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Objective Idiopathic burning mouth syndrome ( iBMS) is characterized by oral persistent pain without any clinical or biological abnormality. The aim of this study was to evaluate taste function in iBMS subjects and healthy controls. Material and Methods Electrogustometric thresholds ( EGMt) were recorded in 21 iBMS patients and 21 paired-matched controls at nine loci of the tongue assessing fungiform and foliate gustatory papillae function. Comparison of EGMt was performed using the nonparametric Wilcoxon signed-rank test. A correlation between EGMt and self-perceived pain intensity assessed using a visual analogic scale ( VAS) was analyzed with the Spearman coefficient. The level of significance was fixed at P < 0.05. Results Mean EGMt were significantly increased with iBMS for right side of the dorsum of the tongue and right lateral side of the tongue ( P < 0.05). In the iBMS group, VAS scores were significantly correlated to EGMt at the tip of the tongue ( r = −0.59; P < 0.05) and at the right and left lateral sides of the tongue (respectively, r = −0.49 and r = −0.47; P < 0.05). Conclusion These data depicted impaired taste sensitivity in iBMS patients within fungiform and foliate taste bud fields and support potent gustatory/nociceptive interaction in iBMS. [ABSTRACT FROM AUTHOR]

The objective of this study was to freeze sperm of sex-reversed females (neomales) of perch and to test their fertilization ability. Sperm used was testicular (TSN), collected from females that have been inverted by means of externally administered 17-alpha methyltestosterone. Sperm collected from intact males (SSNM) of the same origin were used as control. Prior to freezing, both TSN and SSNM were diluted into 300 mm glucose solution at the ratio of 1 : 6 and DMSO was used as cryoprotectant (10% final concentration). Crypreservation was performed in 0.5 ml straws placed into a polystyrene box, three cm above the liquid nitrogen level for 10 min and thereafter transferred fully into liquid nitrogen. Samples were thawed in 40°C water bath for 8 s and used for the fertilization experiments. Spermatozoa concentration of fresh TSN and SSNM were estimated with 45.3 × 109 and 37.8 × 109 spermatozoa ml−1, respectively. Both sperm velocity and motility showed significant decreases in the TSN (134.6 μm s−1 and 12.8%) compared to the SSNM (203.2 μm s−1 and 94.7%) at 10 s after sperm activation. However, no differences were observed in terms of hatching rates between fresh TSN and SSNM (42.5 vs 49.3%) at fertilization densities of 12 × 105 spermatozoa per egg. Frozen/thawed SSNM exhibited similar hatching rates at 12 × 105 and 2.4 × 105 spermatozoa per egg (37.2% vs 29.1%). Hatching rates for frozen/thawed TSN were about 7.3% with 12 × 105 spermatozoa per egg and did not show any difference at 2.4 × 105 spermatozoa per egg (6.6%). Stripped sperm of normal perch can be successfully frozen. Squeezing of the testes is not a good method for collection of testicular sperm resulting into low velocity, motility and hatching rate. To understand the influences of neomales on sperm quality on reproductive success further studies should be performed addressing a full assay of motility and fertility criteria when using stripped sperm from normal males and neomales. Additionally, the results indicate that many of sex reversed perch neomales are not able to release sperm and that for further studies some well spermiating neomales must to be selected. [ABSTRACT FROM AUTHOR]

Mutations in the gene for the ganglioside- induced-differentiation-associated-protein I on 8q21 were recently reported to cause autosomal recessive Charcot-Marie-Tooth sensorimotor neuropathy. We report a detailed clinical, electrophysiological and genetic study of two young patients harbouring missense GDAPI mutations. The two patients presented severe neuropathy [ABSTRACT FROM AUTHOR]

