Miracle-dz/UniFAR-FTUs huggingface dataset:
HIV‐1 replication is controlled at the level of T cell activation and proviral integration.

During progression of the Acquired Immune Deficiency Syndrome (AIDS), the human immunodeficiency virus type 1 (HIV‐1) is harbored in CD4+ T cells, which act as the primary reservoir for the virus. In vitro, HIV‐1 requires activated T cells for a productive infection; however, in vivo, the number of circulating T cells in the activated state that are potential targets for HIV‐1 infection is low. We have investigated the ability of HIV‐1 to infect resting T cells, and the consequences of such an infection. T cell activation was not required for HIV‐1 infection; however, viral DNA was unable to integrate in resting T cells and was maintained extrachromosomally. Subsequent T cell activation allowed integration of extrachromosomal forms and led to a productive viral life cycle. Extrachromosomal forms of viral DNA were found to persist for several weeks after infection of resting T cells and, following T cell activation, these forms maintained their ability to integrate and act as a template for infectious virus. Several lines of evidence, including temporal analysis of HIV‐1 replication and analysis of an HIV‐1 integrase deletion mutant, indicated that extra‐chromosomal HIV‐1 DNA genomes were transcriptionally active. These results are compatible with a model whereby HIV‐1 can persist in a non‐productive extra‐chromosomal state in resting T cells until subsequent antigen‐induced or mitogen‐induced T cell activation, virus integration and release. Thus agents that induce T cell activation may control the rate of HIV‐1 replication and spread during AIDS progression.
Sodium and Volume Sensitivity of Blood Pressure Age and Pressure Change Over Time

Salt sensitivity has been implicated in the age-related increase in blood pressure. We studied the reproducibility of a rapid method for assessing sodium sensitivity and resistance of blood pressure as well as the effect of age on this phenomenon. Blood pressure after volume expansion with 2 1 intravenous saline (0.9%) over 4 hours was compared with that after 1 day of 10 mmol sodium chloride intake and 3 and 40 mg oral doses of furosemide. Normal and hypertensive subjects (n=28) were studied twice within a year. Cross-sectional observations of the effect of age were made from studies in 230 hypertensive and 430 normotensive subjects. Longitudinal observations of blood pressure change over time were made 10 or more years after categorization of sodium responsivity in 31 subjects. The blood pressure response was reproducible in 28 subjects studied twice (r=0.56,p<0.002). Four subjects changed salt-responsiveness status and six were indeterminate on restudy. Sodium sensitivity of blood pressure increased significantly with increasing age in the entire population (n=660, r= ‐038,p<0.001). The relation was more striking in hypertensive subjects (n=230, r= -0.31,p<0.001) in whom a progressive increase in salt sensitivity with decades was seen than in the normotensive group (n=430, r=‐0.19, p<0.01) in whom salt sensitivity was not observed until the sixth decade. Salt-sensitive subjects had a significantly greater increase in systolic (p<0.001) and diastoiic (/? <0.01) pressure over time than those who were salt-resistant Salt sensitivity is a reproducible phenomenon that is related to the age-associated increase in blood pressure characteristic of industrialized societies. In addition, salt sensitivity can be shown to be a predictor of subsequent, age-related blood pressure increase.
Noncanonical WNT‐5A signaling regulates TGF‐β‐induced extracellular matrix production by airway smooth muscle cells

