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1.
J Fish Biol ; 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38663999

ABSTRACT

Combining fish tracking methods is a promising way of leveraging the strengths of each approach while mitigating their individual weaknesses. Acoustic telemetry provides presence information as the fish move within receiver range, eliminating the need for tag recovery. Archival tags, on the other hand, record environmental variables on tag retrieval, enabling continuous path reconstruction of a fish beyond coastal regions. This study capitalizes on the combination of both methods for geolocating pollack, Pollachius pollachius, an understudied species of the northeast Atlantic, where declining stocks are raising concern. Essential knowledge of population structure and connectivity between essential habitats is critically lacking and could help inform stock assessment and management. The aims of the study were (1) to evaluate the feasibility of double-tagging pollack, known for being challenging to tag, and (2) to track seasonal movements across the Channel to gain first insights into pollack spatial ecology. In 2022, an extensive network of acoustic receivers was been deployed in the Channel along the French, English, and Belgian coasts as part of the Fish Intel project. We tagged 83 pollack with acoustic transmitters, among which 48 were double-tagged with data storage tags. Post-tagging survival assessment, conducted on a subset of 35 individuals, revealed a successful procedure with a 97% short-term survival rate. By October 2023, the acoustic telemetry network detected 30 out of 83 pollack at least once, with no large-scale movements observed across the Channel. Presence in the network fluctuates seasonally, peaking in summer, particularly among immature fish. Integrating acoustic detections with temperature and depth time series in a geolocation model enabled trajectory reconstruction of 10 recaptured pollack, seven of which were detected by the network. This combined tracking approach revealed coastal movements along the coast of Brittany in France, highlighting the ecological significance of the Iroise Sea for pollack throughout the year, particularly in summer. The geolocation model also suggested movements towards the entrance of the western Channel. This study highlights the complementarity of acoustic telemetry and archival tagging in reconstructing fish movements in their natural environment. As data accumulate, these innovative tracking methods promise to continually unveil new insights into the spatial ecology of the understudied pollack, which is essential for the species' management.

2.
Cells ; 13(5)2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38474384

ABSTRACT

Neurotransmission occurs within highly specialized compartments forming the active synapse where the complex organization and dynamics of the interactions are tightly orchestrated both in time and space. Post-translational modifications (PTMs) are central to these spatiotemporal regulations to ensure an efficient synaptic transmission. SUMOylation is a dynamic PTM that modulates the interactions between proteins and consequently regulates the conformation, the distribution and the trafficking of the SUMO-target proteins. SUMOylation plays a crucial role in synapse formation and stabilization, as well as in the regulation of synaptic transmission and plasticity. In this review, we summarize the molecular consequences of this protein modification in the structural organization and function of the mammalian synapse. We also outline novel activity-dependent regulation and consequences of the SUMO process and explore how this protein modification can functionally participate in the compartmentalization of both pre- and post-synaptic sites.


Subject(s)
Protein Processing, Post-Translational , Sumoylation , Animals , Small Ubiquitin-Related Modifier Proteins/metabolism , Synaptic Transmission/physiology , Mammals/metabolism , Synapses/metabolism
3.
Med Sci (Paris) ; 39(10): 722-731, 2023 Oct.
Article in French | MEDLINE | ID: mdl-37943132

ABSTRACT

Brucellosis due to Brucella melitensis affects domestic and wild ruminants, as well as other mammals, including humans. Despite France being officially free of bovine brucellosis since 2005, two human cases of Brucella melitensis infection in the French Alps in 2012 led to the discovery of one infected cattle herd and of one infected population of wild Alpine ibex (Capra ibex). In this review, we present the results of 10 years of research on the epidemiology of brucellosis in this population of Alpine ibex. We also discuss the insights brought by research and expert assessments on the efficacy of disease management strategies used to mitigate brucellosis in the French Alps.


Title: La brucellose du bouquetin des Alpes - Un exemple de dix années de recherche et d'expertise. Abstract: La brucellose à Brucella melitensis touche les ruminants domestiques et sauvages, ainsi que d'autres mammifères, dont les humains. Bien que la France soit officiellement indemne depuis 2005, deux cas humains reportés en Haute-Savoie en 2012 ont conduit à la découverte de l'infection dans un élevage bovin et chez les bouquetins des Alpes (Capra ibex) du massif du Bargy. Nous présentons dans cette synthèse les principales découvertes de ces dix dernières années sur le système brucellose-bouquetins. Nous discuterons également de l'apport de la recherche et de l'expertise sur l'évaluation de l'efficacité des mesures de gestion sanitaire mises en place dans le massif du Bargy pour lutter contre la brucellose.


