Alpha thalassaemia-mental retardation, X linked

X-linked alpha thalassaemia mental retardation (ATR-X) syndrome in males is associated with profound developmental delay, facial dysmorphism, genital abnormalities and alpha thalassaemia. Female carriers are usually physically and intellectually normal. So far, 168 patients have been reported. Language is usually very limited. Seizures occur in about one third of the cases. While many patients are affectionate with their caregivers, some exhibit autistic-like behaviour. Patients present with facial hypotonia and a characteristic mouth. Genital abnormalities are observed in 80% of children and range from undescended testes to ambiguous genitalia. Alpha-thalassaemia is not always present. This syndrome is X-linked recessive and results from mutations in the ATRX gene. This gene encodes the widely expressed ATRX protein. ATRX mutations cause diverse changes in the pattern of DNA methylation at heterochromatic loci but it is not yet known whether this is responsible for the clinical phenotype. The diagnosis can be established by detection of alpha thalassaemia, identification of ATRX gene mutations, ATRX protein studies and X-inactivation studies. Genetic counselling can be offered to families. Management is multidisciplinary: young children must be carefully monitored for gastro-oesophageal reflux as it may cause death. A number of individuals with ATR-X are fit and well in their 30s and 40s

Lévy patterns in seabirds are multifaceted describing both spatial and temporal patterning

BACKGROUND: The flight patterns of albatrosses and shearwaters have become a touchstone for much of Lévy flight research, spawning an extensive field of enquiry. There is now compelling evidence that the flight patterns of these seabirds would have been appreciated by Paul Lévy, the mathematician after whom Lévy flights are named. Here we show that Lévy patterns (here taken to mean spatial or temporal patterns characterized by distributions with power-law tails) are, in fact, multifaceted in shearwaters being evident in both spatial and temporal patterns of activity. RESULTS: We tested for Lévy patterns in the at-sea behaviours of two species of shearwater breeding in the North Atlantic Ocean (Calonectris borealis) and the Mediterranean sea (C. diomedea) during their incubating and chick-provisioning periods. We found that distributions of flight durations, on/in water durations and inter-dive time-intervals have power-law tails and so bear the hallmarks of Lévy patterns. CONCLUSIONS: The occurrence of these statistical laws is remarkable given that bird behaviours are strongly shaped by an individual’s motivational state and by complex environmental interactions. Our observations could take Lévy patterns as models of animal behaviour to a new level by going beyond the characterisation of spatial movements to characterise how different behaviours are interwoven throughout daily animal life

The ALMA Frontier Fields Survey

CONTEXT: Dusty star-forming galaxies are among the most prodigious systems at high redshift (z > 1), characterized by high star-formation rates and huge dust reservoirs. The bright end of this population has been well characterized in recent years, but considerable uncertainties remain for fainter dusty star-forming galaxies, which are responsible for the bulk of star formation at high redshift and thus play a key role in galaxy growth and evolution. AIMS: In this first paper of our series, we describe our methods for finding high redshift faint dusty galaxies using millimeter observations with ALMA. METHODS: We obtained ALMA 1.1 mm mosaic images for three strong-lensing galaxy clusters from the Frontier Fields Survey, which constitute some of the best studied gravitational lenses to date. The ≈2′ × 2′ mosaics overlap with the deep HST WFC3/IR footprints and encompass the high magnification regions of each cluster for maximum intrinsic source sensitivity. The combination of extremely high ALMA sensitivity and the magnification power of these clusters allows us to systematically probe the sub-mJy population of dusty star-forming galaxies over a large surveyed area. RESULTS: We present a description of the reduction and analysis of the ALMA continuum observations for the galaxy clusters Abell 2744 (z = 0.308), MACS J0416.1-2403 (z = 0.396) and MACS J1149.5+2223 (z = 0.543), for which we reach observed rms sensitivities of 55, 59 and 71 μJy beam-1 respectively. We detect 12 dusty star-forming galaxies at S/N ≥ 5.0 across the three clusters, all of them presenting coincidence with near-infrared detected counterparts in the HST images. None of the sources fall close to the lensing caustics, thus they are not strongly lensed. The observed 1.1 mm flux densities for the total sample of galaxies range from 0.41 to 2.82 mJy, with observed effective radii spanning ≲0.̋05 to 0.̋37 ± 0.̋21 . The lensing-corrected sizes of the detected sources appear to be in the same range as those measured in brighter samples, albeit with possibly larger dispersion

The ALMA Frontier Fields Survey. II. Multiwavelength Photometric analysis of 1.1 mm continuum sources in Abell 2744, MACSJ0416.1-2403 and MACSJ1149.5+2223

