A general stochastic matching model on multigraphs

We extend the general stochastic matching model on graphs introduced in (Mairesse and Moyal, 2016), to matching models on multigraphs, that is, graphs with self-loops. The evolution of the model can be described by a discrete time Markov chain whose positive recurrence is investigated. Necessary and sufficient stability conditions are provided, together with the explicit form of the stationary probability in the case where the matching policy is `First Come, First Matched'

Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency

Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. Objective: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. Design: The study design comprised single-nucleotide polymorphism genotyping and mutation detection. Setting: The study was conducted at secondary and tertiary referral centers. Patients: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. Interventions: There were no interventions. Results: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. Conclusions: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD

Calcium-dependent mitochondrial cAMP production enhances aldosterone secretion

Glomerulosa cells secrete aldosterone in response to agonists coupled to Ca2+ increases such as angiotensin II and corticotrophin, coupled to a cAMP dependent pathway. A recently recognized interaction between Ca2+ and cAMP is the Ca2+-induced cAMP formation in the mitochondrial matrix. Here we describe that soluble adenylyl cyclase (sAC) is expressed in H295R adrenocortical cells. Mitochondrial cAMP formation, monitored with a mitochondria-targeted fluorescent sensor (4mtH30), is enhanced by HCO3 - and the Ca2+ mobilizing agonist angiotensin II. The effect of angiotensin II is inhibited by 2-OHE, an inhibitor of sAC, and by RNA interference of sAC, but enhanced by an inhibitor of phosphodiesterase PDE2A. Heterologous expression of the Ca2+ binding protein S100G within the mitochondrial matrix attenuates angiotensin II-induced mitochondrial cAMP formation. Inhibition and knockdown of sAC significantly reduce angiotensin II-induced aldosterone production. These data provide the first evidence for a cell-specific functional role of mitochondrial cAMP. © 2015 Elsevier Ireland Ltd

Holocene land cover and population dynamics in southern France

International audienceThis paper describes long-term changes in human population andvegetation cover in southern France, using summed radiocarbon probabilitydistributions and site count data as population proxies and informationfrom fossil pollen cores as a proxy for past land cover. Southern France isparticularly well-suited to this type of study as a result of previousprogrammes of intensive survey work and excavation in advance of largescale construction. These make it possible to calibrate the larger scale occupation patterns in the light of the visibility issues created by the burial of archaeological sites beneath alluvial sediments. For purposes of analysis the region was divided into three biogeographical zones, going from the Mediterranean coast to the middle Rhône valley. All the different population proxies in a given zone show broadly similar patterns of fluctuation, though with varying levels of resolution. The long-term patterns in the different zones all show significant differences from the overall regional pattern but this is especially the case for the non-mediterranean middle Rhône area. Cluster analysis of pollen samples has been carried out to identify the mainregional land cover types through the Holocene, which are increasingly dominated by open types over time. A variety of other pollen indicators show evidence of increasing human impact through time. Measures of human impact correlate strongly with the population proxies. A series of thresholds are identified in the population-human impact trajectory that are related to other changes in the cultural sequence. The lack of independent climate data for the region means that its impact cannot currently be assessed with confidence. However, for the later periods it is clear that the incorporation of southern France into larger regional systems played a major role in accounting for changes in land cover and settlement

POMC: The Physiological Power of Hormone Processing.

Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon

Signaling interactions in the adrenal cortex

The major physiological stimuli of aldosterone secretion are angiotensin II (AII) and extracellular K+ whereas cortisol production is primarily regulated by corticotrophin (ACTH) in fasciculata cells. AII triggers Ca2+ release from internal stores that is followed by store-operated and voltage-dependent Ca2+ entry whereas K+-evoked depolarisation activates voltage-dependent Ca2+ channels. ACTH acts primarily through the formation of cAMP and subsequent protein phosphorylation by protein kinase A. Both Ca2+ and cAMP facilitate the transfer of cholesterol to mitochondrial inner membrane. The cytosolic Ca2+ signal is transferred into the mitochondrial matrix and enhances pyridine nucleotide reduction. Increased formation of NADH results in increased ATP production whereas that of NADPH supports steroid production. In reality, the control of adrenocortical function is a lot more sophisticated with second messengers crosstalking and mutually modifying each other’s pathways. Cytosolic Ca2+ and cGMP are both capable of modifying cAMP metabolism whilst cAMP may enhance Ca2+ release and voltage-activated Ca2+ channel activity. Besides, mitochondrial Ca2+ signal brings about cAMP formation within the organelle and this further enhances aldosterone production. Maintained aldosterone and cortisol secretion are optimized by the concurrent actions of Ca2+ and cAMP, as exemplified by the apparent synergism of Ca2+ influx (inducing cAMP formation) and Ca2+ release during response to AII. Thus, cross-actions of parallel signal transducing pathways are not mere intracellular curiosities but rather substantial phenomena which fine-tune the biological response. Our review focuses on these functionally relevant interactions between the Ca2+ and the cyclic nucleotide signal transducing pathways hitherto described in the adrenal cortex

Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

The result of our previous study has shown that the K-ras mutant (pK568MRSV) transfected human adrenocortical cells can significantly increase cortisol production and independently cause cell transformation. The aim of this study is to investigate the effect of the active K-ras oncogene on the cortisol production in normal human adrenocortical cells. First we used isopropyl thiogalactoside to induce the inducible mutant K-ras expression plasmid, pK568MRSV, in the stable transfected human adrenocortical cells. The result showed that the increase of RasGTP levels in transfected cells was time-dependent after isopropyl thiogalactoside induction. Additionally, results from Western blot analysis revealed significant elevation in phosphorylation of c-Raf-1 and Mitogen-activated protein kinase. We also detected the levels of mRNA encoding Cholesterol side-chain cleavage enzyme (P450SCC), 17α-Hydroxylase/17,20-lyase (P450c17) and 3β-Hydroxysteroid dehydrogenase (3βHSD) were increased in human adrenocortical cells transfected with mutant K-ras after IPTG treatment. The increase of mRNA amount in P450scc P450c17 and 3βHSD and the elevation of cortisol level were inhibited with a pretreatment of PD098059, a specific extracellular signal-regulated kinase inhibitor. In our previous report, we proved that lovastatin, a pharmacological inhibitor of p21ras function, also reversed the increase of cortisol level in mutant K-ras stably transfected human adrenocortical cells. Taken together, these findings proved that the active mutant Ras enhanced not only cell proliferation but also steroidogenesis in steroidogenic phenotype cells by activating Raf-MEK-MAPK related signal transduction pathway. Therefore, we believe that K-ras mutants influence regulation of steroidogenesis in adrenocortical cells through RAF-MEK-MAPK pathway

SU(VAR)3-7 Links Heterochromatin and Dosage Compensation in Drosophila

In Drosophila, dosage compensation augments X chromosome-linked transcription in males relative to females. This process is achieved by the Dosage Compensation Complex (DCC), which associates specifically with the male X chromosome. We previously found that the morphology of this chromosome is sensitive to the amounts of the heterochromatin-associated protein SU(VAR)3-7. In this study, we examine the impact of change in levels of SU(VAR)3-7 on dosage compensation. We first demonstrate that the DCC makes the X chromosome a preferential target for heterochromatic markers. In addition, reduced or increased amounts of SU(VAR)3-7 result in redistribution of the DCC proteins MSL1 and MSL2, and of Histone 4 acetylation of lysine 16, indicating that a wild-type dose of SU(VAR)3-7 is required for X-restricted DCC targeting. SU(VAR)3-7 is also involved in the dosage compensated expression of the X-linked white gene. Finally, we show that absence of maternally provided SU(VAR)3-7 renders dosage compensation toxic in males, and that global amounts of heterochromatin affect viability of ectopic MSL2-expressing females. Taken together, these results bring to light a link between heterochromatin and dosage compensation