Transforming growth factor β (TGF‐β), a key mediator of fibrotic responses, is increased in asthma and drives airway remodeling by inducing expression of extracellular matrix (ECM) proteins. We investigated the molecular mechanisms underlying TGF‐β‐induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF‐β and Wingless/integrase 1 (WNT) signaling in ECM deposition. Airway smooth muscle expresses abundant WNT ligands, with the noncanonical WNT‐5A being the most profoundly expressed. Interestingly, WNT‐5A shows ~2‐fold higher abundance in airway smooth muscle cells isolated from individuals with asthma than individuals without asthma. WNT‐5A is markedly induced in response to TGF‐β (4–16‐fold; EC50 0.3 ng/ml) and is required for collagen and fibronectin expression by airway smooth muscle. WNT‐5A engages noncanonical WNT signaling pathways, as inhibition of Ca2+ and c‐Jun N‐terminal kinase (JNK) signaling attenuated this TGF‐β response, whereas the canonical WNT antagonist Dickkopf 1 (DKK‐1) did not. Accordingly, WNT‐5A induced JNK phosphorylation and nuclear translocation of nuclear factor of activated T cells c1 (NFATc1). Furthermore, silencing of the WNT‐5A receptors Frizzled 8 (FZD8) and RYK attenuated TGF‐β‐induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT‐5A signaling is activated by and necessary for TGF‐β‐induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis. —Kumawat, K. , Menzen, M. H. , Bos, I. S. T. , Baarsma, H. A. , Borger, P., Roth, M. , Tamm, M. , Halayko, A. J., Simoons, M. , Prins, A. , Postma, D. S. , Schmidt, M. , and Gosens, R. Noncanonical WNT‐5A signaling regulates TGF‐β‐induced extracellular matrix production by airway smooth muscle cells. FASEB J. 27, 1631–1643 (2013). www.fasebj. org
Preliminary evaluation of a multimodal early intervention program for behaviorally inhibited preschoolers.

OBJECTIVE Approximately 15%-20% of young children can be classified as having a behaviorally inhibited (BI) temperament. Stable BI predicts the development of later anxiety disorders (particularly social anxiety), but not all inhibited children develop anxiety. Parenting characterized by inappropriate warmth/sensitivity and/or intrusive control predicts the stability of BI and moderates risk for anxiety among high-BI children. For these reasons, we developed and examined the preliminary efficacy of the Turtle Program: a multimodal early intervention for inhibited preschool-age children. METHOD Forty inhibited children between the ages of 42-60 months and their parent(s) were randomized to either the Turtle Program (n = 18) or a waitlist control (WLC; n = 22) condition. Participants randomized to the Turtle Program condition received 8 weeks of concurrent parent and child group treatment. Participants were assessed at baseline and posttreatment with multisource assessments, including parent and teacher report measures of child anxiety, diagnostic interviews, and observations of parenting behavior. RESULTS The Turtle Program resulted in significant beneficial effects relative to the WLC condition on maternal-reported anxiety symptoms of medium to large magnitude; large effects on parent-reported BI; medium to large effects on teacher-rated school anxiety symptoms; and medium effects on observed maternal positive affect/sensitivity. CONCLUSIONS This study provides encouraging preliminary support for the Turtle Program for young behaviorally inhibited children. Effects of the Turtle Program generalized to the school setting. Future studies should examine whether this early intervention program improves long-term developmental outcomes for this at-risk group.
La traversée de rue chez le piéton sénior : conception d'un simulateur, étude biomécanique et comportementale

Dans un contexte de vieillissement demographique et de mutation des modes de deplacements urbains majorant la place du pieton, ce travail de these vise a mieux comprendre les caracteristiques comportementales et biomecaniques de la traversee de rue des pietons âges. La methodologie est essentiellement experimentale. Si quelques donnees ont ete recueillies en laboratoire ou en environnement naturel, l'etude principale a ete conduite dans un simulateur immersif de realite projetee, outil denomme Simulateur de Rues pour Pietons (SRP). La hauteur de trottoir est modulable. Le dispositif integre differents outils de mesures, tels des plates-formes de force et un systeme d'analyse gestuelle en trois dimensions. Hors simulateur, la comparaison des temps de traversee reelle et estimee, sur un champ de marche, revele l'occurrence d'un risque de sous-estimation a priori du temps necessaire chez certains seniors. L'experience en simulateur confirme l'importance de la modulation exercee par le vieillissement sur la perception du temps en tant que determinant des estimations a posteriori des temps de traversees quantifiees via la sensation de mise en danger. En simulateur, les seniors adoptent un comportement securitaire, requerant des intervalles temporels plus longs pour decider d'initier une traversee. Dans des conditions de trafic favorables, ils marchent plus rapidement que les jeunes. Leurs marges de securite sont plus grandes. L'approche biomecanique, revele des differences intergroupes, dont certaines sont potentiellement a risque (ex. la flexion plantaire) alors que d’autres (ex. les rotations exploratoires) participent a l’adaptation.
Kv4.2 Phosphorylation by Cyclic AMP-dependent Protein Kinase*

