Search

Cognitive modifications during ageing can affect decision-making competence (DMC). As this ability is central to the preservation of autonomy, our study aims to investigate how it changes in elderly adults and to determine whether such changes are linked to the deterioration of executive functions and working memory. To this end, 50 young adults and 50 elderly adults were assessed with executive, working memory, and DMC tasks. The latter comprised the Iowa Gambling Task (IGT) and a scenario task based on situations inspired by everyday life, under conditions of both risk and ambiguity. The results revealed lower performances in old than in young adults for the updating, inhibition, and working memory tasks. The IGT failed to distinguish between the two age groups. However, the scenario task did permit such a distinction, with young adults seeking more risky and ambiguous choices than elderly adults. Moreover, updating and inhibition capacities appeared to influence DMC., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The measurement of the pressure field radiated by a sound source has many applications in the fields of noise control and loudspeaker system design. In this paper, the radiation mode method is used to measure the field radiated by a complex acoustic source whose surface impedance is arbitrary and does not correspond to the Neumann boundary condition used for the calculation of radiation modes. The most effective radiation modes are used as test functions to calculate a pressure expansion around the source under test, an expansion that matches the measured pressure at a limited number of points close to the source. This expansion is then used to calculate the radiated pressure at a greater distance at unmeasured locations. In a first step, numerical simulations are performed to evaluate the method's most influential parameters. Then, measurements are performed in a semi-anechoic room on two real sources of increasing complexity. Obtained results show that the radiation mode method allows an accurate evaluation of the pressure field radiated by the test object over a fairly wide frequency band (between 100 Hz and 2 kHz) even for complex sources., (© 2024 Acoustical Society of America.)

The incorporation of fly ash in polybutyl succinate (PBS) and polybutyl adipate terephtalate (PBAT) in the partial replacement of ammonium polyphosphate and/or melamine polyphosphate is evaluated in the present work. Furthermore, the influence of the surface modification of fly ash with two silanes and titanate coupling agents was also studied. Cone calorimeter experiments, pyrolysis combustion flow calorimeters (PCFCs), and UL94V tests were used to assess the fire performance of the composites. Scanning electronic microscopy, X-microanalysis, and X-ray diffractometry analysis were carried out on cone calorimeter residues in order to access the fire-retardant mode of action. The formation of new components due to the presence of fly ash was highlighted by X-ray diffractometry, indicating the synergistic effects between the flame-retardant system and fly ash. The X-microanalysis results showed that the main fraction of initial phosphorous is present in the cone calorimeter residue, indicating that the proposed system acts in a condensed phase., Competing Interests: The authors declare no conflicts of interest.

Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome. WHAT THIS PAPER ADDS: Recent advances shed light on the promises of gene replacement therapy with new vectors designed to control the levels of MeCP2 expression. New developments in DNA/RNA editing approaches or reactivation of the silenced X chromosome open the possibility to re-express the native MeCP2 locus at endogenous levels. Current strategies still face limitations in transduction efficiency and future work is needed to improve brain delivery., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

This work investigates the aerosols emitted from carbon fibre-reinforced epoxy composites (CFC) incorporating nanomaterials (nanoclays and nanotubes), subjected to simultaneous fire and impact, representing an aeroplane or automotive crash. Simultaneous fire and impact tests were performed using a previously described bespoke testing methodology with the capability to collect particles released from the front/back faces of the impacted composites plus the effluents. In this work the methodology has been further developed by connecting the Dekati Low Pressure Impactor (DLPI) and Mini Particle Sampler (MPS) sampling system in the extraction chimney. The aerosols emitted have been characterized using various devices devoted to the analysis of aerosols. The influence of the nanoadditives in the matrix on the number concentration and the size distribution of airborne particles produced, was studied with a cascade impactor in the 5 nm-10 μm range. The morphology of the separated soot fractions was examined by SEM. The measurement of aerodynamic size of particles that can deposit in human respiratory tract indicate that 75% of the soot and particles released from CFC could deposit in the lungs reaching the bronchi region at a minimum. There was however, a minimal difference between the number particle concentrations or particle-size mass distribution of particles from CFC and CFC containing nanoadditives. Moreover, no fibres were found in the effluents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder characterized by neurodevelopmental regression between 6 and 18 months of life and associated with multi-system comorbidities. Caused mainly by pathogenic variants in the MECP2 (methyl CpG binding protein 2) gene, it is the second leading genetic cause of intellectual disability in girls after Down syndrome. RTT affects not only neurological function but also a wide array of non-neurological organs. RTT-related disorders involve abnormalities of the respiratory, cardiovascular, digestive, metabolic, skeletal, endocrine, muscular, and urinary systems and immune response. Here, we review the different aspects of RTT affecting the main peripheral groups of organs and sometimes occurring independently of nervous system defects., Competing Interests: The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2021 Roux JC et al.)

