Participation of connexin-based channels in the control of vascular function

SUMMARYIntercellular communication is achieved at specialized regions of the plasma membrane by gap junctions. The proteins constituting the gap junctions are called connexins and are encoded by a family of genes highly conserved during evolution. In adult mouse, four connexins (Cxs) are known to be expressed in the vasculature: Cx37, Cx40, Cx43 and Cx45. Several recent studies have provided evidences that vascular connexins expression and blood pressure regulation are closely linked, suggesting a role for connexins in the control of blood pressure. However, the precise function that each vascular connexin plays under physiological and pathophysiological conditions is still not elucidated. In this context, this work was dedicated to evaluate the contribution of each of the four vascular connexins in the control of the vascular function and in the blood pressure regulation.In the present work, we first demonstrated that vascular connexins are differently regulated by hypertension in the mouse aorta. We also observed that endothelial connexins play a regulatory role on eNOS expression levels and function in the aorta, therefore in the control of vascular tone. Then, we demonstrated that Cx40 plays a pivotal role in the kidney by regulating the renal levels of COX-2 and nNOS, two key enzymes of the macula densa known to participate in the control of renin secreting cells. We also found that Cx43 forms the functional gap junction involved in intercellular Ca2+ wave propagation between vascular smooth muscle cells. Finally, we have started to generate transgenic mice expressing specifically Cx40 in the endothelium to investigate the involvement of Cx40 in the vasomotor tone, or in the renin secreting cells to evaluate the role of Cx40 in the control of renin secretion.In conclusion, this work has allowed us to identify new roles for connexins in the vasculature. Our results suggest that vascular connexins could be interesting targets for new therapies caring hypertension and vascular diseases.

Constitutively active G protein-coupled receptor mutants: implications on receptor function and drug action.

Mutations of GPCRs can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis; others occur spontaneously in human diseases. The analysis of constitutively active GPCR mutants has attracted a large interest in the past decade, providing an important contribution to our understanding of the molecular mechanisms underlying receptor function and drug action.

Do pseudo-absence selection strategies influence species distribution models and their predictions? An information-theoretic approach based on simulated data

Background Multiple logistic regression is precluded from many practical applications in ecology that aim to predict the geographic distributions of species because it requires absence data, which are rarely available or are unreliable. In order to use multiple logistic regression, many studies have simulated "pseudo-absences" through a number of strategies, but it is unknown how the choice of strategy influences models and their geographic predictions of species. In this paper we evaluate the effect of several prevailing pseudo-absence strategies on the predictions of the geographic distribution of a virtual species whose "true" distribution and relationship to three environmental predictors was predefined. We evaluated the effect of using a) real absences b) pseudo-absences selected randomly from the background and c) two-step approaches: pseudo-absences selected from low suitability areas predicted by either Ecological Niche Factor Analysis: (ENFA) or BIOCLIM. We compared how the choice of pseudo-absence strategy affected model fit, predictive power, and information-theoretic model selection results. Results Models built with true absences had the best predictive power, best discriminatory power, and the "true" model (the one that contained the correct predictors) was supported by the data according to AIC, as expected. Models based on random pseudo-absences had among the lowest fit, but yielded the second highest AUC value (0.97), and the "true" model was also supported by the data. Models based on two-step approaches had intermediate fit, the lowest predictive power, and the "true" model was not supported by the data. Conclusion If ecologists wish to build parsimonious GLM models that will allow them to make robust predictions, a reasonable approach is to use a large number of randomly selected pseudo-absences, and perform model selection based on an information theoretic approach. However, the resulting models can be expected to have limited fit.

Monitoring of illicit pill distribution networks using an image collection exploration framework

This paper proposes a novel approach for the analysis of illicit tablets based on their visual characteristics. In particular, the paper concentrates on the problem of ecstasy pill seizure profiling and monitoring. The presented method extracts the visual information from pill images and builds a representation of it, i.e. it builds a pill profile based on the pill visual appearance. Different visual features are used to build different image similarity measures, which are the basis for a pill monitoring strategy based on both discriminative and clustering models. The discriminative model permits to infer whether two pills come from the same seizure, while the clustering models groups of pills that share similar visual characteristics. The resulting clustering structure allows to perform a visual identification of the relationships between different seizures. The proposed approach was evaluated using a data set of 621 Ecstasy pill pictures. The results demonstrate that this is a feasible and cost effective method for performing pill profiling and monitoring.

Parameter estimation for the distribution of single cell lag times.

