Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice.

Dyslipidemia is a known risk factor for cardiovascular diseases and may associate with renal injury. Using mouse models with various degrees of hypercholesterolemia and hypertryliceridemia, we investigated the effects of lipids on the renin-angiotensin system (RAS). ApoE-/- mice were fed either a high fat diet (HF-ApoE-/-; mice developed hypertriglyceridemia and severe hypercholesterolemia) or regular chow (R-ApoE(-/-); mice developed less severe hypercholesterolemia only). Renal histopathology in the HF-ApoE-/- revealed massive lipid accumulation especially at the glomerular vascular pole. In these mice plasma renin concentration was significantly reduced (489+/-111 ng/(ml h) versus 1023+/-90 ng/(ml h) in R-ApoE-/- mice) and blood pressure was consequently significantly lower than in R-ApoE-/- (104+/-2 mmHg versus 115+/-2 mmHg, respectively). A model of renin-dependent renovascular hypertension (two-kidney, one clip) was generated and HF-ApoE-/- mice proved unable to increase renin secretion, and blood pressure, in response to diminished renal perfusion as compared to regular chow fed mice (665+/-90 ng/(ml h) versus 2393+/-372 ng/(ml h), respectively and 106+/-3 mmHg versus 140+/-2 mmHg, respectively). Hypertriglyceridemia and severe hypercholesterolemia are associated with renal lipid deposition and impaired renin secretion in ApoE-/- mice exposed to high fat diet. These observations further characterize the phenotype of this widely used mouse model and provide a rationale for the use of these mice to study lipid induced organ damage.

Neogene antecedents of the modern human hand and its relation to bipedalism

El present projecte s'ha dut a terme a l'American Museum of Natural History (AMNH, New York) entre el 31 de Desembre de 2010 i el 30 de Desembre de 2012. L'objectiu del projecte era elucidar la història evolutiva de la mà humana: traçar els canvis evolutius en la seva forma i proporcions que van propiciar la seva estructura moderna que permet als humans manipular amb precisió. El treball realitzat ha inclòs recol•lecció de dades i anàlisis, redacció de resultats i formació en mètodes analítics específics. Durant aquest temps, l'autor a completat la seva de base de dades existent en mesures lineals de la mà a hominoides. També s'han agafat dades del peu; d'aquesta forma ara mateix es compta amb una base de dades amb més de 500 individus, amb més de 200 mesures per cada un. També s'han agafat dades en tres imensions utilitzant un làser escàner. S'han après tècniques de morfometria geomètrica 3D directament dels pioners al camp a l'AMNH. Com a resultat d'aquesta feina s'han produït 10 resums (publicats a congressos internacionals) i 9 manuscrits (molts d'ells ja publicats a revistes internacionals) amb resultats de gran rellevància: La mà humana posseeix unes proporcions relativament primitives, que són més similars a les proporciones que tenien els hominoides fòssils del Miocè que no pas a la dels grans antropomorfs actuals. Els darrers tenen unes mans allargades amb un polzes molt curts que reflexen l'ús de la mà com a eina de suspensió sota les branques. En canvi, els hominoides del Miocè tenien unes mans relativament curtes amb un polze llarg que feien servir per estabilitzar el seu pes quan caminaven per sobre de les branques. Una vegada els primers homínids van aparèixer al final del Miocè (fa uns 6 Ma) i van començar a fer servir el bipedisme com a mitjà més comú de locomoció, les seves mans van ser "alliberades" de les seves funcions locomotores. La selecció natural—ara només treballant en la manipulació—va convertir les proporcions ja existents de la mà d'aquests primats en l'òrgan manipulatori que representa la mà humana avui dia.

NCoR1 is a conserved physiological modulator of muscle mass and oxidative function.

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function.