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2 -deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent genetic cause of intellectual disability in girls, and there is currently no cure for the disease. We have previously shown that gene therapy using a self-complementary AAV9 viral vector expressing a codon-optimized Mecp2 version (AAV9-MCO) significantly improved symptoms and increased survival in male Mecp2-deficient mice. Here, we pursued our studies and investigated the safety and efficacy of long-term gene therapy in the genetically relevant RTT mouse model: the heterozygous (HET) Mecp2 deficient female mouse. These mice were injected with the AAV9-MCO vector through the tail vein and an array of behavioral tests was performed. At 16- and 30-weeks post-injection, this treatment was able to rescue apneas and improved the spontaneous locomotor deficits and circadian locomotor activity in Mecp2 HET mice treated with AAV9-MCO at a dose of 5 × 10 11 vg/mouse. To examine whether a higher dose of vector could result in increased improvements, we injected Mecp2 HET mice with a higher MCO vector dose (10 12 vg/mouse), which resulted in some severe, sometimes lethal, side effects. In order to confirm these effects, a new cohort of Mecp2 HET mice were administered increasing doses of MCO vector (10 11 , 5 × 10 11 and 10 12 vg/mouse). Again, two weeks after vector administration, some Mecp2 HET mice were found dead while others displayed severe side effects and had to be euthanized. These deleterious effects were not observed in Mecp2 HET mice injected with a high dose of AAV9-GFP and were directly proportionate to vector dosage (0, 23 or 54% mortality at an AAV9-MCO dose of 10 11 , 5 × 10 11 , 10 12 vg/mouse, respectively), and no such lethality was observed in wild-type (WT) mice. In the Mecp2 HET mice treated with the high and medium AAV9-MCO doses, blood chemistry analysis and post-mortem histology showed liver damage with drastically elevated levels of liver transaminases and disorganized liver architecture. Apoptosis was confirmed by the presence of TUNEL- and cleaved-caspase 3-positive cells in the Mecp2 HET mice treated with the higher doses of AAV9-MCO. We then studied the involvement of the unfolded protein response (UPR) in triggering apoptosis since it can be activated by AAV vectors. Increased expression of the C/EBP homologous protein (CHOP), one of UPR downstream effectors, was confirmed in Mecp2 HET mice after vector administration. The toxic reaction seen in some treated mice indicates that, although gene therapy for RTT improved breathing deficits observed in Mecp2 HET mice, further studies are needed to better understand the underlying mechanisms and caution must be exercised before similar attempts are undertaken in female Rett patients., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Early onset epileptic encephalopathy with suppression-burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage-dependent potassium channel subunit, leading to so-called KCNQ2-related epileptic encephalopathy (KCNQ2-REE). To study the pathophysiology of KCNQ2-REE in detail and to provide a relevant preclinical model, we generated and described a knock-in mouse model carrying the recurrent p.(Thr274Met) variant., Methods: We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre-deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests., Results: The Kcnq2 Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2 Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2 Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development., Significance: Taken together, our results indicate that we have generated a relevant model to study the pathophysiology of KCNQ2-related epileptic encephalopathy and perform preclinical research for that devastating and currently intractable disease., (© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