In Quantitative Microbial Risk Assessment, it is vital to understand how lag times of individual cells are distributed over a bacterial population. Such identified distributions can be used to predict the time by which, in a growth-supporting environment, a few pathogenic cells can multiply to a poisoning concentration level. We model the lag time of a single cell, inoculated into a new environment, by the delay of the growth function characterizing the generated subpopulation. We introduce an easy-to-implement procedure, based on the method of moments, to estimate the parameters of the distribution of single cell lag times. The advantage of the method is especially apparent for cases where the initial number of cells is small and random, and the culture is detectable only in the exponential growth phase.

The adaptative function of melanin-based colour variants

Résumé : Les mécanismes de contrôle des couleurs mélaniques chez les vertébrés sont encore discutés parmi les biologistes de l'évolution. Une hypothèse récente affirme que les effets pléiotropies du système des mélanocortines expliquent l'association fréquente entre la coloration eumélanique noire (due à la déposition d'eumélanine) et de nombreux traits physiologiques et comportementaux. De nombreuses études suggèrent, en effet, que des niveaux plus élevés des mélanocortines induisent l'assombrissement des téguments eumélaniques et affectent d'autres traits phénotypiques simultanément. Cependant, il n'est pas encore établi si ce mécanisme de pléiotropie peut s'appliquer aux colorations dues à la déposition de phaeomélanine, une autre forme commune de mélanine. Les antagonistes des mélanocortines déclenchent le phaeomélanogenèse et bloquent l'effet des mélanocortines ou ont un effet pharmacologique opposé. Nous nous proposons donc d'évaluer l'hypothèse que les effets pléiotropes des antagonistes des mélanocortines génèrent des covariations entre la coloration phaeomélanique et des aspects de la qualité individuelle. Comme prédit par cette hypothèse, nous constatons chez la chouette effraie (Tyto alba) que les traits phénotypiques (résistance au stress oxydatif et aux parasites) corrèlent positivement au degré d'expression d'une couleur eumélanique mais négativement au degré d'expression d'une coloration phaeomélanique. Puis, nous montrons chez la chouette hulotte (Strix aluco) que les associations génétiques entre la coloration phaeomélanique et la physiologie (immunité et la régulation de l'homéostasie) confèrent des avantages aux individus de différentes couleurs dans différents environnements caractérisés par l'abondance de nourriture et le niveau d'exposition aux parasites. Ainsi, nos études soutiennent l'hypothèse que les effets pléiotropes des antagonistes des mélanocortines génèrent des covariations entre les traits mélaniques et divers aspects de la qualité individuelle. Finalement, nous montrons chez le faucon crécerelle (Falco Tinnunculus) que l'expression des ornements mélaniques est sensible à la qualité de l'environnement dans lequel les individus grandissent. Ceci suggère que les gènes codant pour les mélanocortines et leurs antagonistes pourraient induire une expression des traits mélaniques dépendante de la condition de l'individu, un pattern d'expression rarement observé pour des traits généralement sous fort contrôle génétique. Summary : The information content and control mechanisms of melanin-based colour signals in vertebrates are still debated among evolutionary biologists. A recent hypothesis contends that pleiotropic effects of the melanocortin system accounts for the frequent association between black eumelanic coloration and physiological and behavioural traits. Accordingly, empirical evidence suggests that higher levels of melanocortins concurrently promote darker eumelanic integuments and affect other phenotypic traits. However, whether this mechanism may apply to signals relying on phaeomelanin, another common form of melanin pigments, remains to be established. Melanocortin antagonists trigger phaeomelanogenesis and block the effect of melanocortins or result in the opposite pharmacological effect. Therefore, we tested the hypothesis that pleiotropic effects of melanocortin antagonists and inverse agonists account for covariations between phaeomelanin-based coloration and aspects of individual quality. As predicted, we found that phenotypic traits (resistance to oxidative stress and parasites) correlated positively with a eumelanic trait and negatively with a phaeomelanic trait in the barn owl (Tyto alba). Then, we showed in the tawny owl (Strix aluco) that genetic associations between phaeomelanin-based coloration and physiology (immunity and regulation of energy homeostasis) confer benefits to differently coloured individuals under different levels of food abundance and parasite exposure. Altogether, our studies support the hypothesis that pleiotropic effects of melanocortins antagonists can indeed account for covariations between phaeomelanin-based traits and aspects of individual quality. Eventually, we show in the Eurasian kestrel (Falco Tinnunculus) that expression of melanin-based ornaments is sensitive to the environment in which individuals grow. This suggests that genes coding for melanocortins and their antagonists can mediate the condition-dependent component of melanin-based traits.