Effect of dronedarone on renal function in healthy sujects

Rapport de synthèse : But : Evaluer l'effet de la dronédarone sur la fonction rénale et le transport tubulaire des cations. Méthodes : Douze sujets masculins en bonne santé ont été inclus dans une étude randomisée, croisée, comparée à un placebo, en double aveugle. Ils ont reçu 400 mg de dronédarone ou un placebo deux fois par jour pendant sept jours. Des tests fonctionnels rénaux ont été effectués avant le traitement et en cours de traitement après une standardisation stricte des apports, par détermination de la clairance de la créatinine, de la sinistrine, du para-amino-hippurate (PAH) et du N-méthylnicotinamide (NMN) et de l'excrétion des électrolytes. Résultats : Comparée au placebo, la dronédarone a réduit de manière significative la clairance de la créatinine (en moyenne 138-119 ml/min après dronédarone vs 142-149 ml/min après placebo) et la clairance du NMN (448-368 ml/min vs 435-430 ml/min), mais n'a pas eu d'effet sur la clairance rénale de la sinistrine, du PAH ou sur d'autres paramètres rénaux. Conclusion : La dronédarone réduit la clairance rénale de la créatinine et du NMN d'environ 18%, sans évidence d'effet sur la filtration glomérulaire, sur le flux plasmatique rénal ou sur les échanges électrolytiques. Cela suggère une inhibition spécifique partielle du transport tubulaire organique des cations (OCT). Une augmentation limitée de la créatininémie est donc à attendre sous traitement de dronédarone, sans que cela ne soit assimilable à une baisse de la fonction rénale.

Relationship between imatinib population pharmacokinetics and alpha-1-acid glycoprotein

Objectives: Considering the large inter-individual differences in the function of the systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. Among those known systems is alpha-1-acid glycoprotein (AGP), a circulating protein that strongly binds imatinib. This observational study aimed to explore the influence of plasma AGP on imatinib pharmacokinetics. Methods: A population pharmacokinetic analysis was performed using NONMEM based on 278 plasma samples from 51 oncologic patients, for whom both total imatinib and AGP plasma concentrations were measured. The influence of this biological covariate on oral clearance and volume of distribution was examined. Results: A one-compartment model with first-order absorption appropriately described the data. A hyperbolic relationship between plasma AGP levels and oral clearance, as well as volume of distribution was observed. A mechanistic approach was built up, postulating that only the unbound imatinib concentration was able to undergo first-order elimination through an unbound clearance process, and integrating the dissociation constant as a parameter in the model. This approach allowed determining an average (± SEM) free clearance of 1310 (± 172) L/h and a volume of distribution of 301 (± 23) L. By comparison, the total clearance previously determined was 14 (± 1) L/h. Free clearance was affected by body weight and pathology diagnosis. Moreover, this model provided consistent estimates of the association constant between imatinib and AGP (5.5?106 L/mol) and of the average in vivo free fraction of imatinib (1.1%). The variability observed (17% for free clearance and 66% for volume of distribution) was less than the one previously reported without considering AGP impact. AGP explained indeed about one half of the variability observed in total imatinib disposition. Conclusion: Such findings clarify in part the in vivo impact of protein binding on imatinib disposition and might raise again the question whether high levels of AGP could represent a resistance factor to imatinib. This remains however questionable, as it is not expected to affect free drug concentrations. On the other hand, would imatinib be demonstrated as a drug requiring therapeutic drug monitoring, either the measurement of free concentration or the correction of the total concentration by the actual AGP plasma levels should be considered for accurate interpretation of the results.

Pharmacological stimulation of edar signaling in the adult enhances sebaceous gland size and function.

Impaired ectodysplasin A (EDA) receptor (EDAR) signaling affects ectodermally derived structures including teeth, hair follicles, and cutaneous glands. The X-linked hypohidrotic ectodermal dysplasia (XLHED), resulting from EDA deficiency, can be rescued with lifelong benefits in animal models by stimulation of ectodermal appendage development with EDAR agonists. Treatments initiated later in the developmental period restore progressively fewer of the affected structures. It is unknown whether EDAR stimulation in adults with XLHED might have beneficial effects. In adult Eda mutant mice treated for several weeks with agonist anti-EDAR antibodies, we find that sebaceous gland size and function can be restored to wild-type levels. This effect is maintained upon chronic treatment but reverses slowly upon cessation of treatment. Sebaceous glands in all skin regions respond to treatment, although to varying degrees, and this is accompanied in both Eda mutant and wild-type mice by sebum secretion to levels higher than those observed in untreated controls. Edar is expressed at the periphery of the glands, suggesting a direct homeostatic effect of Edar stimulation on the sebaceous gland. Sebaceous gland size and sebum production may serve as biomarkers for EDAR stimulation, and EDAR agonists may improve skin dryness and eczema frequently observed in XLHED.