VOCs in paper mills have severely exceeded the emission standards and their photo-catalytic degradations should focus on the experimental and theoretical studies. This work used TiO 2 colloid as catalyst to study the photo-catalytic degradations of mixed HCHO and C 6 H 6 at five mixing ratios. The adsorption behaviors of pure forms and mixtures on the TiO 2 (101) surface were simulated using density functional theory (DFT), and their catalytic reaction mechanisms were also analyzed. The following results were found: (1) With increasing initial concentration, the enhanced adsorption and easy degradation interpreted the increased degradation rate for pure HCHO, while the counteractions of enhanced adsorption and inhibited catalytic reaction kept the constant degradation rate for pure C 6 H 6 . (2) For their mixtures, the HCHO degradation was inhibited at high C 6 H 6 concentration due to the inhibited adsorption and catalytic reaction of HCHO. The C 6 H 6 degradation was slightly weakened at high HCHO concentration and then restored to the normal degradation rate of C 6 H 6 , which could be attributed to the weakened adsorption of C 6 H 6 and the easy degradation of HCHO in the initial stage. The combined experimental, simulation, and theoretical results provides sufficient information to understand the photo-catalytic degradation process for mixed gaseous pollutants in different realistic environments., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain-derived neurotrophic factor (BDNF) levels, but non-specific overexpression of BDNF only partially improves the phenotype of Mecp2-deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in Mecp2 knockout brains. Here, we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho-mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice-even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

The emotion generated by the touch of materials is studied via a protocol based on blind assessment of various stimuli. The human emotional reaction felt toward a material is estimated through (i) explicit measurements, using a questionnaire collecting valence and intensity, and (ii) implicit measurements of the activity of the autonomic nervous system, via a pupillometry equipment. A panel of 25 university students (13 women, 12 men), aged from 18 to 27, tested blind twelve materials such as polymers, sandpapers, wood, velvet and fur, randomly ordered. After measuring the initial pupil diameter, taken as a reference, its variation during the tactile exploration was recorded. After each touch, the participants were asked to quantify the emotional value of the material. The results show that the pupil size variation follows the emotional intensity. It is significantly larger during the touch of materials considered as pleasant or unpleasant, than with the touch of neutral materials. Moreover, after a time period of about 0.5 s following the stimulus, the results reveal significant differences between pleasant and unpleasant stimuli, as well as differences according to gender, i.e., higher pupil dilatation of women than men. These results suggest (i) that the autonomic nervous system is initially sensitive to high arousing stimulation, and (ii) that, after a certain period, the pupil size changes according to the cognitive interest induced and the emotional regulation adopted. This research shows the interest of the emotional characterization of materials for product design., (Copyright © 2020 Bertheaux, Toscano, Fortunier, Roux, Charier and Borg.)

Rett Syndrome is a severe neurological disorder mainly due to de novo mutations in the methyl-CpG-binding protein 2 gene ( MECP2 ). Mecp2 is known to play a role in chromatin organization and transcriptional regulation. In this review, we report the latest advances on the molecular function of Mecp2 and the new animal and cellular models developed to better study Rett syndrome. Finally, we present the latest innovative therapeutic approaches, ranging from classical pharmacology to correct symptoms to more innovative approaches intended to cure the pathology., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT., Methods: The trial was a 6-month, multicenter, randomized, double-blind, placebo-controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2-3 mg/kg Desipramine per day (high Desipramine), 1-2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention-to-treat analysis was applied., Results: The median change in AHI from baseline to 6 months was -31 (IQR: -37 to -11) for the high Desipramine, -17.5 (IQR: -31 to 13) for the low Desipramine, and -13 (IQR:-31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups ( P  = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI ( r  = -0.44; P  = 0.0002) was underlined., Interpretation: This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.

A method to characterize macroscopically homogeneous rigid frame porous media from impedance tube measurements by deterministic and statistical inversion is presented. Equivalent density and bulk modulus of the samples are reconstructed with the scattering matrix formalism, and are then linked to its physical parameters via the Johnson-Champoux-Allard-Lafarge model. The model includes six parameters, namely the porosity, tortuosity, viscous and characteristic lengths, and static flow and thermal permeabilities. The parameters are estimated from the measurements in two ways. The first one is a deterministic procedure that finds the model parameters by minimizing a cost function in the least squares sense. The second approach is based on statistical inversion. It can be used to assess the validity of the least squares estimate, but also presents several advantages since it provides valuable information on the uncertainty and correlation between the parameters. Five porous samples with a range of pore properties are tested, and the pore parameter estimates given by the proposed inversion processes are compared to those given by other characterization methods. Joint parameter distributions are shown to demonstrate the correlations. Results show that the proposed methods find reliable parameter and uncertainty estimates to the six pore parameters quickly with minimal user input.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent cause of intellectual disability in girls and there is currently no cure for the disease. The finding that the deficits caused by the loss of Mecp2 are reversible in the mouse has bolstered interest in gene therapy as a cure for RTT. In order to assess the feasibility of gene therapy in a RTT mouse model, and in keeping with translational goals, we investigated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (AAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2-deficient (KO) mice. Our results show that AAV9-MCO administered at a dose of 2×10 11 viral genome (vg)/mouse was able to significantly increase survival and weight gain, and delay the occurrence of behavioral deficits. Apneas, which are one of the core RTT breathing deficits, were significantly decreased to WT levels in Mecp2 KO mice after AAV9-MCO administration. Semi-quantitative analysis showed that AAV9-MCO administration in Mecp2 KO mice resulted in 10 to 20% Mecp2 immunopositive cells compared to WT animals, with the highest Mecp2 expression found in midbrain regions known to regulate cardio-respiratory functions. In addition, we also found a cell autonomous increase in tyrosine hydroxylase levels in the A1C1 and A2C2 catecholaminergic Mecp2+ neurons in treated Mecp2 KO mice, which may partly explain the beneficial effect of AAV9-MCO administration on apneas occurrence., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional- and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder.