Subject(s)
Brucellosis , Humans , Animals , Cattle , Brucellosis/epidemiology , Brucellosis/veterinary , Goats , France/epidemiology
4.
Front Mol Biosci ; 9: 954087, 2022.
Article in English | MEDLINE | ID: mdl-36237573

ABSTRACT

Fragile X-Syndrome (FXS) represents the most common inherited form of intellectual disability and the leading monogenic cause of Autism Spectrum Disorders. In most cases, this disease results from the absence of expression of the protein FMRP encoded by the FMR1 gene (Fragile X messenger ribonucleoprotein 1). FMRP is mainly defined as a cytoplasmic RNA-binding protein regulating the local translation of thousands of target mRNAs. Interestingly, FMRP is also able to shuttle between the nucleus and the cytoplasm. However, to date, its roles in the nucleus of mammalian neurons are just emerging. To broaden our insight into the contribution of nuclear FMRP in mammalian neuronal physiology, we identified here a nuclear interactome of the protein by combining subcellular fractionation of rat forebrains with pull- down affinity purification and mass spectrometry analysis. By this approach, we listed 55 candidate nuclear partners. This interactome includes known nuclear FMRP-binding proteins as Adar or Rbm14 as well as several novel candidates, notably Ddx41, Poldip3, or Hnrnpa3 that we further validated by target-specific approaches. Through our approach, we identified factors involved in different steps of mRNA biogenesis, as transcription, splicing, editing or nuclear export, revealing a potential central regulatory function of FMRP in the biogenesis of its target mRNAs. Therefore, our work considerably enlarges the nuclear proteins interaction network of FMRP in mammalian neurons and lays the basis for exciting future mechanistic studies deepening the roles of nuclear FMRP in neuronal physiology and the etiology of the FXS.

5.
Cell Mol Life Sci ; 79(7): 378, 2022 Jun 23.
Article in English | MEDLINE | ID: mdl-35739402

ABSTRACT

SUMOylation is a post-translational modification essential to cell homeostasis. A tightly controlled equilibrium between SUMOylation and deSUMOylation processes is also critical to the neuronal function including neurotransmitter release and synaptic transmission and plasticity. Disruption of the SUMOylation homeostasis in neurons is associated with several neurological disorders. The balance between the SUMOylation and deSUMOylation of substrate proteins is maintained by a group of deSUMOylation enzymes called SENPs. We previously showed that the activation of type 5 metabotropic glutamate receptors (mGlu5R) first triggers a rapid increase in synaptic SUMOylation and then upon the sustained activation of these receptors, the deSUMOylase activity of SENP1 allows the increased synaptic SUMOylation to get back to basal levels. Here, we combined the use of pharmacological tools with subcellular fractionation and live-cell imaging of individual hippocampal dendritic spines to demonstrate that the synaptic accumulation of the deSUMOylation enzyme SENP1 is bidirectionally controlled by the activation of type 1 mGlu1 and mGlu5 receptors. Indeed, the pharmacological blockade of mGlu1R activation during type 1 mGluR stimulation leads to a faster and greater accumulation of SENP1 at synapses indicating that mGlu1R acts as a brake to the mGlu5R-dependent deSUMOylation process at the post-synapse. Altogether, our findings reveal that type 1 mGluRs work in opposition to dynamically tune the homeostasis of SUMOylation at the mammalian synapse.


Subject(s)
Receptors, Metabotropic Glutamate , Sumoylation , Animals , Hippocampus/metabolism , Mammals/metabolism , Neurons/metabolism , Receptors, Metabotropic Glutamate/metabolism , Synapses/metabolism
6.
Front Mol Neurosci ; 14: 780535, 2021.
Article in English | MEDLINE | ID: mdl-34887727

ABSTRACT

Synapses are highly specialized structures that interconnect neurons to form functional networks dedicated to neuronal communication. During brain development, synapses undergo activity-dependent rearrangements leading to both structural and functional changes. Many molecular processes are involved in this regulation, including post-translational modifications by the Small Ubiquitin-like MOdifier SUMO. To get a wider view of the panel of endogenous synaptic SUMO-modified proteins in the mammalian brain, we combined subcellular fractionation of rat brains at the post-natal day 14 with denaturing immunoprecipitation using SUMO2/3 antibodies and tandem mass spectrometry analysis. Our screening identified 803 candidate SUMO2/3 targets, which represents about 18% of the synaptic proteome. Our dataset includes neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins as well as vesicular trafficking and cytoskeleton-associated proteins, defining SUMO2/3 as a central regulator of the synaptic organization and function.