Adaptação cultural e validação do instrumento The Bowel Function in the Community para o Brasil

Estudos sobre hábito intestinal, considerando cultura, hábitos alimentares e de vida entre outros, não existem no Brasil. O objetivo deste artigo é apresentar o The Bowel Function in the Community, ferramenta específica para avaliação do hábito intestinal das populações, adaptado e validado para o Brasil. O processo de adaptação cultural incluiu tradução, retrotradução e avaliação por comitê de especialistas, obtendo-se uma versão traduzida do instrumento, posteriormente submetida a análises que atestaram a validade de conteúdo do mesmo. A confiabilidade inter-observadores e estabilidade (teste-reteste) foram confirmadas por níveis de concordância de boa a excelente e de moderada a excelente para a maioria das questões e agrupamentos do instrumento. Concluiu-se que a versão adaptada do instrumento pode ser aplicada em nosso meio para dar continuidade ao processo de validação, bem como para ampliar o conhecimento do hábito intestinal na população brasileira.

Targeted Gene Deletion and In Vivo Analysis of Putative Virulence Gene Function in the Pathogenic Dermatophyte Arthroderma benhamiae.

Dermatophytes cause the majority of superficial mycoses in humans and animals. However, little is known about the pathogenicity of this specialized group of filamentous fungi, for which molecular research has been limited thus far. During experimental infection of guinea pigs by the human pathogenic dermatophyte Arthroderma benhamiae, we recently detected the activation of the fungal gene encoding malate synthase AcuE, a key enzyme of the glyoxylate cycle. By the establishment of the first genetic system for A. benhamiae, specific ΔacuE mutants were constructed in a wild-type strain and, in addition, in a derivative in which we inactivated the nonhomologous end-joining pathway by deletion of the A. benhamiae KU70 gene. The absence of AbenKU70 resulted in an increased frequency of the targeted insertion of linear DNA by homologous recombination, without notably altering the monitored in vitro growth abilities of the fungus or its virulence in a guinea pig infection model. Phenotypic analyses of ΔacuE mutants and complemented strains depicted that malate synthase is required for the growth of A. benhamiae on lipids, major constituents of the skin. However, mutant analysis did not reveal a pathogenic role of the A. benhamiae enzyme in guinea pig dermatophytosis or during epidermal invasion of the fungus in an in vitro model of reconstituted human epidermis. The presented efficient system for targeted genetic manipulation in A. benhamiae, paired with the analyzed infection models, will advance the functional characterization of putative virulence determinants in medically important dermatophytes.

Assembling genes from predicted exons in linear time with dynamic programming

In a number of programs for gene structure prediction in higher eukaryotic genomic sequences, exon prediction is decoupled from gene assembly: a large pool of candidate exons is predicted and scored from features located in the query DNA sequence, and candidate genes are assembled from such a pool as sequences of nonoverlapping frame-compatible exons. Genes are scored as a function of the scores of the assembled exons, and the highest scoring candidate gene is assumed to be the most likely gene encoded by the query DNA sequence. Considering additive gene scoring functions, currently available algorithms to determine such a highest scoring candidate gene run in time proportional to the square of the number of predicted exons. Here, we present an algorithm whose running time grows only linearly with the size of the set of predicted exons. Polynomial algorithms rely on the fact that, while scanning the set of predicted exons, the highest scoring gene ending in a given exon can be obtained by appending the exon to the highest scoring among the highest scoring genes ending at each compatible preceding exon. The algorithm here relies on the simple fact that such highest scoring gene can be stored and updated. This requires scanning the set of predicted exons simultaneously by increasing acceptor and donor position. On the other hand, the algorithm described here does not assume an underlying gene structure model. Indeed, the definition of valid gene structures is externally defined in the so-called Gene Model. The Gene Model specifies simply which gene features are allowed immediately upstream which other gene features in valid gene structures. This allows for great flexibility in formulating the gene identification problem. In particular it allows for multiple-gene two-strand predictions and for considering gene features other than coding exons (such as promoter elements) in valid gene structures.

PPAR expression and function during vertebrate development.

The peroxisome proliferator activated receptors (PPARs) are ligand activated receptors which belong to the nuclear hormone receptor family. As with other members of this superfamily, it is thought that the ability of PPAR to bind to a ligand was acquired during metazoan evolution. Three different PPAR isotypes (PPARalpha, PPARbeta, also called 6, and PPARgamma) have been identified in various species. Upon binding to an activator, these receptors stimulate the expression of target genes implicated in important metabolic pathways. The present article is a review of PPAR expression and involvement in some aspects of Xenopus laevis and rodent embryonic development. PPARalpha and beta are ubiquitously expressed in Xenopus early embryos but become more tissue restricted later in development. In rodents, PPARalpha, PPARbeta and PPARgamma show specific time- and tissue-dependent patterns of expression during fetal development and in the adult animals. PPARs are implicated in several aspects of tissue differentiation and rodent development, such as differentiation of the adipose tissue, brain, placenta and skin. Particular attention is given to studies undertaken by us and others on the implication of PPARalpha and beta in rodent epidermal differentiation.