Recent evidence suggests that K+ channels composed of Kv4.2 α-subunits underlie a transient current in hippocampal CA1 neurons and ventricular myocytes, and activation of the cAMP second messenger cascade has been shown to modulate this transient current. We determined if Kv4.2 α-subunits were directly phosphorylated by cAMP-dependent protein kinase (PKA). The intracellular domains of the amino and carboxyl termini of Kv4.2 were expressed as glutathioneS-transferase fusion protein constructs; we observed that both of these fusion proteins were substrates for PKA in vitro. By using phosphopeptide mapping and amino acid sequencing, we identified PKA phosphorylation sites on the amino- and carboxyl-terminal fusion proteins corresponding to Thr38and Ser552, respectively, within the Kv4.2 sequence. Kinetic characterization of the PKA sites demonstrated phosphorylation kinetics comparable to Kemptide. To evaluate PKA site phosphorylationin situ, phospho-selective antisera for each of the sites were generated. By using COS-7 cells expressing an EGFP-Kv4.2 fusion protein, we observed that stimulation of the endogenous PKA cascade resulted in an increase in phosphorylation of Thr38 and Ser552 within Kv4.2 in the intact cell. We also observed modulation of PKA phosphorylation at these sites within Kv4.2 in hippocampal area CA1. These results provide insight into likely sites of regulation of Kv4.2 by PKA.
Tripeptide feG prevents and ameliorates acute pancreatitis-associated acute lung injury in a rodent model.

BACKGROUND The synthetic tripeptide feG (D-Phe-D-Glu-Gly) is a novel pharmacologic agent that decreases neutrophil recruitment, infiltration, and activation in various animal models of inflammatory disease. We aimed to investigate the effect of feG as both a preventive treatment when administered before acute lung injury and as a therapeutic treatment administered following initiation of acute lung injury. METHODS Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a “two-hit” rodent model of acute pancreatitis plus intratracheal lipopolysaccharide. RESULTS Following both prophylactic and therapeutic feG administration, there were significant improvements in arterial blood oxygenation and respiratory mechanics and decreased lung edema, BAL protein concentration, histologic tissue injury scores, BAL cell infiltration, and lung myeloperoxidase activity. Most indices of lung damage were reduced to baseline control values. CONCLUSIONS feG reduced leukocyte infiltration, ameliorated the severity of inflammatory damage, and restored lung function when administered either prophylactically or therapeutically in a two-hit rat model of acute pancreatitis plus intratracheal lipopolysaccharide.
Etude de modalités multithérapeutiques et diagnostiques appliquées au cancer du pancréas

L'adenocarcinome du pancreas est une des causes les plus communes de deces par cancer dans les pays developpes. La plupart des patients ont la maladie localement avancee ou metastasee a l'heure du diagnostic et sont donc defavorables a la resection, tandis que la chimiotherapie et la radiotherapie sont generalement inefficaces. La therapie genique offre une alternative aux strategies auxiliaires courantes. Couramment, la therapie multi-modale a ete employee dans le traitement du cancer pour augmenter l'efficacite therapeutique, reduire la toxicite, et empecher ou retarder le developpement de la resistance. Cependant, comme les differences dans les signaux biochimiques entre les cellules normales et malignes sont habituellement insignifiantes, les combinaisons des therapies conventionnelles causent souvent des niveaux de toxicite intolerablement eleves pour la plupart des patients. En outre, la therapie genique peut egalement etre utilisee pour augmenter les voies biochimiques induites lors de la chimio- et la radiotherapie. Ainsi dans ce travail, deux objectifs ont ete fixe: l'un concerne donc la therapeutique, l'autre la detection et le diagnostic. Dans un premier temps, nous avons evalue le potentiel d'une combinaison d'une strategie de la therapie genique : deux genes suicides transferes simultanement par une solution lipidique dans un modele de carcinose peritoneale. Puis, cette meme strategie a ete utilisee en combinaison avec des agents anti-cancereux tels que la gemcitabine et le tomudex. Une autre approche des plus prometteuses en therapie genique, est l'utilisation des genes de la voie de l'apoptose, nous avons pu constate un effet synergique entre l'expression de deux genes pro-apoptotiques, bax et TRAIL et le traitement a la gemcitabine. Afin de re��pondre aux aspects critiques de la therapie genique tels que le transfert et l'efficacite du transgene, des techniques d'imagerie in vivo se sont progressivement imposees au cours de la decennie passee. Nous avons etudie la sensibilite et la specificite d'un systeme d'imagerie moleculaire de fluorescence de la GFP induite par laser, applique sur nos modeles in vivo. Ainsi, les resultats obtenus suggerent que la combinaison de la therapie du gene avec les therapies conventionnelles fournit une amelioration du traitement des cancers, particulierement pour ceux resistants aux therapies conventionnelles.
Transmembrane Asymmetry and Lateral Domains in Biological Membranes