Abstract The modulatory influence of nicotinic acetylcholine receptor (nAChRs) on thalamocortical transmission was characterized in the prelimbic area (PrL) of the rat prefrontal cortex. In the first experiment, rats received a unilateral excitotoxic lesion centred on the mediodorsal thalamic nucleus (MD), and were sacrificed 1 week later. The lesion resulted in a 40% reduction of 3H-nicotine autoradiographic labelling in the ipsilateral prefrontal cortex, particularly in areas that are innervated by the MD. Electrophysiological experiments were subsequently performed in non-lesioned anaesthetized animals, in order to study modulation of short- and long-latency responses of PrL neurons evoked by electrical stimulation of the MD. The short-latency responses result from activation of the MD–PrL pathway and are mediated via AMPA-type glutamatergic receptors, whereas the long-latency responses reflect activation of the recurrent collaterals of cortical pyramidal neurons. Iontophoretic application of nicotinic agonists (nicotine, DMPP) facilitated both types of response. Local application of the nAChR antagonists dihydro-beta-erythroidine, mecamylamine and methyllycaconitine, prevented both kinds of facilitation. Finally, intracerebral microdialysis experiments were performed in order to test for nicotinic modulation of extracellular glutamate concentrations in the PrL. Direct application of nicotine via the dialysis probe increased glutamate levels in a dose-dependent manner. This effect was blocked by local perfusion of dihydro-beta-erythroidine. These findings therefore provide anatomical and functional evidence for nAChR-mediated modulation of thalamocortical input to the prefrontal cortex. Such a mechanism may be relevant to the cognitive effects of nicotine and nicotinic antagonists. [ABSTRACT FROM AUTHOR]

Studies the potential peripheral targets for the final secretory maturation product of submandibular rat 1 protein (SMR1)-pentapeptide and examines the in vivo tissue distribution of the radiolabeled peptide using beta-radio imager whole body autoradiography. SMR1-derived pentapeptide bloodstream secretion pattern; Localization of [3H]pentapeptide receptors.

Examines in vivo the tissue distribution of the radiolabeled peptide using ...-radio imager whole body autoradiography, by mapping peripheral targets for the final secretory maturation product of submandibular rat 1 protein (SMR1). Methodology used in study; What the characteristics of tissue uptake allowed; Suggestions on the circulating androgen-regulated SMR1-derived pentapeptide.

Objective Hypomyelinating leukodystophy (HDL) with atrophy of basal ganglia (BG) and cerebellum (H-ABC or HDL6) has recently been associated with de Novo mutations of tubulin beta 4 (TUBB4A), a gene known to be involved in a dominant form of dystonia (DYT4). We propose to illustrate the large clinicoradiological spectrum of TUBB4A-gene-related mutations. Methods We report on 4 patients. Results Patient 1 presented with a classic form: nytagmus at 3 months of age, no head control; spastic tetraparesis, choreo-athetosic movements and axial dystonia were obvious before the age of 2 years. MRI showed hypomyelination with progressive BG atrophy. Patient 2 and 3 presented with predominant motor dysfunction which manifested as delayed acquisition of milestones and progressive severe spastic quadriplegia. Communication and receptive language were relatively preserved. Extrapyramidal symptomatology and cognitive dysfunction appeared after several years of evolution. MRI dysplayed hypomyelination, corpus callosum and cerebellar atrophy in patients 2 and 3, associated with cortical and BG atrophy in patient 3. Patient 4 acquired independent but unsteady walking at 12 months of age. He could run and read. He was explored for the first time at around 2 years for nystagmus and delayed acquisition of language. Motor functions deteriorated after a limb fracture (7y) in a context of very slowly progressive cerebellar syndrome, which had been evident at 3 years of age. Independent ambulation was lost at 8. MRI at 10 years showed hypomyelination and a slight atrophy of the striatum. All patients have diferent de Novo TUBB4A mutations. 2 are known, 2 are reported for the first time (patients 2, 4). Conclusion These observations illustrate a phenotypic continuum linked to TUBB4A mutations, as reported in the others HDL. This diagnosis should be discussed when HDL is associated with BG and/or cerebellum atrophy in a patient presenting with spasticity and/or progressive cerebellar symptoms. [ABSTRACT FROM AUTHOR]