Rett syndrome is a neurological disorder caused by mutations in the MECP2 gene.  MeCP2 transcripts are alternatively spliced to generate two protein isoforms (MeCP2_e1 and MeCP2_e2) that differ at their N-termini. Whilst mRNAs for both forms are expressed ubiquitously, the one for MeCP2_e1 is more abundant than for MeCP2_e2 in the central nervous system. In transfected cells, both protein isoforms are nuclear and colocalize with densely methylated heterochromatic foci. With a view to understanding the physiological contribution of each isoform, and their respective roles in the pathogenesis of Rett syndrome, we set out to generate isoform-specific anti-MeCP2 antibodies. To this end, we immunized rabbits against the peptides corresponding to the short amino-terminal portions that are different between the two isoforms. The polyclonal antibodies thus obtained specifically detected their respective isoforms of MeCP2 in Neuro2a (N2A) cells transfected to express either form. Both antisera showed comparable sensitivities when used for Western blot or immunofluorescence, and were highly specific for their respective isoform. When those antibodies were used on mouse tissues, specific signals were easily detected for Mecp2_e1, whilst Mecp2_e2 was very difficult to detect by Western blot, and even more so by immunofluorescence. Our results thus suggest that brain cells express low amounts of the Mecp2-e2 isoform. Our findings are compatible with recent reports showing that MeCP2_e2 is dispensable for healthy brain function, and that it may be involved in the regulation of neuronal apoptosis and embryonic development.

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.

BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Mecp2 deficiency or overexpression causes a wide spectrum of neurological diseases in humans among which Rett Syndrome is the prototype. Pathogenic mechanisms are thought to involve transcriptional deregulation of target genes such as Bdnf together with defects in the general transcriptional program of affected cells. Here we found that two master genes, Huntingtin (Htt) and huntingtin-associated protein (Hap1), involved in the control of Bdnf axonal transport, are altered in the brain of Mecp2-deficient mice. We also revealed an in vivo defect of Bdnf transport throughout the cortico striatal pathway of Mecp2-deficient animals. We found that the velocity of Bdnf-containing vesicles is reduced in vitro in the Mecp2-deficient axons and this deficit can be rescued by the re-expression of Mecp2. The defect in axonal transport is not restricted to Bdnf since transport of the amyloid precursor protein (App) that is Htt and Hap1-dependent is also altered. Finally, treating Mecp2-deficient mice with cysteamine, a molecule increasing the secretion of Bdnf vesicles, improved the lifespan and reduced motor defects, suggesting a new therapeutic strategy for Rett syndrome., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Rett syndrome (RTT, MIM #312750) is a severe neurological disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Female patients are affected with an incidence of 1/15000 live births and develop normally from birth to 6-18 months of age before the onset of deficits in autonomic, cognitive, motor functions (stereotypic hand movements, impaired locomotion) and autistic features. Studies on Mecp2 mouse models, and specifically null mice, revealed morphological and functional alterations of neurons. Several functions that are regulated by bioaminergic nuclei or peripheral ganglia are impaired in the absence of Mecp2., Results: Using high performance liquid chromatography, combined with electrochemical detection (HPLC/EC) we found that Mecp2(-/y) mice exhibit an alteration of DA metabolism in the ponto-bulbar region at 5 weeks followed by a more global alteration of monoamines when the disease progresses (8 weeks). Hypothalamic measurements suggest biphasic disturbances of norepinephrine and serotonin at pathology onset (5 weeks) that were found stabilized later on (8 weeks). Interestingly, the postnatal nigrostriatal dopaminergic deficit identified previously does not parallel the reduction of the other neurotransmitters investigated. Finally, dosage in cortical samples do not suggest modification in the monoaminergic content respectively at 5 and 8 weeks of age., Conclusions: We have identified that the level of catecholamines and serotonin is differentially affected in Mecp2(-/y) brain areas in a time-dependent fashion.

Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the MECP2 gene, in which older patients often develop parkinsonian features. Although Mecp2 has been shown to modulate the catecholaminergic metabolism of the RTT mouse model, little is known about the central dopaminergic neurons. Here we found that the progression of the motor dysfunction in the Mecp2-deficient mouse becomes more severe between 4 and 9 weeks of age. We then studied the phenotype of the dopaminergic neurons of the substantia nigra pars compacta (SNpc). We found a major reduction in the number of tyrosine hydroxylase (Th)-expressing neurons, as well as a reduction in their soma size, by 5 weeks of age. We showed that this deficit is not due to apoptosis and that the remaining neurons express a mature dopaminergic phenotype. A reduction in the Th-staining intensity was also found in the caudate-putamen (CPu), the main dopaminergic target for SNpc. We found that the amount of activated-Th (pSer40-Th) is slightly reduced at 5 weeks of age in the Mecp2-deficient mouse, but that this amount is affected more importantly by 9 weeks of age. Neurochemical measurements revealed a significant reduction of dopamine content at 5 and 9 weeks of age in the CPu whereas SNpc contents were preserved. Finally, we found that chronic L-Dopa treatment improved the motor deficits previously identified. Altogether, our findings demonstrate that Mecp2-deficiency induces nigrostriatal deficits, and they offer a new perspective to better understand the origin of motor dysfunction in RTT., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The methyl-CpG binding protein 2 (Mecp2) gene encodes a nuclear transcriptional modulator highly expressed in post-mitotic neurons. Mutations of this gene cause a large spectrum of neurological disorders in humans. Several lines of mice harboring a constitutional deletion of Mecp2 are available. The use of these models is crucial to understand the basis of Mecp2-related pathologies. However, most of the studies performed using these lines focused on different postnatal time points. The aim of the present study was to provide a more complete description of the behavioral phenotype of the Mecp2(tm1.1Bird) mice. To this aim, we used a modified version of the SHIRPA protocol and a set of sensorimotor tests and respiratory metabolism measurements, in a longitudinal study of the Mecp2-null male mice (Mecp2(-/y)) from three weeks (weaning) to eight weeks of age. Our data document, for the first time, the sequential appearance of the in vivo deficits in this mouse line. The observed deficits initially concern major parameters (such as body weight), and are followed by involuntary and sensitive defects (reflexes). Subsequently, motor functions and respiratory metabolism are severally impaired. A detailed description of these gradual defects may help to identify their neuronal origin and to elaborate novel therapeutic strategies., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Near-field acoustic holography (NAH) is an effective tool for visualizing acoustic sources from pressure measurements made in the near-field of sources using a microphone array. The method involving the Fourier transform and some processing in the frequency-wavenumber domain is suitable for the study of stationary acoustic sources, providing an image of the spatial acoustic field for one frequency. When the behavior of acoustic sources fluctuates in time, NAH may not be used. Unlike time domain holography or transient method, the method proposed in the paper needs no transformation in the frequency domain or any assumption about local stationary properties. It is based on a time formulation of forward sound prediction or backward sound radiation in the time-wavenumber domain. The propagation is described by an analytic impulse response used to define a digital filter. The implementation of one filter in forward propagation and its inverse to recover the acoustic field on the source plane implies by simulations that real-time NAH is viable. Since a numerical filter is used rather than a Fourier transform of the time-signal, the emission on a point of the source may be rebuilt continuously and used for other post-processing applications.