7.
Sci Rep ; 11(1): 22057, 2021 11 11.
Article in English | MEDLINE | ID: mdl-34764361

ABSTRACT

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72-77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I-II and III-IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5-17.5), median OS was 11.7 months (CI 95%: 10-13 months). Median PFS was 9.5 months (CI 95%: 9-10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for "real-life" elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.


Subject(s)
Brain Neoplasms/therapy , Glioblastoma/therapy , Age Factors , Aged , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/diagnosis , Chemoradiotherapy , Female , Follow-Up Studies , Glioblastoma/diagnosis , Humans , Male , Survival Analysis , Temozolomide/adverse effects , Temozolomide/therapeutic use
8.
Rev Sci Instrum ; 92(5): 053552, 2021 May 01.
Article in English | MEDLINE | ID: mdl-34243347

ABSTRACT

A new diagnostic tool to study dielectric barrier discharges (DBDs) at atmospheric pressure by local electrical measurements is introduced. The square ground electrode is divided into 64 square segments (3.44 mm side length) so as to measure the discharge currents and gas voltages with spatial resolutions, which allows a 2D mapping. The electrical measurement results are validated by a comparison with short exposure time photographs taken from the top view of the discharge cell. For this purpose, we changed the local discharge behavior by varying locally the gas gap and the barrier capacitance and also by using a gas flow. Then, in both situations, the breakdown voltage depends on the position, and the discharge current and gas voltage are different as well. The measurements performed for a planar DBD in nitrogen with admixed nitrous oxide gas show that even if the discharge operates in a diffuse regime, the discharge does not behave exactly homogeneously on the whole surface area. The resulting electrical parameters allow us to refine the understanding of planar DBDs. The discharge activity changes the gas composition and thus, the level of preionization in the direction of the gas flow. This influences the local breakdown voltage and thus, the discharge morphology and local power density on the surface. The use of this new electrical diagnostic tool will allow us to refine the analysis of the spatial development of the discharge. This work gives some clues to improve the spatial resolution of this tool in the future.

9.
Nat Commun ; 12(1): 1557, 2021 03 10.
Article in English | MEDLINE | ID: mdl-33692361

ABSTRACT

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.


Subject(s)
Cognitive Dysfunction/genetics , Cognitive Dysfunction/physiopathology , Fragile X Mental Retardation Protein/metabolism , Mutation, Missense/physiology , Receptors, Glutamate/metabolism , Animals , Biotinylation , Brain/metabolism , Brain/physiopathology , Cells, Cultured , Cognitive Dysfunction/metabolism , Female , Fragile X Mental Retardation Protein/genetics , Hippocampus/metabolism , Hippocampus/physiopathology , Humans , Immunoblotting , Long-Term Potentiation/genetics , Long-Term Potentiation/physiology , Male , Mice , Mutation, Missense/genetics , Patch-Clamp Techniques , Receptors, Glutamate/genetics
10.
Mar Environ Res ; 161: 105131, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32966914

ABSTRACT

An increasing number of offshore structures are being deployed worldwide to meet the growing demand for renewable energy. Besides energy production, these structures can also provide new artificial habitats to a diversity of fish and crustacean species. This study characterises how concrete mattresses that stabilise the submarine power cable of a tidal energy test site can increase habitat capacity for benthic megafauna. A five-year monitoring, which relied on both visual counts and video-based surveys by divers, revealed that these mattresses provide a suitable habitat for 5 taxa of large crustaceans and fish. In particular, two commercially valuable species, i.e. the edible crab Cancer pagurus and the European lobster Homarus gammarus, showed a constant occupancy of these artificial habitats throughout the course of the project. The shape and the number of shelters available below individual mattresses largely determine potential for colonisation by mobile megafauna. Local physical characteristics of the implantation site (e.g. substratum type, topography, exposition to current etc.) significantly impact amount and type of shelters provided by the concrete mattresses. Thus, to characterise habitat potential of artificial structures, it is not only essential to consider (i) the design of the structures, but also to (ii) account for their interactions with local environmental conditions when deployed on the seafloor.