A somatostatin deficit occurs in the cerebral cortex of Alzheimer''s disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer''s disease. By size exclusion chromatography, the cleavage of prosomatostatin to somatostatin-14 is almost totally abolished in the cortex of PC2 null mice, while the proportions of prosomatostatin and somatostatin-28 are increased. By immunohistochemistry, PC1 and PC2 were localized in many neuronal elements in human frontal and temporal cortex. The convertases levels were quantified by Western blot, as well as the protein 7B2 which is required for the production of active PC2. No significant change in PC1 levels was observed in Alzheimer''s disease. In contrast, a marked decrease in the ratio of the PC2 precursor to the total enzymatic pool was observed in the frontal cortex of Alzheimer patients. This decrease coincides with an increase in the binding protein 7B2. However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer''s disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Domestication might be a possible way to reduce the physiological response to long-term stressors and deleterious effects on immunity. The present study aimed to evaluate the chronic immune response induced by repeated emersions and the possible impact of domestication by comparing farmed Eurasian perch with short (F1) and long (F4) captive-life history. In the first experiment, fish were exposed to a single emersion and physiological stress response was measured in the short term to characterize fish sensitivity to the tested stressor. Serum cortisol and glucose elevated within 6h post-stress and splenosomatic index (SSI) decreased within 48h, indicating that the species was affected by emersion stressor. In the second experiment, F1 and F4 generations were submitted to repeated water emersions (3 times/week during 44days). On day 9, 18 and 44, samplings were performed 48h post-stressor to highlight any sustained disruption of immune system. Serum cortisol, glucose, SSI and lysozyme activity were evaluated and serum proteome was analyzed using 2D-DIGE. Any of the tested variables were affected by repeated emersions and proteomic analysis only revealed that alpha-2 macroglobulins (a2Ms) were up-regulated in the serum of stressed individuals. Domestication also resulted in the up-regulation of five a2M isoforms and down-regulation of complement C3 and Ig light chain proteins, independently of any stressor exposure. In conclusion, the results suggested that repeated emersions are not severe stressors for Eurasian perch, probably explaining why domestication had no influence on fish responses. Changes associated with domestication are highly complex and certainly need further investigations. [Copyright &y& Elsevier]

Abstract: The objective was to evaluate the impact of domestication process on the physiological stress response of cultured Eurasian perch confronted to a chronic stress situation. Briefly, F1 and F4 juveniles were submitted to chronic confinement and investigated on days 5, 15 and 30. Capture and 15min-anesthesia were imposed on fish to assess the effect of preceding confinement on acute stress response. On day 30, the fish were finally challenged with Aeromonas hydrophila and sampled after 5 and 10days for immune parameter measurements. Cortisol and glucose levels were not affected by confinement but increased significantly after acute stressor exposure. Moreover, cortisol rise following capture and anesthesia was higher in F1 confined-fish, suggesting that they have previously been affected by chronic confinement. A higher HSP70 level was also observed on day 30 in F1 confined-juveniles. During bacterial challenge, regardless of confinement level, F4 juveniles displayed higher lysozyme activity and agglutination response than F1 which may indicate a higher immune capacity in domesticated fish. In conclusion, chronic confinement stressor induced few physiological responses but may increase the responsiveness to other aquacultural stressors. Domestication process also seems to improve chronic stress resistance, growth as well as the immune status of the fish. [Copyright &y& Elsevier]

Abstract: In fish, the reasons for the inhibition of reproduction by constant photothermal conditions of rearing are far from clear. In an in vivo experiment, two groups of females reared under natural (4–28°C) or constant photothermal conditions (20–22°C, photoperiod 12/12) were investigated for gonad development, sex-steroids (testosterone-T, 17-β-estradiol-E2 and 11 Keto-Testosterone-11KT) dynamics and brain aromatase activity in January, February and March. Two days before each sampling date, a group of females reared under constant conditions was injected with HCG (Human Chorionic Gonadotropin: 100UI/kg) and evaluated for the same parameters. In addition, in vitro ovarian steroidogenesis capacity for each female was determined with or without stimulation by HCG and/or IGF-1 (Insulin-like Growth Factor-1). The results indicate that vitellogenesis stage is the limit ovarian stage never reached in females submitted to constant photothermal conditions. This was associated with gonadogenesis delay and low levels of circulating sex-steroids (T, E2 and 11KT). Nevertheless, HCG injections partly counteracted the plasma steroid deprivation, indicating that ovaries from fish reared under constant photothermal conditions suffer from a lack of gonadotropin stimulation, maybe caused by plasma LH suppression. Such finding was confirmed by the in vitro ovary incubation test. HCG and IGF-1 treatments induced broad testosterone and 17-β-estradiol elevations and the exposure to constant photothermal conditions, in some cases, decreased that response to HCG. In conclusion, we show that the inhibition of reproductive cycle in Eurasian perch females by constant photothermal conditions of rearing may be related to lower sex-steroid levels and to an inhibition of ovarian regulation by gonadotropins (at least LH), probably stopping gonadogenesis before vitellogenesis stage. [Copyright &y& Elsevier]

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders., Competing Interests: Declaration of interests B.S. is a shareholder in EpiSign Inc, involved in commercial uses of EpiSign(TM) technology D.A.C. and K.G.M. are employees of GeneDx, LLC., (Copyright © 2024. Published by Elsevier Inc.)