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator. Mutations in this gene cause a wide range of neurological disorders. Mecp2 deficiency has been previously associated to catecholaminergic dysfunctions leading to autonomic defects in the brainstem and the sympathoadrenergic system of the mouse. The present study was undertaken to determine if the locus coeruleus (LC), the main noradrenergic cell group of the brain, is affected. Using real type PCR, we found a reduction of the tyrosine hydroxylase (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, in the whole pons of P15 (-36%), P30 (-47%) and P50 (-42%) Mecp2 null male as well as in adult heterozygous female (-44%) mice. Using immunoquantification we did not observe any difference of the Th staining level in P30 null male mice. However at P50, we demonstrated a significant decrease in both the Th staining level (-24%), and the number of Th-positive neurons (-23%). We subsequently characterized a reduction (-28%) of the dendritic density of the Th-positive fibers surrounding the LC in P50 null male mice. In heterozygous female mice immunoquantification did not revealed significant modifications, but only a tendency towards reduction. Finally, we did not found any apoptotic neurons in the pons indicating that LC neurons are not dying but are more likely loosing their catecholaminergic phenotype. In conclusion, our results showing a progressive catecholaminergic deficit in the LC of Mecp2 deficient null male mice could open new perspectives to better understand the autonomic and cognitive deficits due to the lack of Mecp2., ((c) 2009 Wiley-Liss, Inc.)

Rett syndrome (RTT) is a severe postnatal neurological disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. In affected children, most biological parameters, including brain structure, are normal (although acquired microcephaly is usually present). However, in recent years, a deficit in bioaminergic metabolism has been identified at the cellular and molecular levels, in more than 200 patients. Recently available transgenic mouse strains with a defective Mecp2 gene also show abnormalities, strongly suggesting that there is a direct link between the function of the MECP2 protein and the metabolism of biogenic amines. Biogenic amines appear to have an important role in the pathophysiology of Rett syndrome, for several reasons. Firstly, biogenic amines modulate a large number of autonomic and cognitive functions. Secondly, many of these functions are affected in RTT patients. Thirdly, biogenic amines are the only neurotransmitters that have repeatedly been found to be altered in RTT patients. Importantly, pharmacological interventions can be envisaged to try to counteract the deficits observed. Here, we review the available human and mouse data and present how they have been and could be used in the development of pharmacological treatments for children affected by the syndrome. Given our current knowledge and the tools available, modulating biogenic amine metabolism may prove to be the most promising strategy for improving the life quality of Rett syndrome patients in the short term.

The aim of this work is to continuously provide the acoustic pressure field radiated from nonstationary sources. From the acquisition in the nearfield of the sources of a planar acoustic field which fluctuates in time, the method gives instantaneous sound field with respect to time by convolving wavenumber spectra with impulse response and then inverse Fourier transforming into space for each time step. The quality of reconstruction depends on the impulse response which is composed of investigated parameters as transition frequency and propagation distance. Sampling frequency also affects errors of the practically discrete impulse response used for calculation. To avoid aliasing, the impulse response is low-pass filtered with Chebyshev or Kaiser-Bessel filter. Another approach to implement the impulse response consists of applying an inverse Fourier transform to the theoretical transfer function for propagation. To estimate the performance of each processing method, a simulation test involving several source monopoles driven by nonstationary signals is executed. Some indicators are proposed to assess the accuracy of the temporal signals predicted in a forward plane. The results show that the use of a Kaiser-Bessel filter numerically implemented or that of the inverse Fourier transform can provide the most accurate instantaneous acoustic signals.

We previously identified an inactivating disruption of the X-linked KIAA2022 gene by a chromosomal rearrangement in two male patients with severe mental retardation. In order to determine if KIAA2022 has a role during the development of the central nervous system, we have cloned its murine ortholog, Kiaa2022, determined its genomic structure and studied its expression during mouse development. We show that Kiaa2022 is preferentially expressed in the central nervous system and that the transcript is highly expressed in postmitotic neurons. The expression of Kiaa2022 is first detectable at E10.5 to reach a maximum at P3 where it is notably expressed in the hippocampus, the entorhinal cortex and strongly in the ventral premammillary nucleus. After P3, the expression of Kiaa2022 decreases and maintains very low levels thereafter. Our results show that Kiaa2022 is expressed in the developing brain and that it may play a role in postmitotic, maturing neurons.