Running versus strength-based warm-up : acute effects on isometric knee extension function

This study investigated the influence of two warm-up protocols on neural and contractile parameters of knee extensors. A series of neuromuscular tests including voluntary and electrically evoked contractions were performed before and after running- (R (WU); slow running, athletic drills, and sprints) and strength-based (S (WU); bilateral 90 degrees back squats, Olympic lifting movements and reactivity exercises) warm ups (duration ~40 min) in ten-trained subjects. The estimated overall mechanical work was comparable between protocols. Maximal voluntary contraction torque (+15.6%; P < 0.01 and +10.9%; P < 0.05) and muscle activation (+10.9 and +12.9%; P < 0.05) increased to the same extent after R (WU) and S (WU), respectively. Both protocols caused a significant shortening of time to contract (-12.8 and -11.8% after R (WU) and S (WU); P < 0.05), while the other twitch parameters did not change significantly. Running- and strength-based warm ups induce similar increase in knee extensors force-generating capacity by improving the muscle activation. Both protocols have similar effects on M-wave and isometric twitch characteristics.

Post-detection analysis for grating-based ultra-small angle X-ray scattering.

Until recently, the hard X-ray, phase-sensitive imaging technique called grating interferometry was thought to provide information only in real space. However, by utilizing an alternative approach to data analysis we demonstrated that the angular resolved ultra-small angle X-ray scattering distribution can be retrieved from experimental data. Thus, reciprocal space information is accessible by grating interferometry in addition to real space. Naturally, the quality of the retrieved data strongly depends on the performance of the employed analysis procedure, which involves deconvolution of periodic and noisy data in this context. The aim of this article is to compare several deconvolution algorithms to retrieve the ultra-small angle X-ray scattering distribution in grating interferometry. We quantitatively compare the performance of three deconvolution procedures (i.e., Wiener, iterative Wiener and Lucy-Richardson) in case of realistically modeled, noisy and periodic input data. The simulations showed that the algorithm of Lucy-Richardson is the more reliable and more efficient as a function of the characteristics of the signals in the given context. The availability of a reliable data analysis procedure is essential for future developments in grating interferometry.

Radial forearm free flap donor site morbidity: ulnar-based transposition flap vs split-thickness skin graft.

OBJECTIVES: To evaluate morbidity associated with the radial forearm free flap donor site and to compare functional and aesthetic outcomes of ulnar-based transposition flap (UBTF) vs split-thickness skin graft (STSG) closure of the donor site.¦DESIGN: Case-control study.¦SETTING: Tertiary care institution.¦PATIENTS: The inclusion criteria were flap size not exceeding 30 cm(2), patient availability for a single follow-up visit, and performance of surgery at least 6 months previously. Forty-four patients were included in the study and were reviewed. Twenty-two patients had UBTF closure, and 22 had STSG closure.¦MAIN OUTCOME MEASURES: Variables analyzed included wrist mobility, Michigan Hand Outcomes Questionnaire scores, pinch and grip strength (using a dynamometer), and hand sensitivity (using monofilament testing over the radial nerve distribution). In analyses of operated arms vs nonoperated arms, variables obtained only for the operated arms included Vancouver Scar Scale scores and visual analog scale scores for Aesthetics and Overall Arm Function.¦RESULTS: The mean (SD) wrist extension was significantly better in the UBTF group (56.0° [10.4°] for nonoperated arms and 62.0° [9.7°] for operated arms) than in the STSG group (59.0° [7.1°] for nonoperated arms and 58.4° [12.1°] for operated arms) (P = .02). The improvement in wrist range of motion for the UBTF group approached statistical significance (P = .07). All other variables (Michigan Hand Outcomes Questionnaire scores, pinch and grip strength, hand sensitivity, and visual analog scale scores) were significantly better for nonoperated arms vs operated arms, but no significant differences were observed between the UBTF and STSG groups.¦CONCLUSIONS: The radial forearm free flap donor site carries significant morbidity. Donor site UBTF closure was associated with improved wrist extension and represents an alternative method of closure for small donor site defects.

Decoding stimulus-related information from single-trial EEG responses based on voltage topographies

Neuroimaging studies typically compare experimental conditions using average brain responses, thereby overlooking the stimulus-related information conveyed by distributed spatio-temporal patterns of single-trial responses. Here, we take advantage of this rich information at a single-trial level to decode stimulus-related signals in two event-related potential (ERP) studies. Our method models the statistical distribution of the voltage topographies with a Gaussian Mixture Model (GMM), which reduces the dataset to a number of representative voltage topographies. The degree of presence of these topographies across trials at specific latencies is then used to classify experimental conditions. We tested the algorithm using a cross-validation procedure in two independent EEG datasets. In the first ERP study, we classified left- versus right-hemifield checkerboard stimuli for upper and lower visual hemifields. In a second ERP study, when functional differences cannot be assumed, we classified initial versus repeated presentations of visual objects. With minimal a priori information, the GMM model provides neurophysiologically interpretable features - vis à vis voltage topographies - as well as dynamic information about brain function. This method can in principle be applied to any ERP dataset testing the functional relevance of specific time periods for stimulus processing, the predictability of subject's behavior and cognitive states, and the discrimination between healthy and clinical populations.