Subject(s)
Brachyura , Ecosystem , Animals , Fishes , Renewable Energy
11.
Mol Psychiatry ; 25(8): 1688-1703, 2020 08.
Article in English | MEDLINE | ID: mdl-31822816

ABSTRACT

The Fragile X Mental Retardation Protein (FMRP) is an RNA-binding protein essential to the regulation of local translation at synapses. In the mammalian brain, synapses are constantly formed and eliminated throughout development to achieve functional neuronal networks. At the molecular level, thousands of proteins cooperate to accomplish efficient neuronal communication. Therefore, synaptic protein levels and their functional interactions need to be tightly regulated. FMRP generally acts as a translational repressor of its mRNA targets. FMRP is the target of several post-translational modifications (PTMs) that dynamically regulate its function. Here we provide an overview of the PTMs controlling the FMRP function and discuss how their spatiotemporal interplay contributes to the physiological regulation of FMRP. Importantly, FMRP loss-of-function leads to Fragile X syndrome (FXS), a rare genetic developmental condition causing a range of neurological alterations including intellectual disability (ID), learning and memory impairments, autistic-like features and seizures. Here, we also explore the possibility that recently reported missense mutations in the FMR1 gene disrupt the PTM homoeostasis of FMRP, thus participating in the aetiology of FXS. This suggests that the pharmacological targeting of PTMs may be a promising strategy to develop innovative therapies for patients carrying such missense mutations.


Subject(s)
Fragile X Mental Retardation Protein/chemistry , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/metabolism , Fragile X Syndrome/physiopathology , Neurons/metabolism , Neurons/pathology , Protein Processing, Post-Translational , Animals , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Humans , Synapses/metabolism , Synapses/pathology
12.
World Neurosurg ; 128: 541-546, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31059855

ABSTRACT

BACKGROUND: The trigeminal ganglion is an atypical site for metastasis, especially for renal clear cell carcinoma. CASE DESCRIPTION: We report 2 clinical cases of a 66-year-old man and a 58-year-old man with trigeminal symptoms. Both patients had a history of renal clear cell (RCC) that was considered to be cured at 6 and 9 years, respectively. Brain magnetic resonance imaging (MRI) showed a trigeminal ganglion lesion with increased gadolinium enhancement associated with petrous apex erosion. The main diagnostic hypothesis based on MRI was trigeminal schwannoma for both patients. One patient underwent subtotal removal, the other a biopsy. Histologic examinations resulted in the diagnosis of RCC metastasis. Body computed tomography revealed pancreatic metastasis for both but no renal recurrence. The patients were treated by local radiotherapy, and 1 of the patients had associated chemotherapy. We added to these clinical cases a literature review of skull base metastasis of RCC. Trigeminal ganglion metastasis of RCC is very rare and can persist until 10 years after the first RCC diagnosis. It seems that the best treatment is surgical removal. To date, the role of local radiotherapy is not demonstrated, and the prognosis seems to be poor. CONCLUSIONS: In the case of trigeminal symptoms, rapid tumoral growth on brain MRI, or a history of RCC, we think that a body computed tomography should be performed, and surgery should be considered.


Subject(s)
Carcinoma, Renal Cell/secondary , Cranial Nerve Neoplasms/secondary , Kidney Neoplasms/pathology , Trigeminal Ganglion , Aged , Biopsy , Carcinoma, Renal Cell/diagnostic imaging , Cranial Nerve Neoplasms/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/secondary
13.
Cell Mol Life Sci ; 76(15): 3019-3031, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30904951

ABSTRACT

Sumoylation is a reversible post-translational modification essential to the modulation of neuronal function, including neurotransmitter release and synaptic plasticity. A tightly regulated equilibrium between the sumoylation and desumoylation processes is critical to the brain function and its disruption has been associated with several neurological disorders. This sumoylation/desumoylation balance is governed by the activity of the sole SUMO-conjugating enzyme Ubc9 and a group of desumoylases called SENPs, respectively. We previously demonstrated that the activation of type 5 metabotropic glutamate receptors (mGlu5R) triggers the transient trapping of Ubc9 in dendritic spines, leading to a rapid increase in the overall synaptic sumoylation. However, the mechanisms balancing this increased synaptic sumoylation are still not known. Here, we examined the diffusion properties of the SENP1 enzyme using a combination of advanced biochemical approaches and restricted photobleaching/photoconversion of individual hippocampal spines. We demonstrated that the activation of mGlu5R leads to a time-dependent decrease in the exit rate of SENP1 from dendritic spines. The resulting post-synaptic accumulation of SENP1 restores synaptic sumoylation to initial levels. Altogether, our findings reveal the mGlu5R system as a central activity-dependent mechanism to maintaining the homeostasis of sumoylation at the mammalian synapse.