Mutations in the gene encoding the transcriptional methyl-CpG binding protein 2 (Mecp2) cause a wide range of neurological disorders and the better known of these diseases is Rett syndrome (RS). Mecp2 deficiency has been previously associated to catecholaminergic dysfunction in the mouse brainstem. Here we report a catecholaminergic deficit in the peripheral nervous system of the Mecp2-/y males and heterozygous Mecp2+/- female mice. We used immunoquantification associated to densitometry to evaluate the amount of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, in the key organs of the chemoafferent and sympathoadrenergic pathways: the carotid body (CB), the petrosal ganglion (PG), the superior cervical ganglion (SCG) and the adrenal medulla (AM). Our results show that the TH staining level is weaker in the CB (-15%), PG (-26%), SCG (-34%), AM (-35%) of Mecp2-/y mice and to a lesser extent in the PG (-11%) and AM (-18%) in Mecp2+/- mice. We evaluated in vivo the chemoreflex sensitivity of Mecp2-/y mice using whole-body plethysmography to record the breathing of Mecp2-/y mice in normoxia and in response to acute hypoxia (10% O(2)). Our results show that the hypoxic ventilatory response is significantly increased in Mecp2-/y mice (+50%) demonstrating in vivo disturbances of the chemoafferent pathway. In conclusion, our results offer new insights to better understand the mechanisms leading to autonomic dysfunction in RS.

Methyl CpG binding protein 2 (MeCP2) is a member of the methylated DNA binding protein family able to modulate the transcription of target genes. Mutations in MECP2 lead to a wide range of neurological phenotypes and the better known of these diseases is Rett Syndrome. All patients having a mutation in MECP2 are mentally retarded and most of them exhibit dysfunctions in autonomic processes that are controlled by the brainstem. Previous studies have shown that Mecp2 is developmentally and spatially regulated throughout the rodent brain but none of them investigated the brainstem. In the present study, we have quantified the levels of expression of the Mecp2 mRNA by real time PCR and MeCP2 protein by immunoquantifications, in different areas of the mouse brainstem during the postnatal development (P0, P7, P21, P35 and P55). We focused on regions of the pons and the medulla oblongata directly involved in the regulation of autonomic functions. Our results show that the expression of MeCP2 is heterogeneously expressed throughout the postnatal mouse brainstem. MeCP2 expression in each area studied is restricted to neurones. The developmental pattern is mainly characterized by a postnatal decrease of the Mecp2 mRNA and an increase of the MeCP2 protein staining level in spite of the local variability. However, we were not able to correlate the developmental expression of MeCP2 in a given area of the brainstem with autonomic dysfunctions occurring in the presence of a mutation in Mecp2.

A semi-industrial bioscrubber was developed to treat a complex mixture of VOCs: oxygenated, aromatic and chlorinated compounds. In order to optimize the VOCs mass transfer, an original washing agent made up of water and cutting oil was tested, and the impact of this washing agent on bioscrubbing performances was investigated. The results obtained with a laboratory unit show that the addition of oil strongly increases the quantity of transferred aromatics. For these compounds, the apparent mass transfer coefficient k(L)a is lower than with water alone. In term of bioscrubbing performances, comparison of the results obtained with the water-oil mixture and water alone showed that the removal efficiency for aromatics is enhanced: from 12% to 36% (applied load of 852 g VOCs m(-3)h(-1)); the elimination of chlorinated compounds is slightly improved. The addition of oil does not seem to lead to any dysfunction of the microbial communities that metabolize the transferred compounds.

The chemoreflex pathway undergoes postnatal maturation, and the perinatal environment plays a critical role in shaping respiratory control system. We investigated the role of prenatal hypoxia on the maturation of the chemoreflex neural circuits regulating ventilation in rat. Effects of hypoxia (10% O2) from the 5th to the 20th day of gestation were studied on male offspring at birth and on postnatal days 3, 7, 21 and 68. Maturation of the respiratory control system was assessed by in vivo tyrosine hydroxylase (TH) activity measurement in peripheral chemoreceptors (carotid bodies, petrosal ganglia), and in brainstem catecholaminergic cell groups (A2C2c and A1C1 areas in the medulla, A5 and A6 areas in the pons). Resting ventilation and ventilatory response to hypoxia were evaluated as functional sequelae. In peripheral structures, prenatal hypoxia reduced TH activity within the first postnatal week and enhanced it later. In contrast, in central areas, prenatal hypoxia upregulated TH activity within the first postnatal week and downregulated it later. The in vivo TH activity impairment is therefore tissue specific, with an opposite effect on the peripheral and central neural circuits. A shift of the effect of prenatal hypoxia occurred between 1 and 3 weeks, indicating a postnatal temporal effect of prenatal hypoxia. An important period in the development of the chemoafferent pathway occurred between the first and the third postnatal week. Functionally, prenatal hypoxia impaired resting ventilation and ventilatory response to hypoxia. The alterations of the catecholaminergic components of the chemoafferent pathway resulting from prenatal hypoxia might contribute to impair postnatal respiratory behaviour.

