A Protocol to Detect Local Affinities Involved in Proteins Distant Interactions

The tridimensional structure of a protein is constrained or stabilized by some local interactions between distant residues of the protein, such as disulfide bonds, electrostatic interactions, hydrogen links, Wan Der Waals forces, etc. The correct prediction of such contacts should be an important step towards the whole challenge of tridimensional structure prediction. The in silico prediction of the disulfide connectivity has been widely studied: most results were based on few amino-acids around bonded and non-bonded cysteines, which we call local environments of bonded residues. In order to evaluate the impact of such local information onto residue pairing, we propose a machine learning based protocol, independent from the type of contact, to detect affinities between local environments which would contribute to residues pairing. This protocol requires that learning methods are able to learn from examples corrupted by class-conditional classification noise. To this end, we propose an adapted version of the perceptron algorithm. Finally, we experiment our protocol with this algorithm on proteins that feature disulfide or salt bridges. The results show that local environments contribute to the formation of salt bridges. As a by-product, these results prove the relevance of our protocol. However, results on disulfide bridges are not significantly positive. There can be two explanations: the class of linear functions used by the perceptron algorithm is not enough expressive to detect this information, or cysteines local environments do not contribute significantly to residues pairing

Displacement damage effects due to neutron and proton irradiations on CMOS image sensors manufactured in deep submicron technology

Displacement damage effects due to proton and neutron irradiations of CMOS image sensors dedicated to imaging are presented through the analysis of the dark current behavior in pixel arrays and isolated photodiodes. The mean dark current increase and the dark current nonuniformity are investigated. Dark current histogram observations are compared to damage energy distributions based on GEANT 4 calculations. We also discuss, through annealing analysis, which defects could be responsible for the dark current in CMOS image sensors

Orbital alignment and mass segregation in galactic nuclei via vector resonant relaxation

Supermassive black holes dominate the gravitational potential in galactic nuclei. In these dense environments, stars follow nearly Keplerian orbits and see their orbital planes relax through the potential fluctuations generated by the stellar cluster itself. For typical astrophysical galactic nuclei, the most likely outcome of this vector resonant relaxation (VRR) is that the orbital planes of the most massive stars spontaneously self-align within a narrow disc. We present a maximum entropy method to systematically determine this long-term distribution of orientations and use it for a wide range of stellar orbital parameters and initial conditions. The heaviest stellar objects are found to live within a thin equatorial disk. The thickness of this disk depends on the stars' initial mass function, and on the geometry of the initial cluster. This work highlights a possible (indirect) novel method to constrain the distribution of intermediate mass black holes in galactic nuclei.Comment: 14 pages, 17 figures, accepted for publication in MNRA

The local GLP-1 system in the olfactory bulb is required for odor-evoked cephalic phase of insulin release in mice

Objective: The olfactory bulb (OB) codes for sensory information and contributes to the control of energy metabolism by regulating foraging and cephalic phase responses. Mitral cells are the main output neurons of the OB. The glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) system in the OB (GLP-1ᴼᴮ) has been shown to be a major regulator of mitral cell activity but its function in vivo is unclear. Therefore, we investigated the role of GLP-1ᴼᴮ in foraging behavior and odor-evoked Cephalic Phase Insulin Release (CPIR)./ Methods and results: By fluorescent labeling, we confirmed the presence of GLP-1 producing neurons and the expression of GLP-1R in the mouse OB. In response to food odor presentation, we collected blood, quantified plasma insulin by ELISA and showed the existence of an odor-evoked CPIR in lean mice but its absence in obese animals. Expression of shRNA against preproglucagon mRNA in the OB resulted in blunted CPIR in lean mice. Injecting Exendin (9-39), a GLP-1R antagonist, into the OB of lean mice also resulted in decreased CPIR. Since parasympathetic cholinergic input to the pancreas is known to be partly responsible for CPIR, we systemically administered the muscarinic M3 receptor antagonist 4-DAMP which resulted in a reduced odor-evoked CPIR. Finally, local injection of Exendin (9-39) in the OB extinguished olfactory foraging in lean mice whereas the injection of the GLP-1R agonist Exendin-4 rescued the loss of foraging behavior in obese mice./ Conclusions: Our results demonstrate that GLP-1ᴼᴮ controls olfactory foraging and is required for odor-evoked CPIR. We describe a new crucial brain function for GLP-1 and GLP-1R expressed within the brain

The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis and its deterioration during aging