Subject(s)
Receptor, Metabotropic Glutamate 5/metabolism , Synapses/metabolism , Animals , COS Cells , Cells, Cultured , Chlorocebus aethiops , Cysteine Endopeptidases/metabolism , Fluorescence Recovery After Photobleaching , Humans , Microscopy, Fluorescence , Neurons/cytology , Neurons/metabolism , Rats, Wistar , SUMO-1 Protein/metabolism , Sumoylation , Ubiquitin-Conjugating Enzymes/metabolism
14.
Cereb Cortex ; 29(8): 3241-3252, 2019 07 22.
Article in English | MEDLINE | ID: mdl-30137253

ABSTRACT

The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in translational regulation of mRNAs that play key roles in synaptic morphology and plasticity. The functional absence of FMRP causes the fragile X syndrome (FXS), the most common form of inherited intellectual disability and the most common monogenic cause of autism. No effective treatment is available for FXS. We recently identified the Phosphodiesterase 2A (Pde2a) mRNA as a prominent target of FMRP. PDE2A enzymatic activity is increased in the brain of Fmr1-KO mice, a recognized model of FXS, leading to decreased levels of cAMP and cGMP. Here, we pharmacologically inhibited PDE2A in Fmr1-KO mice and observed a rescue both of the maturity of dendritic spines and of the exaggerated hippocampal mGluR-dependent long-term depression. Remarkably, PDE2A blockade rescued the social and communicative deficits of both mouse and rat Fmr1-KO animals. Importantly, chronic inhibition of PDE2A in newborn Fmr1-KO mice followed by a washout interval, resulted in the rescue of the altered social behavior observed in adolescent mice. Altogether, these results reveal the key role of PDE2A in the physiopathology of FXS and suggest that its pharmacological inhibition represents a novel therapeutic approach for FXS.


Subject(s)
Animal Communication , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dendritic Spines/drug effects , Fragile X Syndrome/enzymology , Hippocampus/drug effects , Imidazoles/pharmacology , Long-Term Synaptic Depression/drug effects , Neurons/drug effects , Phosphodiesterase Inhibitors/pharmacology , Social Behavior , Triazines/pharmacology , Animals , Animals, Newborn , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Dendritic Spines/pathology , Embryo, Mammalian , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Fragile X Syndrome/pathology , Fragile X Syndrome/physiopathology , Gene Knockout Techniques , Hippocampus/metabolism , Mice , Mice, Knockout , Neurons/metabolism , Neurons/pathology , Primary Cell Culture , Rats , Receptors, Metabotropic Glutamate/drug effects , Receptors, Metabotropic Glutamate/metabolism
15.
Front Mol Neurosci ; 11: 342, 2018.
Article in English | MEDLINE | ID: mdl-30319351

ABSTRACT

Fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and a leading cause of autism, results from the loss of expression of the Fmr1 gene which encodes the RNA-binding protein Fragile X Mental Retardation Protein (FMRP). Among the thousands mRNA targets of FMRP, numerous encode regulators of ion homeostasis. It has also been described that FMRP directly interacts with Ca2+ channels modulating their activity. Collectively these findings suggest that FMRP plays critical roles in Ca2+ homeostasis during nervous system development. We carried out a functional analysis of Ca2+ regulation using a calcium imaging approach in Fmr1-KO cultured neurons and we show that these cells display impaired steady state Ca2+ concentration and an altered entry of Ca2+ after KCl-triggered depolarization. Consistent with these data, we show that the protein product of the Cacna1a gene, the pore-forming subunit of the Cav2.1 channel, is less expressed at the plasma membrane of Fmr1-KO neurons compared to wild-type (WT). Thus, our findings point out the critical role that Cav2.1 plays in the altered Ca2+ flux in Fmr1-KO neurons, impacting Ca2+ homeostasis of these cells. Remarkably, we highlight a new phenotype of cultured Fmr1-KO neurons that can be considered a novel cellular biomarker and is amenable to small molecule screening and identification of new drugs to treat FXS.