The effect of the addition of nitrate to winery wastewaters to control the formation of VFA in order to prevent odours during storage and treatment was studied in batch bioreactors at different NO(3)/chemical oxygen demand (COD) ratios and at full scale in natural evaporation ponds (2 x 7000 m(2)) by measuring olfactory intensity. In the absence of nitrate, butyric acid (2304 mgL(-1)), acetic acid (1633 mgL(-1)), propionic acid (1558 mgL(-1)), caproic acid (499 mgL(-1)) and valeric acid (298 mgL(-1)) were produced from reconstituted winery wastewater. For a ratio of NO(3)/COD=0.4 gg(-1), caproic and valeric acids were not formed. The production of butyric and propionic acids was reduced by 93.3% and 72.5%, respectively, at a ratio of NO(3)/COD=0.8, and by 97.4% and 100% at a ratio of NO(3)/COD=1.2 gg(-1). Nitrate delayed and decreased butyric acid formation in relation to the oxidoreduction potential. Studies in ponds showed that the addition of concentrated calcium nitrate (NITCAL) to winery wastewaters (3526 m(3)) in a ratio of NO(3)/COD=0.8 inhibited VFA production, with COD elimination (94%) and total nitrate degradation, and no final nitrite accumulation. On the contrary, in ponds not treated with nitrate, malodorous VFA (from propionic to heptanoïc acids) represented up to 60% of the COD. Olfactory intensity measurements in relation to the butanol scale of VFA solutions and the ponds revealed the pervasive role of VFA in the odour of the untreated pond as well as the clear decrease in the intensity and not unpleasant odour of the winery wastewater pond enriched in nitrates. The results obtained at full scale underscored the feasibility and safety of the calcium nitrate treatment as opposed to concentrated nitric acid.

Rett syndrome (RS) is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein2 (MECP2) gene. No effective treatment exists. We previously showed that the Mecp2-deficient mice, a mouse model of RS, have highly variable respiratory rhythm and frequent apneas due to reduced norepinephrine (NE) content, and a drastic decrease of tyrosine hydroxylase (TH)-expressing neurons in the medulla. We showed here that treating these mice with desipramine (DMI), which specifically inhibits NE reuptake, significantly improved their respiratory rhythm during several weeks. In addition, the treatment significantly extended their lifespan. At the cellular level, we showed that the reduced number of TH-expressing neurons before treatment in the mutant animals was not due to apoptosis. Conversely, we found that DMI treatment increased the number of TH-expressing neurons in the mutant brainstem to reach wild-type levels. We showed that this increase was not due to cellular proliferation. We propose that the Mecp2-deficient TH-expressing neurons lose their ability to synthesize TH at some point during their postnatal development. Our results suggest that a pharmacological stimulation of the noradrenergic system could be a promising approach for the treatment of the respiratory dysfunction which causes a significant proportion of death in RS patients.

Although compelling evidence exist that the respiratory rhythm generator is modulated by endogenous noradrenaline released from pontine A5 and A6 neurones, we examined whether medullary catecholaminergic neurones also participated in respiratory rhythm modulation. Experiments were performed in neonatal (postnatal days 0-6, P0-P6) and young mice (P14-P18) using "en bloc" medullary preparations (pons resected) and transverse medullary slices. In "en bloc" preparations, blockade of medullary alpha2 adrenoceptors with yohimbine and activation of catecholamine biosynthesis with L-tyrosine significantly depresses and facilitates the respiratory rhythm, respectively. In slices from neonatal and young mice, blockade of medullary alpha2 adrenoceptors also depressed the respiratory rhythm. Yohimbine local applications and lesion-ablation experiments of the dorsal medulla revealed implication of A1/C1 neurones in the yohimbine depressing effect. Although the mechanisms responsible for the yohimbine-depressing effect remain to be elucidated, our in vitro results in neonatal and young mice suggest that endogenous catecholamines released from A1/C1 neurones participate in respiratory rhythm modulation via medullary alpha2 adrenoceptors.