It is generally assumed that rafts exist in both the external and internal leaflets of the membrane, and that they overlap so that they are coupled functionally and structurally. However, the two monolayers of the plasma membrane of eukaryotic cells have different chemical compositions. This out‐of‐equilibrium situation is maintained by the activity of lipid translocases, which compensate for the slow spontaneous transverse diffusion of lipids. Thus rafts in the outer leaflet, corresponding to domains enriched in sphingomyelin and cholesterol, cannot be mirrored in the inner cytoplasmic leaflet. The extent to which lipids contribute to raft properties can be conveniently studied in giant unilamellar vesicles. In these, cholesterol can be seen to condense with saturated sphingolipids or phosphatidylcholine to form μm scale domains. However, such rafts fail to model biological rafts because they are symmetric, and because their membranes lack the mechanism that establishes this asymmetry, namely proteins. Biological rafts are in general of nm scale, and almost certainly differ in size and stability in inner and outer monolayers. Any coupling between rafts in the two leaflets, should it occur, is probably transient and dependent not upon the properties of lipids, but on transmembrane proteins within the rafts.
Hydrogen Bonding of 7,8-Dihydro-8-oxodeoxyguanosine with a Charged Residue in the Little Finger Domain Determines Miscoding Events in Sulfolobus solfataricus DNA Polymerase Dpo4*♦

Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) has been shown to catalyze bypass of 7,8-dihydro-8-oxodeoxyguanosine (8-oxoG) in a highly efficient and relatively accurate manner. Crystal structures have revealed a potential role for Arg332 in stabilizing the anti conformation of the 8-oxoG template base by means of a hydrogen bond or ion-dipole pair, which results in an increased enzymatic efficiency for dCTP insertion and makes formation of a Hoogsteen pair between 8-oxoG and dATP less favorable. Site-directed mutagenesis was used to replace Arg332 with Ala, Glu, Leu, or His in order to probe the importance of Arg332 in accurate and efficient bypass of 8-oxoG. The double mutant Ala331Ala332 was also prepared to address the contribution of Arg331. Transientstate kinetic results suggest that Glu332 retains fidelity against bypass of 8-oxoG that is similar to wild type Dpo4, a result that was confirmed by tandem mass spectrometric analysis of full-length extension products. A crystal structure of the Dpo4 Glu332 mutant and 8-oxoG:C pair revealed water-mediated hydrogen bonds between Glu332 and the O-8 atom of 8-oxoG. The space normally occupied by Arg332 side chain is empty in the crystal structures of the Ala332 mutant. Two other crystal structures show that a Hoogsteen base pair is formed between 8-oxoG and A in the active site of both Glu332 and Ala332 mutants. These results support the view that a bond between Arg332 and 8-oxoG plays a role in determining the fidelity and efficiency of Dpo4-catalyzed bypass of the lesion.
Work stress and mental health in a changing society.

BACKGROUND The aim of this representative study in the Hungarian population was to analyse the association between work-related factors and self-reported mental and physical health after controlling for negative affect and hostility as personality traits. METHODS The effects of job related factors on Beck Depression Score, WHO well-being score and self-rated health (SRH) were analysed in a representative sample of 3153 male and 2710 female economically active Hungarians. RESULTS In both genders negative affect was the most important correlate of depression, well-being and SRH, whereas hostility was closely associated only with depression. Job insecurity, low control and low social support at work, weekend work hours, job-related life events and dissatisfaction with work and with boss were independent mental health risk factors, but there were important gender differences. Job related factors seem to be equally important predictors of mental health as social support from family. CONCLUSION The results of this large national representative study indicate that independent of negative affect and hostility, a cluster of stressful work-related psychosocial conditions accounts for a substantial part of variation in self-reported mental and physical health of the economically active population in Hungary.
Preoperative risk stratification using stress myocardial perfusion scintigraphy with electrocardiographic gating.