16.
Nat Commun ; 9(1): 757, 2018 02 22.
Article in English | MEDLINE | ID: mdl-29472612

ABSTRACT

Fragile X syndrome (FXS) is the most frequent inherited cause of intellectual disability and the best-studied monogenic cause of autism. FXS results from the functional absence of the fragile X mental retardation protein (FMRP) leading to abnormal pruning and consequently to synaptic communication defects. Here we show that FMRP is a substrate of the small ubiquitin-like modifier (SUMO) pathway in the brain and identify its active SUMO sites. We unravel the functional consequences of FMRP sumoylation in neurons by combining molecular replacement strategy, biochemical reconstitution assays with advanced live-cell imaging. We first demonstrate that FMRP sumoylation is promoted by activation of metabotropic glutamate receptors. We then show that this increase in sumoylation controls the homomerization of FMRP within dendritic mRNA granules which, in turn, regulates spine elimination and maturation. Altogether, our findings reveal the sumoylation of FMRP as a critical activity-dependent regulatory mechanism of FMRP-mediated neuronal function.


Subject(s)
Dendritic Spines/metabolism , Fragile X Mental Retardation Protein/metabolism , Sumoylation , Amino Acid Sequence , Animals , Cells, Cultured , Dendritic Spines/genetics , Dendritic Spines/pathology , Female , Fragile X Mental Retardation Protein/chemistry , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Fragile X Syndrome/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Models, Neurological , Phenotype , Pregnancy , RNA, Messenger/metabolism , Rats , Rats, Wistar , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Secretory Vesicles/metabolism , Sequence Homology, Amino Acid
17.
World Neurosurg ; 111: e395-e402, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29277595

ABSTRACT

OBJECTIVE: A three-dimensional reconstruction technique using the CustomBone (CB) prosthesis allows custom-made cranioplasty (CP) possessing osseointegration properties owing to its porous hydroxyapatite (HA) composition. This reconstruction technique has replaced less expensive techniques such as subcutaneously preserved autologous bone (SP). Our primary objective was to evaluate complications between CB and SP CP techniques. A secondary objective was to assess cosmetic results and osseointegration of CPs. METHODS: This single-center study comprised patients undergoing delayed CB or SP CP after craniectomy between 2007 and 2014. A prospective interview was conducted to collect all data, including 2-year follow-up clinical and radiologic data. Cosmetic results were assessed by a qualitative score, and osseointegration was assessed by measuring relative fusion at the CP margins. RESULTS: Of 100 patients undergoing CB or SP CP between 2007 and 2014, 92 (CB, n = 44; SP, n = 48) participated in the prospective interview. No significant difference in complication rates was observed between the 2 groups. The main complication specific to the CB group was fracture of the prosthesis observed in 20.8% patients. A higher rate of good cosmetic results was observed in the CB group (92.5% vs. 74.3%, P = 0.031). In the CB group, 51% of patients demonstrated no signs of bone fusion of the CP. CONCLUSIONS: Although the CB prosthesis is associated with cosmetic advantages, the porous hydroxyapatite composition makes it fragile in the short-term and long-term, and effective osseointegration remains uncertain.


Subject(s)
Bone Substitutes/therapeutic use , Osseointegration , Plastic Surgery Procedures/methods , Skull/surgery , Adult , Durapatite/adverse effects , Durapatite/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Satisfaction , Postoperative Complications/epidemiology , Prosthesis Implantation/adverse effects , Prosthesis Implantation/methods , Time
19.
Int J Radiat Oncol Biol Phys ; 99(5): 1179-1189, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28974415