Not all inflammatory markers are linked to kidney function: results from a population-based study.

BACKGROUND: Several studies have reported increased levels of inflammatory biomarkers in chronic kidney disease (CKD), but data from the general population are sparse. In this study, we assessed levels of the inflammatory markers C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 across all ranges of renal function. METHODS: We conducted a cross-sectional study in a random sample of 6,184 Caucasian subjects aged 35-75 years in Lausanne, Switzerland. Serum levels of hsCRP, TNF-α, IL-6, and IL-1β were measured in 6,067 participants (98.1%); serum creatinine-based estimated glomerular filtration rate (eGFR(creat), CKD-EPI formula) was used to assess renal function, and albumin/creatinine ratio on spot morning urine to assess microalbuminuria (MAU). RESULTS: Higher serum levels of IL-6, TNF-α and hsCRP and lower levels of IL-1β were associated with a lower renal function, CKD (eGFR(creat) <60 ml/min/1.73 m(2); n = 283), and MAU (n = 583). In multivariate linear regression analysis adjusted for age, sex, hypertension, smoking, diabetes, body mass index, lipids, antihypertensive and hypolipemic therapy, only log-transformed TNF-α remained independently associated with lower renal function (β -0.54 ±0.19). In multivariate logistic regression analysis, higher TNF-α levels were associated with CKD (OR 1.17; 95% CI 1.01-1.35), whereas higher levels of IL-6 (OR 1.09; 95% CI 1.02-1.16) and hsCRP (OR 1.21; 95% CI 1.10-1.32) were associated with MAU. CONCLUSION: We did not confirm a significant association between renal function and IL-6, IL-1β and hsCRP in the general population. However, our results demonstrate a significant association between TNF-α and renal function, suggesting a potential link between inflammation and the development of CKD. These data also confirm the association between MAU and inflammation.

Improving telecommunication security level by integrating quantum key distribution in communication protocols

Résumé La cryptographie classique est basée sur des concepts mathématiques dont la sécurité dépend de la complexité du calcul de l'inverse des fonctions. Ce type de chiffrement est à la merci de la puissance de calcul des ordinateurs ainsi que la découverte d'algorithme permettant le calcul des inverses de certaines fonctions mathématiques en un temps «raisonnable ». L'utilisation d'un procédé dont la sécurité est scientifiquement prouvée s'avère donc indispensable surtout les échanges critiques (systèmes bancaires, gouvernements,...). La cryptographie quantique répond à ce besoin. En effet, sa sécurité est basée sur des lois de la physique quantique lui assurant un fonctionnement inconditionnellement sécurisé. Toutefois, l'application et l'intégration de la cryptographie quantique sont un souci pour les développeurs de ce type de solution. Cette thèse justifie la nécessité de l'utilisation de la cryptographie quantique. Elle montre que le coût engendré par le déploiement de cette solution est justifié. Elle propose un mécanisme simple et réalisable d'intégration de la cryptographie quantique dans des protocoles de communication largement utilisés comme les protocoles PPP, IPSec et le protocole 802.1li. Des scénarios d'application illustrent la faisabilité de ces solutions. Une méthodologie d'évaluation, selon les critères communs, des solutions basées sur la cryptographie quantique est également proposée dans ce document. Abstract Classical cryptography is based on mathematical functions. The robustness of a cryptosystem essentially depends on the difficulty of computing the inverse of its one-way function. There is no mathematical proof that establishes whether it is impossible to find the inverse of a given one-way function. Therefore, it is mandatory to use a cryptosystem whose security is scientifically proven (especially for banking, governments, etc.). On the other hand, the security of quantum cryptography can be formally demonstrated. In fact, its security is based on the laws of physics that assure the unconditional security. How is it possible to use and integrate quantum cryptography into existing solutions? This thesis proposes a method to integrate quantum cryptography into existing communication protocols like PPP, IPSec and the 802.l1i protocol. It sketches out some possible scenarios in order to prove the feasibility and to estimate the cost of such scenarios. Directives and checkpoints are given to help in certifying quantum cryptography solutions according to Common Criteria.