OBJECTIVE: Islets secrete neurotransmitters including glutamate which participate in fine regulation of islet function. The excitatory ionotropic glutamate receptor GluK2 of the kainate receptor family is widely expressed in brain and also found in islets, mainly in alpha and gamma cells. alpha cells co-release glucagon and glutamate and the latter increases glucagon release via ionotropic glutamate receptors. However, neither the precise nature of the ionotropic glutamate receptor involved nor its role in glucose homeostasis is known. As isoform specific pharmacology is not available, we investigated this question in constitutive GluK2 knock-out mice (GluK2-/-) using adult and middle-aged animals to also gain insight in a potential role during aging. METHODS: We compared wild-type GluK2+/+ and knock-out GluK2-/- mice using adult (14-20 weeks) and middle-aged animals (40-52 weeks). Glucose (oral OGTT and intraperitoneal IPGTT) and insulin tolerance as well as pyruvate challenge tests were performed according to standard procedures. Parasympathetic activity, which stimulates hormones secretion, was measured by electrophysiology invivo. Isolated islets were used invitro to determine islet beta-cell electrical activity on multi-electrode arrays and dynamic secretion of insulin as well as glucagon was determined by ELISA. RESULTS: Adult GluK2-/- mice exhibit an improved glucose tolerance (OGTT and IPGTT), and this was also apparent in middle-aged mice, whereas the outcome of pyruvate challenge was slightly improved only in middle-aged GluK2-/- mice. Similarly, insulin sensitivity was markedly enhanced in middle-aged GluK2-/- animals. Basal and glucose-induced insulin secretion invivo was slightly lower in GluK2-/- mice, whereas fasting glucagonemia was strongly reduced. Invivo recordings of parasympathetic activity showed an increase in basal activity in GluK2-/- mice which represents most likely an adaptive mechanism to counteract hypoglucagonemia rather than altered neuronal mechanism. Invitro recording demonstrated an improvement of glucose-induced electrical activity of beta-cells in islets obtained from GluK2-/- mice at both ages. Finally, glucose-induced insulin secretion invitro was increased in GluK2-/- islets, whereas glucagon secretion at 2mmol/l of glucose was considerably reduced. CONCLUSIONS: These observations indicate a general role for kainate receptors in glucose homeostasis and specifically suggest a negative effect of GluK2 on glucose homeostasis and preservation of islet function during aging. Our observations raise the possibility that blockade of GluK2 may provide benefits in glucose homeostasis especially during aging.Transistors multimodaux sensibles aux ions à polymères ambivalents pour biocapteurs hybridesIdentification de biomarqueurs du stress et de l'inflammation des cellules B pancréatiques en explorant les communications inter-organes dans des modèles précliniques d'obésité et de diabète de type

Glucose-Induced O2 Consumption Activates Hypoxia Inducible Factors 1 and 2 in Rat Insulin-Secreting Pancreatic Beta-Cells

Glucose increases the expression of glycolytic enzymes and other hypoxia-response genes in pancreatic beta-cells. Here, we tested whether this effect results from the activation of Hypoxia-Inducible-factors (HIF) 1 and 2 in a hypoxia-dependent manner

Odor-Induced Neuronal Rhythms in the Olfactory Bulb Are Profoundly Modified in ob/ob Obese Mice

Leptin, the product of the Ob(Lep) gene, is a peptide hormone that plays a major role in maintaining the balance between food intake and energy expenditure. In the brain, leptin receptors are expressed by hypothalamic cells but also in the olfactory bulb, the first central structure coding for odors, suggesting a precise function of this hormone in odor-evoked activities. Although olfaction plays a key role in feeding behavior, the ability of the olfactory bulb to integrate the energy-related signal leptin is still missing. Therefore, we studied the fate of odor-induced activity in the olfactory bulb in the genetic context of leptin deficiency using the obese ob/ob mice. By means of an odor discrimination task with concomitant local field potential recordings, we showed that ob/ob mice perform better than wild-type (WT) mice in the early stage of the task. This behavioral gain of function was associated in parallel with profound changes in neuronal oscillations in the olfactory bulb. The distribution of the peaks in the gamma frequency range was shifted toward higher frequencies in ob/ob mice compared to WT mice before learning. More notably, beta oscillatory activity, which has been shown previously to be correlated with olfactory discrimination learning, was longer and stronger in expert ob/ob mice after learning. Since oscillations in the olfactory bulb emerge from mitral to granule cell interactions, our results suggest that cellular dynamics in the olfactory bulb are deeply modified in ob/ob mice in the context of olfactory learning

Prosthetic repair of fractured fangs in military working dogs

During training sessions, the fangs of dogs used for defence are subjected to major forces, which may lead to dental fractures. Among the several protocols of prosthetic repair tested by army veterinarians, two were preferred: repair using alloy prosthesis with a Richemond-type monobloc intraradicular post, and prosthesis combining an inlay Core and cast crown. A total of 192 fang prostheses were installed in 102 military working dogs between 2000 and 2004, of which 111 (58%) were still in place on December 31, 2004. This experience has lead to the proposal of guidelines for each technique. The current trend is to repair the first fractured fang with the technique combining inlay core and cast crown, in an attempt to restore the balance between forces applied to the teeth, and prevent further fractures.Pendant l’entraînement, les crocs des chiens de défense sont soumis à des contraintes importantes, qui peuvent entraîner leur fracture. Les vétérinaires militaires ont testé plusieurs protocoles de réparation prothétique et en ont retenu deux : la reconstitution par prothèse en alliage avec tenon intraradiculaire monobloc de type « Richemond » et la prothèse associant une reconstitution de type « Inlay core » et une couronne coulée. Cent quatre vingt douze prothèses de crocs ont été posées sur 102 chiens militaires entre 2000 et 2004, dont 111 (58 %) sont toujours en place au 31/12/2004. L’expérience acquise a permis de proposer un concept d’utilisation de chaque technique. L’orientation actuelle du traitement est de reconstituer le premier croc fracturé par la technique associant Inlay core et couronne collée, espérant rétablir un équilibre des forces appliquées sur les dents et de prévenir l’apparition d’autres fractures