The high temperature sex reversal process leading to functional phenotypic masculinization during development has been widely described in Nile tilapia ( Oreochromis n iloticus ) under laboratory or aquaculture conditions and in the wild. In this study, we selected five wild populations of O. niloticus from different river basins in Benin and produced twenty full-sib families of mixed-sex (XY and XX) by natural reproduction. Progenies were exposed to room temperature or high (36.5°C) temperatures between 10 and 30 days post-fertilization (dpf). In control groups, we observed sex ratios from 40% to 60% males as expected, except for 3 families from the Gobé region which showed a bias towards males. High temperature treatment significantly increased male rates in each family up to 88%. Transcriptome analysis was performed by RNA-sequencing (RNA-seq) on brains and gonads from control and treated batches of six families at 15 dpf and 40 dpf. Analysis of differentially expressed genes, differentially spliced genes, and correlations with sex reversal was performed. In 40 dpf gonads, genes involved in sex determination such as dmrt1, cyp11c1, amh, cyp19a1b, ara , and dax1 were upregulated. In 15 dpf brains, a negative correlation was found between the expression of cyp19a1b and the reversal rate, while at 40 dpf a negative correlation was found between the expression of foxl2, cyp11c1 , and sf1 and positive correlation was found between dmrt1 expression and reversal rate. Ontology analysis of the genes affected by high temperatures revealed that male sex differentiation processes, primary male sexual characteristics, autophagy, and cilium organization were affected. Based on these results, we conclude that sex reversal by high temperature treatment leads to similar modifications of the transcriptomes in the gonads and brains in offspring of different natural populations of Nile tilapia, which thus may activate a common cascade of reactions inducing sex reversal in progenies., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17)., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A ., Methods: We selected 53 patients with pathogenic variants on CC2D2A , compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature., Results: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype., Conclusion: This study contradicts previous literature stating an association between CC2D2A -related JS and ventriculomegaly. Our study implies that CC2D2A -related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Chiral molecules are challenging for the pharmaceutical industry because although physical properties of the enantiomers are the same in achiral systems, they exhibit different effects in chiral systems, such as the human body. The separation of enantiomers is desired but complex, as enantiomers crystallize most often as racemic compounds. A technique to enable the chiral separation of racemic compounds is to create an asymmetry in the thermodynamic system by generating chiral cocrystal(s) using a chiral coformer and using the solubility differences to enable separation through crystallization from solution. However, such quaternary systems are complex and require analytical methods to quantify different chiral molecules in solution. Here, we develop a new chiral quantification method using ultraviolet-circular dichroism spectroscopy and multivariate partial least squares calibration models, to build multicomponent chiral phase diagrams. Working on the quaternary system of ( R )- and ( S )-2-(2-oxopyrrolidin-1-yl)butanamide enantiomers with ( S )-mandelic acid in acetonitrile, we measure accurately the full quaternary phase diagram for the first time. By understanding the phase stabilities of the racemic compound and the enantiospecific cocrystal, the chiral resolution of levetiracetam could be designed due to a large asymmetry in overall solubility between both sides of the racemic composition. This new method offers improvements for chiral molecule quantification in complex multicomponent chiral systems and can be applied to other chiral spectroscopy techniques.

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10)., Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data., Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%., Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts., Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts., Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts., Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification., (© 2019 Wiley Periodicals, Inc.)

Purpose: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes., Methods: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes., Results: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant., Conclusion: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