ABSTRACT

PURPOSE: To retrospectively report the outcomes of a large multicenter cohort of patients treated with surgery and hypofractionated stereotactic radiation therapy (HFSRT) to the resection cavities of brain metastases (BMs). METHODS AND MATERIALS: Between March 2008 and February 2015, 181 patients with no prior whole-brain radiation therapy (WBRT) were treated by HFSRT to the surgical bed of BM at the dose of 33 Gy (3 × 11 Gy). The primary endpoint was local control. Secondary endpoints were distant brain control, overall survival (OS), risk of radionecrosis, and leptomeningeal disease (LMD). RESULTS: Of the 189 resected lesions, 44% were metastatic from a non-small cell lung cancer primary tumor, and 76% of patients had a single BM at the time of treatment. With a median follow-up of 15 months, the 6- and 12-month local control rates were 93% and 88%, respectively. On multivariate analysis, planning target volume (P=.005), graded prognostic assessment score (P=.021), and meningeal contact of BM (P=.032) were predictive of local failure. The 6- and 12-month distant brain control rates were 70% and 61%, respectively. Twenty-six patients (14%) developed signs of LMD at a median time of 3.8 months. The preoperative tumor volume was predictive of LMD (P=.029). The median OS was 17 months. The 6-, 12-, and 24-month OS rates were 79%, 62%, and 39%, respectively. Recursive partitioning analysis class 3 (P=.02), piecemeal resection (P=.017), and an increasing number of BMs (P<.01) were independent unfavorable prognostic factors for OS. Fifty-four patients (30%) were subsequently treated with salvage WBRT at a median time of 6.5 months, and 41% were reirradiated with SRT. Radionecrosis occurred in 19% of cases at a median time of 15 months and was associated with the infratentorial location of the BM (P=.0025). CONCLUSIONS: This study demonstrated the safety and efficacy of a 3 × 11 Gy HFSRT regimen for the irradiation of BMs resection cavities. It was an alternative to adjuvant WBRT.


Subject(s)
Brain Neoplasms/radiotherapy , Brain Neoplasms/secondary , Brain Neoplasms/surgery , Cranial Irradiation/methods , Radiation Dose Hypofractionation , Radiosurgery/methods , Adult , Aged , Aged, 80 and over , Brain Neoplasms/mortality , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Non-Small-Cell Lung/secondary , Carcinoma, Non-Small-Cell Lung/surgery , Cranial Irradiation/adverse effects , Female , Follow-Up Studies , Humans , Lung Neoplasms , Male , Meningeal Neoplasms/etiology , Meningeal Neoplasms/pathology , Middle Aged , Necrosis/etiology , Radiation Injuries/etiology , Radiation Injuries/pathology , Radiosurgery/adverse effects , Radiotherapy Planning, Computer-Assisted/methods , Retrospective Studies , Salvage Therapy/methods , Time Factors
20.
Mov Ecol ; 5: 20, 2017.
Article in English | MEDLINE | ID: mdl-28944062

ABSTRACT

BACKGROUND: Movement pattern variations are reflective of behavioural switches, likely associated with different life history traits in response to the animals' abiotic and biotic environment. Detecting these can provide rich information on the underlying processes driving animal movement patterns. However, extracting these signals from movement time series, requires tools that objectively extract, describe and quantify these behaviours. The inference of behavioural modes from movement patterns has been mainly addressed through hidden Markov models. Until now, the metrics implemented in these models did not allow to characterize cyclic patterns directly from the raw time series. To address these challenges, we developed an approach to i) extract new metrics of cyclic behaviours and activity levels from a time-frequency analysis of movement time series, ii) implement the spectral signatures of these cyclic patterns and activity levels into a HMM framework to identify and classify latent behavioural states. RESULTS: To illustrate our approach, we applied it to 40 high-resolution European sea bass depth time series. Our results showed that the fish had different activity regimes, which were also associated (or not) with the spectral signature of different environmental cycles. Tidal rhythms were observed when animals tended to be less active and dived shallower. Conversely, animals exhibited a diurnal behaviour when more active and deeper in the water column. The different behaviours were well defined and occurred at similar periods throughout the annual cycle amongst individuals, suggesting these behaviours are likely related to seasonal functional behaviours (e.g. feeding, migrating and spawning). CONCLUSIONS: The innovative aspects of our method lie within the combined use of powerful, but generic, mathematical tools (spectral analysis and hidden Markov Models) to extract complex behaviours from 1-D movement time series. It is fully automated which makes it suitable for analyzing large datasets. HMMs also offer the flexibility to include any additional variable in the segmentation process (e.g. environmental features, location coordinates). Thus, our method could be widely applied in the bio-logging community and contribute to prime issues in movement ecology (e.g. habitat requirements and selection, site fidelity and dispersal) that are crucial to inform mitigation, management and conservation strategies.

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