Autour de la stabilité de différents modèles d'appariements aléatoires

Stochastic matching models represent many concrete stochastic systems in which elements of different classes are matched according to specified compatibility rules. For example, we can cite systems dedicated to organs allocation, job search sites, housing allocation programs, etc. Such models are typically associated to a triplet of elements: a connected graph, called compatibility graph, whose vertices represent the classes of elements that can enter the system and whose edges connect two compatible classes, a matching policy which decides the matches to be concretely executed, in case of multiple choices, and an arrival rate according to which the elements enter within it. In this thesis, we consider generalized graphs, meaning that we allow the matching of two elements of the same class, and we therefore extend to this framework some results already known in the case of simple graphs.The stability of a system governed by a matching model is a very important property. It ensures that the admissions within the system under study, are regulated, so that the elements do not accumulate in the system in the long run. It is therefore essential that the arrival rate of the elements allows the system to be stable. In this manuscript, we characterize, algebraically, this stability region for some matching models (general, general with reneging, bipartite, extended bipartite) or skill-based queueing systems.Moreover, we demonstrate that the matching policy called First Come, First Matched (FCFM) has the property of being (generalized) maximal, meaning that the stability region of the general matching model associated with a compatibility graph and with any policy is always included in the one associated with this same graph and ruled by FCFM. Note that this latter then coincides with a set of measures defined by purely algebraic conditions. In this case, the study of stability of the matching model at hand boils down to the more elementary question of characterizing of a deterministic set of measures. We then give a (simple) way to construct the measures belonging to the latter set. This turns out to be very useful for admission control, as checking the algebraic conditions requires a number of operations which is polynomial in the number of vertices of the considered compatibility graph, and therefore becomes very expensive as the number of vertices grows large.We also give, in a product form, the expression of the stationary distribution of the number-in-system process of a stable system governed by a general matching model and under the FCFM policy, allowing, in particular, to explicitly calculate characteristics at equilibrium of concrete systems and to estimate their long-time performance. We can thus, for example, calculate the size average at equilibrium of a waiting list in the case of cross-donation of kidneys, or even, estimate the average waiting time on a peer-to-peer interface or on a dating website.Finally, the matching rates associated with a stable matching model (general or extended bipartite) are studied. They are defined as the asymptotic frequencies of the executed respective matchings, and provide an insightful performance criterion for the corresponding matching systems, as well as the policy-insensitivity and fairness properties of the matching rates, which are also discussed.Les modèles d'appariements aléatoires représentent de nombreux systèmes stochastiques concrets dans lesquels des éléments de différentes classes sont