Nile tilapia (Oreochromis niloticus) is an African freshwater fish that displays a genetic sex determination system (XX|XY) where high temperatures (above 32°C to 36.5°C) induce masculinization. In Nile tilapia, the thermosensitive period was reported from 10 to 30 days post fertilization. In their natural environment, juveniles may encounter high temperatures that are above the optimal temperature for growth (27-30°C). The relevance of the thermal sex reversal mechanism in a natural context remains unclear. The main objective of our study is to determine whether sexually undifferentiated juveniles spontaneously prefer higher, unfavorable temperatures and whether this choice skews the sex ratio toward males. Five full-sib progenies (from 100% XX crosses) were subjected to (1) a horizontal three-compartment thermal step gradient (thermal continuum 28°C- 32°C- 36.5°C) during the thermosensitive period, (2) a control continuum (28°C- 28°C- 28°C) and (3) a thermal control tank (36.5°C). During the first days of the treatment, up to an average of 20% of the population preferred the masculinizing compartment of the thermal continuum (36.5°C) compared to the control continuum. During the second part of the treatment, juveniles preferred the lower, nonmasculinizing 32°C temperature. This short exposure to higher temperatures was sufficient to significantly skew the sex ratio toward males, compared to congeners raised at 28°C (from 5.0 ± 6.7% to 15.6 ± 16.5% of males). The proportion of males was significantly different in the thermal continuum, thermal control tank and control continuum, and it was positively correlated among populations. Our study shows for the first time that Nile tilapia juveniles can choose a masculinizing temperature during a short period of time. This preference is sufficient to induce sex reversal to males within a population. For the first time, behavior is reported as a potential player in the sex determination mechanism of this species., Competing Interests: The authors have declared that no competing interests exist.

Background: Neuropathic pain represents a therapeutic challenge, and treatments with increased efficacy and tolerability still need to be developed. Opiorphin protects endogenous enkephalins from degradation, potentiating enkephalin-dependent analgesia via the activation of opioid pathways. Enkephalins are natural ligands of opioid receptors, with strong affinity for δ-opioid receptors. Expression of functional δ-opioid receptors increases in sensory neurons after peripheral nerve injury in neuropathic pain models. In a postoperative pain model, opiorphin and its stable analog STR-324 have an analgesic potency comparable to that of morphine, but without adverse opioid-related side effects. Consequently, administration of endogenous opiorphin peptides or STR-324 might be effective in managing peripheral neuropathic pain., Methods: In this study, STR-324 was administered intravenously over the course of 7 days to rats with mononeuropathy induced by L5-L6 spinal nerve root ligation. The rats exhibited mechanical allodynia, thermal hyperalgesia, and spontaneous pain-related behavior throughout the testing period., Results: Here, we report that the continuous administration of STR-324 significantly reduced mechanical allodynia and spontaneous pain-related behavior from day 2 to day 7 in animals that received 10 or 50 µg/h of STR-324 as compared to placebo-treated animals (P < .00001 and P < .0011, respectively, for mechanical allodynia; P = .028 and P = .0049, respectively, for spontaneous pain-related behavior). In addition, STR-324 reduced the pain-evoked expression of spinal c-Fos in this model, demonstrating that it acts at least in part through inhibition of endogenous nociceptive pathways., Conclusions: These observations suggested that STR-324 may be an effective addition to the multimodal approach for treating clinical neuropathic pain.

Objectives: Idiopathic Burning mouth syndrome (iBMS) is a poorly understood affection characterized by persistent pain in the oral cavity without any clinical or biological abnormality. Opiorphin is a natural inhibitor of enkephalin-inactivating ectopeptidases, mainly produced by salivary glands, that has demonstrated analgesic properties. The objective of the present case-control study was to test the hypothesis of a decrease in opiorphin levels in iBMS patients., Materials and Methods: Twenty-one iBMS patients and 21 matched controls subjects were included between 2011 and 2013. Submandibular and sublingual salivary, blood, and urinary opiorphin levels of iBMS patients were compared to controls., Results: Results are expressed as mean values ± SD and compared using the Wilcoxon Signed Rank test. Correlations were analyzed with Spearman coefficient. The level of significance was fixed at p < 0.05. Opiorphin levels in iBMS and controls were respectively (in ng/ml) in basal saliva: 37.8 ± 42.5 and 67.6 ± 188.9 (p = NS); stimulated saliva: 28.8 ± 25.3 and 31.1 ± 29.1 (p = NS); blood: 4.6 ± 5.4 and 1.9 ± 1.4 (p < 0.05); and urines: 68.5 ± 259.8 and 8.9 ± 6.2 (p = NS)., Clinical Relevance: In conclusion, the lack of significative difference in salivary opiorphin levels between iBMS and controls does not favor a direct local role for opiorphin in the etiopathogeny of iBMS. However, higher blood opiorphin levels may reflect a systemic dysregulation in iBMS. Trial registration NCT02686359 https://clinicaltrials.gov/ct2/show/NCT02686359.