Mock plectic points

A $p$-arithmetic subgroup of $\mathrm{SL}_2(\mathbb{Q})$ like the Ihara group $\Gamma := \mathrm{SL}_2(\mathbb{Z}[1/p])$ acts by M\"obius transformations on the Poincar\'e upper half plane $\mathcal{H}$ and on Drinfeld's $p$-adic upper half plane $\mathcal{H}_p := \mathbb{P}_1(\mathbb{C}_p)\setminus\mathbb{P}_1(\mathbb{Q}_p)$. The diagonal action of $\Gamma$ on the product is discrete, and the quotient $\Gamma\backslash(\mathcal{H}_p\times \mathcal{H})$ can be envisaged as a "mock Hilbert modular surface". According to a striking prediction of Nekov\'a$\check{\text{r}}$ and Scholl, the CM points on genuine Hilbert modular surfaces should give rise to "plectic Heegner points" that encode non-trivial regulators attached, notably, to elliptic curves of rank two over real quadratic fields. This article develops the analogy between Hilbert modular surfaces and their mock counterparts, with the aim of transposing the plectic philosophy to the mock Hilbert setting, where the analogous plectic invariants are expected to lie in the alternating square of the Mordell-Weil group of certain elliptic curves of rank two over $\mathbb{Q}$

La tryptophane hydroxylase de rat: isolement de clones ADNc et etude de l'expression du gene

SIGLEINIST T 74065 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

A New Vesicular Scaffolding Complex Mediates the G-Protein-Coupled 5-HT1A Receptor Targeting to Neuronal Dendrites

International audienceAlthough essential for their neuronal function, the molecular mechanisms underlying the dendritic targeting of serotonin G-protein-coupled receptors are poorly understood. Here, we characterized a Yif1B-dependent vesicular scaffolding complex mediating the intracellular traffic of the rat 5-HT1A receptor (5-HT1AR) toward dendrites. By combining directed mutagenesis, GST-pull down, and surface plasmon resonance, we identified a tribasic motif in the C-tail of the 5-HT1AR on which Yif1B binds directly with high affinity (K-D approximate to 37 nM). Moreover, we identified Yip1A, Rab6, and Kif5B as new partners of the 5-HT1AR/Yif1B complex, and showed that their expression in neurons is also crucial for the dendritic targeting of the 5-HT1AR. Live videomicroscopy revealed that 5-HT1AR, Yif1B, Yip1A, and Rab6 traffic in vesicles exiting the soma toward the dendritic tree, and also exhibit bidirectional motions, sustaining their role in 5-HT1AR dendritic targeting. Hence, we propose a new trafficking pathway model in which Yif1B is the scaffold protein recruiting the 5-HT1AR in a complex including Yip1A and Rab6, with Kif5B and dynein as two opposite molecular motors coordinating the traffic of vesicles along dendritic microtubules. This targeting pathway opens new insights for G-protein-coupled receptors trafficking in neurons

Key role of the 5-HT 1A receptor addressing protein Yif1B in serotonin neurotransmission and SSRI treatment

International audienceAltered function of serotonin receptor 1A (5-HT1AR) has been consistently implicated in anxiety, major depressive disorder and resistance to antidepressants. Mechanisms by which the function of 5-HT1AR (expressed as an autoreceptor in serotonergic raphe neurons and as a heteroreceptor in serotonin [5-HT] projection areas) is altered include regulation of its expression, but 5-HT1AR traffick-ing may also be involved. Methods: We investigated the consequences of the lack of Yif1B (the 5-HT1AR trafficking protein) on 5-HT neurotransmission in mice, and whether Yif1B expression might be affected under conditions known to alter 5-HT neurotransmission, such as anxious or depressive states or following treatment with fluoxetine (a selective serotonin reuptake inhibitor) in humans, monkeys and mice. Results: Compared with wild-type mice, Yif1B-knockout mice showed a significant decrease in the forebrain density of 5-HT projection fibres and a hypofunctionality of 5-HT1A autoreceptors expressed on raphe 5-HT neurons. In addition, social interaction was less in Yif1B-knockout mice, which did not respond to the antidepressant-like effect of acute fluoxetine injection. In wild-type mice, social defeat was associated with downregulated Yif1B mRNA in the prefrontal cortex, and chronic fluoxetine treatment increased Yif1B expression. The expression of Yif1B was also downregulated in the postmortem prefrontal cortex of people with major depressive dis-order and upregulated after chronic treatment with a selective serotonin reuptake inhibitor in monkeys. Limitations: We found sex differ-ences in Yif1B expression in humans and monkeys, but not in mice under the tested conditions. Conclusion: These data support the concept that Yif1B plays a critical role in 5-HT1AR functioning and brain 5-HT homeostasis. The opposite changes in its expression observed in anxious or depressive states and after therapeutic fluoxetine treatment suggest that Yif1B might be involved in vulnerability to anxiety and depression, and fluoxetine efficac

Performance of Repeated Measures of (1–3)-β-D-Glucan, Mannan Antigen, and Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients: A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial

International audienceBackground. We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan (BDG), mannanantigen (mannan-Ag), and antimannan antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a high-risk nonimmunocompromised population. Methods. This was a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including nonimmunocompromised critically ill patients with intensive care unit-acquired sepsis, multiple Candida colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. BDG (>80 and >250 pg/mL), mannan-Ag (>125 pg/ mL), and antimannan-Ab (>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or repeated measurements and/or increased biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC (cohort 2). Results. Two hundred thirty-four patients were included, and 215 were still alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28 mortality was 29.1%. Finally, BDG >80 pg/mL at inclusion was associated with an increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61-13.5) but not death (CSHR[death], 1.20; 95% CI, 0.71-2.02). Conclusions. Among high-risk patients, a first measurement of BDG >80 pg/mL was strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG >80 pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in this subgroup