University of Paris-Seine

Abstract The microtubule cytoskeleton is a major driving force of neuronal circuit development. Fine-tuned remodelling of this network by selective activation of microtubule-regulating proteins, including microtubule severers, emerged as a central process in neuronal wiring. Tubulin posttranslational modifications control both microtubule properties and the activities of their interacting proteins. However, whether and how tubulin posttranslational modifications may contribute to neuronal connectivity has not yet been addressed. During zebrafish embryogenesis, we show that the microtubule severers p60-katanin and spastin play specific roles in axon guidance and identify a key role for tubulin polyglutamylation in their functional specificity. Furthermore, our work reveals that polyglutamylases with undistinguishable activitiesin vitro, TTLL6 and TTLL11, play exclusive roles in axon navigation by selectively tuning p60-katanin and spastin activities. We confirm the selectivity of TTLL11 towards spastin activation in mammalian cortical neurons and establish its relevance in preventing axonal degeneration triggered by spastin haploinsufficiency. Our work thus provides mechanistic insight on the control of microtubule-driven neuronal development and homeostasis, and opens novel avenues for developing therapeutic strategies in spastin-associated hereditary spastic paraplegia.

Abstract Let M be a compact complex manifold of dimension at least three and Π : M → X a positive principal elliptic fibration, where X is a compact Kähler orbifold. Fix a preferred Hermitian metric on M. In [14], the third author proved that every stable vector bundle on M is of the form L⊕ Π ⃰ B0, where B0 is a stable vector bundle on X, and L is a holomorphic line bundle on M. Here we prove that every stable Higgs bundle on M is of the form (L ⊕ Π ⃰B0, Π ⃰ ɸX), where (B0, ɸX) is a stable Higgs bundle on X and L is a holomorphic line bundle on M.

Abstract Somatostatin (SS) is a cyclic tetradecapeptide able to inhibit the release of growth hormone (GH) mainly through the binding to two G‐protein coupled receptor (GPCR) subtypes, SSTR2 and SSTR5. These receptors are overexpressed in approximately 90% of carcinoid tumors. However, the clinical use of somatostatin is limited by its short half‐life in vivo. In order to overcome this severe drawback, a huge number of analogs have been prepared, leading to the development of Octreotide, which is currently used in the clinic, among other applications, to treat various neuroendocrine tumors and, radiolabeled by, for example, 111In, 11C, and 68Ga, for imaging SS‐secreting tumors. Despite the success of Octreotide, there is an unmet need for the development of novel, more stable and selective Octreotide‐derived radiotherapeutics. To this end, the Cu(I)‐catalyzed azide‐alkyne 1,3‐dipolar Huisgen's cycloaddition, the prototypic click reaction, presents a promising opportunity to replace the susceptible disulfide bridge with a durable [1,2,3]triazolyl containing bridge and to introduce conformational constraints increasing specific receptor binding. Herein we report the design and synthesis of a series of i‐to‐i + 5 1,4‐ and 4,1‐disubstituted [1,2,3]triazolyl‐bridged cyclopeptides derived from the Octreotide scaffold and their detailed conformational analysis via NMR spectroscopy.

The aim of the present study was to strengthen our hypothesis of a common physiological basis for post-traumatic stress disorder (PTSD) and substance use disorders. This paper investigates the possibility that rats exposed to a PTSD model exhibit noradrenergic and behavioral sensitization, as observed following repeated drugs of abuse injections. First, rats received a single prolonged stress (SPS), combining three consecutive stressors. They were then tested, 2weeks after the trauma for PTSD-like symptoms to discriminate between vulnerable and resilient rats. When microdialysis was performed in the prelimbic cortex (Experiment 1), larger increases of noradrenaline (NA) release in response to amphetamine were observed in vulnerable rats when compared to control and resilient animals. Experiment 2 showed that trauma-vulnerable rats exhibited increases in locomotor activity relative to controls, in response to an exposure to trauma-associated cues. These data demonstrate that a single trauma exposure induces in vulnerable animals both, a noradrenergic sensitization evidenced within the prelimbic cortex and behavioral sensitization obtained after a physiologic activation of the noradrenergic system. However, Experiment 3 showed that when NA system was activated by amphetamine (1mg/kg), a decrease in behavioral sensitization was obtained in vulnerable rats. We proposed that this decreased locomotor activity results from an additional stress-induced increased reactivity of mesocortical dopaminergic neurons, known to counteract the consequences of cortical noradrenergic release in rats. These results support our hypothesis that noradrenergic sensitization represents a common physiological basis, involved both in PTSD and drug addiction and suggest new common therapeutic approaches for these pathologies.

Deux biographies de l’ecrivain yiddish Isaac Bashevis Singer, 1904-1991, laureat du prix Nobel de litterature en 1978, ont paru recemment qui se completent de facon tres satisfaisante pour la decouverte de cet auteur chez lequel la figure du double est constamment presente. Ce double est inlassablement decline au fil des romans, ou l’on reconnait sous des noms divers le meme heros en proie aux memes tourments et que l’on devine etre un autoportrait de l’auteur. C’est un double faconne par l’autoderision dans une recherche de lucidite, qui ne connait aucune compensation facile, et par laquelle aucune illusion ne subsiste face a un regard critique impitoyable, face a une absence totale d’auto-complaisance. Par l’usage litteraire de doubles, c’est a des retrouvailles avec soi-meme, avec un soi kaleidoscopique a reunifier, que nous invite l’œuvre de Singer. L’interpretation d’un authentique reve nocturne de Singer donne a voir sa reconciliation avec son double inverse, avec tout ce qu’en lui-meme il meprisait, voulait ignorer L’article, enfin, se termine par la revelation d’un fait majeur et bouleversant de l’histoire litteraire du XXe siecle...