The Capacity of Magnesium to Induce Osteoclast Differentiation Is Greatly Enhanced by the Presence of Zoledronate

Simple Summary A number of skeletal disorders, all characterized by a metabolic or neoplastic loss of bone tissue, are cured with drugs called Bisphosphonates (BPs), which exert their therapeutic effect by suppressing cells named osteoclasts, normally mediating bone resorption. Unfortunately, these drugs can also provoke a dangerous side effect known as osteonecrosis of the jaw (ONJ), a bone infection localized in the oral cavity and characterized by gingival ulceration, sometimes accompanied by suppuration and pain. This condition, occasionally arising spontaneously, is more often started by a tooth extraction. The reduced number of osteoclasts, determined by BPs, is thought to favor the bacterial invasion of healthy bone and the incapacity to eliminate infected bone, that are in turn responsible for the appearance of ONJ. Here we show that Magnesium, used for decades as dietary supplement, can invert the effect of BPs, transforming them, through a sort of paradox effect, into powerful activators of osteoclast production. These results suggest that Magnesium might be used in a topical approach aimed to cure or prevent ONJ. Notably, the capacity of Magnesium to activate osteoclast production was even observed in absence of BPs, suggesting its application also in ONJ forms caused by agents distinct to BPs.Abstract Bisphosphonates (BPs) are successfully used to cure a number of diseases characterized by a metabolic reduction in bone density, such as Osteoporosis, or a neoplastic destruction of bone tissue, such as multiple myeloma and bone metastases. These drugs exert their therapeutic effect by causing a systemic osteoclast depletion that, in turn, is responsible for reduced bone resorption. Unfortunately, in addition to their beneficial activity, BPs can also determine a frightening side effect known as osteonecrosis of the jaw (ONJ). It is generally believed that the inability of osteoclasts to dispose of inflamed/necrotic bone represents the main physiopathological aspect of ONJ. In principle, a therapeutic strategy able to elicit a local re-activation of osteoclast production could counteract ONJ and promote the healing of its lesions. Using an experimental model of Vitamin D3-dependent osteoclastogenesis, we have previously demonstrated that Magnesium is a powerful inducer of osteoclast differentiation. Here we show that, surprisingly, this effect is greatly enhanced by the presence of Zoledronate, chosen for our study because it is the most effective and dangerous of the BPs. This finding allows us to hypothesize that Magnesium might play an important role in the topical therapy of ONJ

Performance Evaluation of Adaptive Autonomous Scheduling Functions for 6TiSCH Networks

The Internet Engineering Task Force (IETF) has recently defined the 6TiSCH architecture to enable the Industrial Internet of Things (IIoT), i.e., the adoption of the IoT paradigm for industrial applications with stringent requirements, in terms of reliability and timeliness. In 6TiSCH networks, the scheduling of communication resources is of paramount importance to meet the application requirements, and many different Scheduling Functions have been proposed to cope with the needs of various applications. Recently, autonomous scheduling has emerged as an efficient and robust approach, as it allows nodes to allocate communication resources autonomously, i.e., without any negotiation with their neighbors, thus avoiding the related overhead. Typically, this is obtained through static resource-allocation algorithms that are not able to adapt to variations in traffic conditions. In this paper, we consider adaptive autonomous scheduling, and compare the performance of three different algorithms in various IIoT scenarios. We investigate their ability to adapt to traffic changes, and evaluate them in terms of performance, resource consumption, and complexity. Based on the results obtained, we also provide a set of guidelines to select the most appropriate Scheduling Function, and its configuration parameters, depending on the specific use case

Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci ; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness

Systèmes linéaires sur le champ algébrique des fibrés quasi-paraboliques sur une courbe

Composition du Jury : Joseph Le Potier, Paris -- Président Peter Newstead, Liverpool -- Rapporteur Christian Pauly, Nice -- Rapporteur Christoph Sorger, Nantes -- Directeur de Thèse Vincent Franjour, Nnates -- ExaminateurThis thesis is a study of linear systems on the algebraic stack of quasi-parabolic bundles on an algebraic curve. In the first part we prove that the $\ell$th tensor power of the determinant line bundle on the moduli space of semistable parabolic bundles is a linear system without base points, as soon as $\ell$ is greater than or equal to an integer $\ell_0$, which just depends on the rank of the underlying vector bundles. This fact results from the existence of a quasi-parabolic analog of Grothendieck's scheme of quotients. In the second part we study the more general case of linear systems on the algebraic stack of quasi-parabolic bundles. The theorem on the parabolic determinant line bundle of the first part allows to identify the base locus of a linear system and the closed substack of quasi-parabolic bundles that are unstable with respect to the parabolic weights, determined by the linear system.L'objet de cette thèse est d'étudier les systèmes linéaires sur le champ algébrique des fibrés quasi-paraboliques sur une courbe algébrique. Dans la première partie nous montrons que la puissance $\ell$-ième du fibré déterminant sur l'espace de modules des fibrés paraboliques semi-stables (au sens de Seshadri) est un système linéaire sans points de base, dès que $\ell$ est supérieur ou égal à un entier $\ell_0$, que nous déterminons et qui ne dépend que du rang des fibrés vectoriels sous-jacents. Ce résultat repose sur l'existence d'un analogue (quasi-)parabolique du schéma des quotients de Grothendieck. Dans la seconde partie nous étudions le lieu de base des systèmes linéaires sur le champ algébrique des fibrés quasi-paraboliques. Le théorème obtenu dans la première partie sur le fibré déterminant parabolique nous permet d'identifier ce lieu de base et le sous-champ fermé des fibrés quasi-paraboliques instables, pour un choix de poids déterminé par le système linéaire

Systèmes linéaires sur le champ algébrique des fibrés quasi-paraboliques sur une courbe

L'objet de cette thèse est d'étudier les systèmes linéaires sur le champ algébrique des fibrés quasi-paraboliques sur une courbe algébrique. Dans la première partie nous montrons que la puissance l-ième du fibré déterminant sur l'espace de modules des fibrés paraboliques semi-stables (au sens de Seshadri) est un système linéaire sans points de base, dès que l est supérieur ou égal à un entier l0, que nous déterminons et qui ne dépend que du rang des fibrés vectoriels sous-jacents. Ce résultat repose sur l'existence d'un analogue (quasi-) parabolique du schéma des quotients de Grothendieck. Dans la seconde partie nous étudions le lieu de base des systèmes linéaires sur le champ algébrique des fibrés quasi-paraboliques. Le théorème obtenu dans la première partie sur le fibré déterminant parabolique nous permet d'identifier ce lieu de base et le sous-champ fermé des fibrés quasi-paraboliques instables, pour un choix de poids déterminé par le système linéaire.NANTES-BU Sciences (441092104) / SudocSudocFranceF

L’infiltrato speciale

In letteratura, esistono pochi casi di mastocitosi cutanea a esordio neonatale, da considerare nella diagnosi differenziale delle lesioni bollose congenite. Descriviamo un caso di mastocitosi cutanea a esordio neonatale, diagnosticato clinicamente