appariés selon des règles de compatibilités spécifiées. Par exemple, on peut citer les systèmes dédiés à l'allocation d'organes, les sites de recherche d'emplois, de logements, etc. De tels modèles sont toujours associés à un triptyque d'éléments : un graphe connexe, dit de compatibilités, dont les sommets représentent les classes des éléments pouvant entrer dans le système et dont chaque arête relie deux classes compatibles, une politique d'appariements permettant de décider, en cas d'incertitude, quels appariements vont s'effectuer à l'intérieur du système, et un taux d'arrivées selon lequel les éléments entrent en son sein. Dans cette thèse, nous considérons des graphes généralisés, c'est-à-dire que l'on autorise l'appariement de deux éléments de la même classe, et nous étendons donc à ce cadre certains résultats déjà connus dans le cas de graphes simples.La stabilité d'un système régi par un modèle d'appariements est une propriété très importante. En effet, elle assure que les admissions au sein du système étudié sont contrôlées de sorte que les éléments ne restent pas bloqués à l'intérieur et que leur nombre n'augmente pas indéfiniment.Il est donc essentiel que le taux d'arrivées des éléments permette au système d'être stable. Dans ce manuscrit, nous caractérisons de manière algébrique cette zone de stabilité pour certains modèles d'appariements (généraux, généraux avec abandons, bipartis, bipartis étendus) ou de files d'attente, dites skill-based.Par ailleurs, nous démontrons que la politique d'appariements dite First Come, First Matched (FCFM) possède la propriété d'être maximale (généralisée), c'est-à-dire que la zone de stabilité du modèle d'appariements général associé à un graphe de compatibilités et à une politique quelconque est toujours incluse dans celle associée à ce même graphe et à FCFM. Notons que cette dernière coïncide alors avec un ensemble de mesures défini par des conditions purement algébriques. Dans ce cas, la question de l'étude des mesures permettant la stabilité des systèmes régis par un modèle d'appariements revient donc à celle, plus élémentaire, de la caractérisation d'un ensemble déterministe. Nous donnons alors un moyen de construction (simple) des mesures appartenant à celui-ci, ce qui peut s'avérer très utile pour calibrer le contrôle d'accès au système. En effet, la vérification algorithmique qu'une mesure quelconque vérifie ces conditions algébriques nécessite un nombre d'opérations polynomial en le nombre de sommets du graphe, et devient donc très coûteuse à mesure que ce cardinal augmente.Nous explicitons également, sous une forme produit, l'expression de la loi stationnaire de l'évolution temporelle du contenu d'un système stable régi par un modèle d'appariements général et sous la politique FCFM, permettant, notamment, de calculer explicitement des caractéristiques à l'équilibre de systèmes concrets et d'estimer leurs performances en temps long. On peut ainsi, par exemple, calculer la taille moyenne à l'équilibre d'une liste d'attente dans le cadre de dons croisés de reins, ou encore, estimer le temps moyen d'attente sur une interface pair-à-pair ou un site de rencontres.Enfin, les taux d'appariements associés à un modèle d'appariements (général ou biparti étendu) stable sont étudiés. Ils sont définis comme étant les fréquences asymptotiques des appariements réalisés et fournissent un critère de performance des systèmes régis par de tels modèles d'appariements, de même que les propriétés de politique-insensibilité et d'équité de ces taux, qui sont également discutées

