Le premier axe de recherche a consiste a developper un simulateur de scotome afin d'etudier la lecture de phrases. Nous avons ainsi demontre (1) le faible effet de l'interligne sur les performances de lecture des sujets avec scotomes centraux, suggerant que l'effet de l'encombrement sur la vitesse de lecture est relativement moins important que les diffi cultes oculomotrices et attentionnelles, et (2) que le nombre de saccades est un predicteur majeur de la vitesse de lecture, plutot que la composante horizontale des saccades progressives, suggerant qu'une partie du probleme de la lecture en basse vision peut provenir de l'integration spatio-temporelle des donnees visuelles. L'utilisation du simulateur nous a egalement permis de mettre en evidence l'effet et de la decomposition syllabique d'un mot sur son temps de reconnaissance. Le deuxieme axe de recherche a consiste en la definition et l'implementation d'un modele mathematique permettant de definir l'extraction d'information visuelle a chaque fixation pour des champs visuels avec ou sans scotomes centraux. Ce modele se base sur la reconnaissance de pixels, ce qui permet de definir des strategies oculomotrices de lecture 2D contrairement aux autres modeles de lecture. En simulant un scotome central symetrique, ce modele suggere clairement l'optimalite d'une strategie utilisant une PRL situee au dessus ou en dessous du scotome pour reconnaitre un mot isolite. Le troisieme axe de recherche concerne Navisio, un logiciel d'aide a la lecture qui permet de diminuer le probleme de navigation present lors de la lecture d'un document complexe chez les patients basse vision. Navisio a ete teste sur des patients basse-vision, et permet une augmentation de leurs performances en terme de vitesse de lecture et de confort. Ces travaux combinent ainsi la mise en evidence de nouveaux axes theoriques concernant les limites des performances de lecture des patients avec scotomes centraux, et la definition de methodes d'afichage et d'outils logiciels permettant l'augmentation des performances de lecture des patients.
Plasma glucose levels and outcome after aneurysmal subarachnoid hemorrhage.

Plasma glucose levels were studied in 616 patients admitted within 72 hours after subarachnoid hemorrhage (SAH). Glucose levels measured at admission showed a statistically significant association with Glasgow Coma Scale scores, Botterell grade, deposition of blood on computerized tomography (CT) scans, and level of consciousness at admission. Elevated glucose levels at admission predicted poor outcome. A good recovery, as assessed by the Glasgow Outcome Scale at 3 months, occurred in 70.2% of patients with normal glucose levels (< or = 120 mg/dl) and in 53.7% of patients with hyperglycemia (> 120 mg/dl) (p = 0.002). The death rates for these two groups were 6.7% and 19.9%, respectively (p = 0.001). The association was still maintained after adjusting for age (> or < or = 50 years) and thickness of clot on CT scans (thin or thick) in the subset of patients who were alert/drowsy at admission. Increased mean glucose levels between Days 3 and 7 also predicted a worse outcome; good recovery was observed in 132 (73.7%) of 179 patients who had normal mean glucose levels (< or = 120 mg/dl) and 160 (49.7%) of 322 who had elevated mean glucose levels (> 120 mg/dl) (p < 0.0001). Death occurred in 6.7% and 20.8% of the two groups, respectively (p < 0.0001). It is concluded that admission plasma glucose levels can serve as an objective prognostic indicator after SAH. Elevated glucose levels during the 1st week after SAH also predict a poor outcome. However, a causal link between hyperglycemia and outcome after delayed cerebral ischemia, although suggested by experimental data, cannot be established on the basis of this study.