UNLABELLED This study was designed to assess the prognostic value of stress myocardial perfusion SPECT with electrocardiographic (ECG) gating in patients undergoing noncardiac surgical treatment. METHODS The study included 481 consecutive patients who underwent noncardiac surgery and had been referred for preoperative myocardial perfusion scintigraphy. Myocardial scintigraphy used (99m)Tc-labeled perfusion agents and dipyridamole stress with ECG gating, permitting qualitative and quantitative analyses of both myocardial perfusion and cardiac function. Reconstructed perfusion images were analyzed qualitatively and semiquantitatively. The Quantitative Gated SPECT (QGS) program was used for gated SPECT analysis to calculate global left ventricular ejection fraction and estimate regional wall motion. We assessed the relationships between perioperative cardiac events and various predictors, including clinical risk factors, radionuclide perfusion, and functional variables. RESULTS Univariate analysis indicated that age (P < 0.001), diabetes mellitus (P < 0.01), history of heart failure (P < 0.05) or perfusion imaging (P < 0.0001), and QGS analysis (P < 0.0001) yielded significant risk stratification. According to multivariate analysis, age, diabetes mellitus, perfusion imaging, and QGS analysis were independent predictors of perioperative cardiac events. The event rate was correlated with quantitative scintigraphic indices of perfusion images (rest perfusion and ischemic scores) and QGS analysis (global ejection fraction and the number of hypokinetic segments). Although QGS functional data offered no significant incremental prognostic value in patients with abnormal perfusion, it classified patients with normal perfusion into 2 risk groups (P < 0.0001). A combination of clinical risk factors, scintigraphic perfusion results, and functional data allowed further detailed risk stratification. CONCLUSION Stress myocardial perfusion SPECT with ECG gating has an incremental prognostic value over conventional nongated stress perfusion imaging in predicting perioperative cardiac events.
EFFICACY OF NITROGLYCERINE INFUSION VERSUS SUBLINGUAL NIFEDIPINE IN SEVERE PRE‐ECLAMPSIA: A RANDOMIZED, TRIPLE‐BLIND, CONTROLLED TRIAL

1 Information regarding the use of continuous i.v. administration of nitroglycerine as an antihypertensive agent in the management of pre‐eclampsia is scarce. In the present study, i.v. nitroglycerine or sublingual nifedipine were administered to 32 women with severe pre‐eclampsia who were being managed with controlled plasma volume expansion and MgSO4 loading and maintenance doses. Maternal blood pressure and heart rate responses, fetal heart rate responses and perinatal fetal–maternal adverse effects were evaluated using classical parametric and non‐parametric data analysis and data modelling by mixed models. 2 An important hypotensive response was observed in both groups, although this reponse was greater, faster and exhibited less variability (more precision) in the nitroglycerine‐treated group. Heart rate also increased in both the nitroglycerine‐ and nifedipine‐treated groups (4.6 ± 4.4 vs 8.6 ± 5.3 b.p.m., respectively), although the increase in the nifedipine‐treated group was almost twofold that in the nitroglycerine‐treated group. There were no significant changes in fetal heart rate in response to vasodilator therapy. The frequency of perinatal fetal–maternal adverse effects was similar in both groups at 40% and the adverse effects observed included flushing, headache, palpitations and nausea. 3 In conclusion, i.v. infusion of nitroglycerine is an effective, safe and alternative therapy for severe pre‐eclampsia.
Efferent connections of the striatum and the nucleus accumbens in the lizard Gekko gecko

The efferent connections of the striatum and the nucleus accumbens of the lizard Gekko gecko were studied with the anterograde tracer Phaseolus vulgaris‐ leucoagglutinin (PHA‐L). These structures were found to have segregated output systems. The striatum shows a major projection to the globus pallidus. Striatal fibers which are more caudally directed run through the lateral forebrain bundle and can be traced as far caudally as the pars reticularis of the substantia nigra where they exhibit many varicosities. Along its course, the lateral forebrain bundle issues fibers with varicosities to the anterior and posterior entopeduncular nuclei. The major recipient structure of the nucleus accumbens is the ventral pallidum. The nucleus accumbens, in addition, projects to the portion of the lateral hypothalamus in the path of the medial forebrain bundle and to the ventral tegmental area, which is its most caudal target.