Around the stability of different stochastic matching models

Les modèles d'appariements aléatoires représentent de nombreux systèmes stochastiques concrets dans lesquels des éléments de différentes classes sont appariés selon des règles de compatibilités spécifiées. Par exemple, on peut citer les systèmes dédiés à l'allocation d'organes, les sites de recherche d'emplois, de logements, etc. De tels modèles sont toujours associés à un triptyque d'éléments : un graphe connexe, dit de compatibilités, dont les sommets représentent les classes des éléments pouvant entrer dans le systèmeet dont chaque arête relie deux classes compatibles, une politique d'appariements permettant de décider, en cas d'incertitude, quels appariements vont s'effectuer à l'intérieur du système, et un taux d'arrivées selon lequel les éléments entrent en son sein. Dans cette thèse, nous considérons des graphes généralisés, c'est-à-dire que l'on autorise l'appariement de deux éléments de la même classe, et nous étendons donc à ce cadre certains résultats déjà connus dans le cas de graphes simples. La stabilité d'un système régi par un modèle d'appariements est une propriété très importante. En effet, elle assure que les admissions au sein du système étudié sont contrôlées de sorte que les éléments ne restent pas bloqués à l'intérieur et que leur nombre n'augmente pas indéfiniment. Il est donc essentiel que le taux d'arrivées des éléments permette au système d'être stable. Dans ce manuscrit, nous caractérisons de manière algébrique cette zone de stabilité pour certains modèles d'appariements (généraux, généraux avec abandons, bipartis, bipartis étendus) ou de files d'attente, dites skill-based. Par ailleurs, nous démontrons que la politique d'appariements dite First Come, First Matched (FCFM) possède la propriété d'être maximale (généralisée), c'est-à-dire que la zone de stabilité du modèle d'appariements général associé à un graphe de compatibilités et à une politique quelconque est toujours incluse dans celle associée à ce même graphe et à FCFM. Notons que cette dernière coïncide alors avec un ensemble de mesures défini par des conditions purement algébriques. Dans ce cas, la question de l'étude des mesures permettant la stabilité des systèmes régis par un modèle d'appariements revient donc à celle, plus élémentaire, de la caractérisation d'un ensemble déterministe. Nous donnons alors un moyen de construction (simple) des mesures appartenant à celui-ci, ce qui peut s'avérer très utile pour calibrer le contrôle d'accès au système. En effet, la vérification algorithmique qu'une mesure quelconque vérifie ces conditions algébriques nécessite un nombre d'opérations polynomial en le nombre de sommets du graphe, et devient donc très coûteuse à mesure que ce cardinal augmente. Nous explicitons également, sous une forme produit, l'expression de la loi stationnaire de l'évolution temporelle du contenu d'un système stable régi par un modèle d'appariements général et sous la politique FCFM, permettant, notamment, de calculer explicitement des caractéristiques à l'équilibre de systèmes concrets et d'estimer leurs performances en temps long. On peut ainsi, par exemple, calculer la taille moyenne à l'équilibre d'une liste d'attente dans le cadre de dons croisés de reins, ou encore, estimer le temps moyen d'attente sur une interface pair-à-pair ou un site de rencontres.Enfin, les taux d'appariements associés à un modèle d'appariements (général ou biparti étendu) stable sont étudiés. Ils sont définis comme étant les fréquences asymptotiques des appariements réalisés et fournissent un critère de performance des systèmes régis par de tels modèles d'appariements, de même que les propriétés de politique-insensibilité et d'équité de ces taux, qui sont également discutées.Stochastic matching models represent many concrete stochastic systems in which elements of different classes are matched according to specified compatibility rules. For example, we can cite systems dedicated to organs allocation, job search sites, housing allocation programs, etc. Such models are typically associated to a triplet of elements: a connected graph, called compatibility graph, whose vertices represent the classes of elements that can enter the system and whose edges connect two compatible classes, amatching policy which decides the matches to be concretely executed, in case of multiple choices, and an arrival rate according to which the elements enter within it. In this thesis, we consider generalized graphs, meaning that we allow the matching of two elements of the same class, and we therefore extend to this framework some results already known in the case of simple graphs.The stability of a system governed by a matching model is a very important property. It ensures that the admissions within the system under study, are regulated, so that the elements do not accumulate in the system in the long run. It is therefore essential that the arrival rate of the elements allows the system to be stable. In this manuscript, we characterize, algebraically, this stability region for some matching models (general, general with reneging, bipartite, extended bipartite) or skill-based queueing systems.Moreover, we demonstrate that the matching policy called First Come, First Matched (FCFM) has the property of being (generalized) maximal, meaning that the stability region of the general matching model associated with a compatibility graph and with any policy is always included in the one associated with this same graph and ruled by FCFM. Note that this latter then coincides with a set of measures defined by purely algebraic conditions. In this case, the study of stability of the matching model at hand boils down to the more elementary question of characterizing of a deterministic set of measures. We then givea (simple) way to construct the measures belonging to the latter set. This turns out to be very useful for admission control, as checking the algebraic conditions requires a number of operations which is polynomial in the number of vertices of the considered compatibility graph, and therefore becomes very expensive as the number of vertices grows large.We also give, in a product form, the expression of the stationary distribution of the number-in-system process of a stable system governed by a general matching model and under the FCFM policy, allowing, in particular, to explicitly calculate characteristics at equilibrium of concrete systems and to estimate their long-time performance. We can thus, for example, calculate the size average at equilibrium of a waiting list in the case of cross-donation of kidneys, or even, estimate the average waiting time on a peer-to-peerinterface or on a dating website.Finally, the matching rates associated with a stable matching model (general or extended bipartite) are studied. They are defined as the asymptotic frequencies of the executed respective matchings, and provide an insightful performance criterion for the corresponding matching systems, as well as the policy-insensitivity and fairness properties of the matching rates, which are also discussed