Hepatitis C virus proteins: from structure to function.

Great progress has been made over the past years in elucidating the structure and function of the hepatitis C virus (HCV) proteins, most of which are now actively being pursued as antiviral targets. The structural proteins, which form the viral particle, include the core protein and the envelope glycoproteins E1 and E2. The nonstructural proteins include the p7 viroporin, the NS2 protease, the NS3-4A complex harboring protease and NTPase/RNA helicase activities, the NS4B and NS5A proteins, and the NS5B RNA-dependent RNA polymerase. NS4B is a master organizer of replication complex formation while NS5A is a zinc-containing phosphoprotein involved in the regulation of HCV RNA replication versus particle production. Core to NS2 make up the assembly module while NS3 to NS5B represent the replication module (replicase). However, HCV proteins exert multiple functions during the viral life cycle, and these may be governed by different structural conformations and/or interactions with viral and/or cellular partners. Remarkably, each viral protein is anchored to intracellular membranes via specific determinants that are essential to protein function in the cell. This review summarizes current knowledge of the structure and function of the HCV proteins and highlights recent advances in the field.

Line bisection by eye and by hand reveal opposite biases

The vision-for-action literature favours the idea that the motor output of an action - whether manual or oculomotor - leads to similar results regarding object handling. Findings on line bisection performance challenge this idea: healthy individuals bisect lines manually to the left of centre, and to the right of centre when using eye fixation. In case that these opposite biases for manual and oculomotor action reflect more universal compensatory mechanisms that cancel each other out to enhance overall accuracy, one would like to observe comparable opposite biases for other material. In the present study, we report on three independent experiments in which we tested line bisection (by hand, by eye fixation) not only for solid lines, but also for letter lines; the latter, when bisected manually, is known to result in a rightward bias. Accordingly, we expected a leftward bias for letter lines when bisected via eye fixation. Analysis of bisection biases provided evidence for this idea: manual bisection was more rightward for letter as compared to solid lines, while bisection by eye fixation was more leftward for letter as compared to solid lines. Support for the eye fixation observation was particularly obvious in two of the three studies, for which comparability between eye and hand action was increasingly adjusted (paper-pencil versus touch screen for manual action). These findings question the assumption that ocular motor and manual output are always inter-changeable, but rather suggest that at least for some situations ocular motor and manual output biases are orthogonal to each other, possibly balancing each other out.

Anti-Nogo-A Antibody Treatment Promotes Recovery of Manual Dexterity after Unilateral Cervical Lesion in Adult Primates--re-examination and Extension of Behavioral Data.

In rodents and nonhuman primates subjected to spinal cord lesion, neutralizing the neurite growth inhibitor Nogo-A has been shown to promote regenerative axonal sprouting and functional recovery. The goal of the present report was to re-examine the data on the recovery of the primate manual dexterity using refined behavioral analyses and further statistical assessments, representing secondary outcome measures from the same manual dexterity test. Thirteen adult monkeys were studied; seven received an anti-Nogo-A antibody whereas a control antibody was infused into the other monkeys. Monkeys were trained to perform the modified Brinkman board task requiring opposition of index finger and thumb to grasp food pellets placed in vertically and horizontally oriented slots. Two parameters were quantified before and following spinal cord injury: (i) the standard 'score' as defined by the number of pellets retrieved within 30 s from the two types of slots; (ii) the newly introduced 'contact time' as defined by the duration of digit contact with the food pellet before successful retrieval. After lesion the hand was severely impaired in all monkeys; this was followed by progressive functional recovery. Remarkably, anti-Nogo-A antibody-treated monkeys recovered faster and significantly better than control antibody-treated monkeys, considering both the score for vertical and horizontal slots (Mann-Whitney test: P = 0.05 and 0.035, respectively) and the contact time (P = 0.008 and 0.005, respectively). Detailed analysis of the lesions excluded the possibility that this conclusion may have been caused by differences in lesion properties between the two groups of monkeys.