CONTEXT: The Hubble and Spitzer Space Telescope surveys of the Frontier Fields provide extremely deep images around six massive, strong-lensing clusters of galaxies. The ALMA Frontier Fields survey aims to cover the same fields at 1.1 mm, with maps reaching (unlensed) sensitivities of <70 μJy, in order to explore the properties of background dusty star-forming galaxies. AIMS: We report on the multi-wavelength photometric analysis of all 12 significantly detected (>5σ) sources in the first three Frontier Fields clusters observed by ALMA, based on data from Hubble and Spitzer, the Very Large Telescope and the Herschel Space Observatory. METHODS: We measure the total photometry in all available bands and determine the photometric redshifts and the physical properties of the counterparts via SED-fitting. In particular, we carefully estimate the far-infrared (FIR) photometry using 1.1 mm priors to limit the misidentification of blended FIR counterparts, which strongly affect some flux estimates in previous FIR catalogs. Due to the extremely red nature of these objects, we used a large range of parameters (e.g. 0.0 <Av< 20.0) and templates (including AGNs and ULIRGs models). RESULTS: We identify robust near-infrared (NIR) counterparts for all 11 sources with Ks detection, the majority of which are quite red, with eight having F814W − Ks ≳ 4 and five having F160W − [ 4.5 ] ≳ 3. From the FIR point of view, all our objects have zphot ~ 1–3, whereas based on the optical SED one object prefers a high-z solution (z ≥ 7). Five objects among our sample have spectroscopic redshifts from the GLASS survey for which we can reproduce their SEDs with existing templates. This verification confirms the validity of our photometric redshift methodology. The mean redshift of our sample is zphot = 1.99 ± 0.27. All 1.1 mm selected objects are massive (10.0 < log  [ M⋆(M⊙) ] < 11.5), with high star formation rates (⟨ log [ SFR(M⊙/ yr) ] ⟩ ≈ 1.6) and high dust contents (8.1 < log  [ Mdust(M⊙) ] < 8.8), consistent with previous ALMA surveys

Biogenic amines and their metabolites are differentially affected in the Mecp2-deficient mouse brain

International audienceBACKGROUND: 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

Contribution of copy number variants (CNVs) to congenital, unexplained intellectual and developmental disabilities in Lebanese patients

International audienceBackground: Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease. Results: We screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups. Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes. Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes. However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient's unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV. Conclusion: This study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs

Multiple Histone Methyl and Acetyltransferase Complex Components Bind the HLA-DRA Gene

Major histocompatibility complex class II (MHC-II) genes are fundamental components that contribute to adaptive immune responses. While characterization of the chromatin features at the core promoter region of these genes has been studied, the scope of histone modifications and the modifying factors responsible for activation of these genes are less well defined. Using the MHC-II gene HLA-DRA as a model, the extent and distribution of major histone modifications associated with active expression were defined in interferon-γ induced epithelial cells, B cells, and B-cell mutants for MHC-II expression. With active transcription, nucleosome density around the proximal regulatory region was diminished and histone acetylation and methylation modifications were distributed throughout the gene in distinct patterns that were dependent on the modification examined. Irrespective of the location, the majority of these modifications were dependent on the binding of either the X-box binding factor RFX or the class II transactivator (CIITA) to the proximal regulatory region. Importantly, once established, the modifications were stable through multiple cell divisions after the activating stimulus was removed, suggesting that activation of this system resulted in an epigenetic state. A dual crosslinking chromatin immunoprecipitation method was used to detect histone modifying protein components that interacted across the gene. Components of the MLL methyltransferase and GCN5 acetyltransferase complexes were identified. Some MLL complex components were found to be CIITA independent, including MLL1, ASH2L and RbBP5. Likewise, GCN5 containing acetyltransferase complex components belonging to the ATAC and STAGA complexes were also identified. These results suggest that multiple complexes are either used or are assembled as the gene is activated for expression. Together the results define and illustrate a complex network of histone modifying proteins and multisubunit complexes participating in MHC-II transcription

Positive Evolutionary Selection of an HD Motif on Alzheimer Precursor Protein Orthologues Suggests a Functional Role

HD amino acid duplex has been found in the active center of many different enzymes. The dyad plays remarkably different roles in their catalytic processes that usually involve metal coordination. An HD motif is positioned directly on the amyloid beta fragment (Aβ) and on the carboxy-terminal region of the extracellular domain (CAED) of the human amyloid precursor protein (APP) and a taxonomically well defined group of APP orthologues (APPOs). In human Aβ HD is part of a presumed, RGD-like integrin-binding motif RHD; however, neither RHD nor RXD demonstrates reasonable conservation in APPOs. The sequences of CAEDs and the position of the HD are not particularly conserved either, yet we show with a novel statistical method using evolutionary modeling that the presence of HD on CAEDs cannot be the result of neutral evolutionary forces (p<0.0001). The motif is positively selected along the evolutionary process in the majority of APPOs, despite the fact that HD motif is underrepresented in the proteomes of all species of the animal kingdom. Position migration can be explained by high probability occurrence of multiple copies of HD on intermediate sequences, from which only one is kept by selective evolutionary forces, in a similar way as in the case of the “transcription binding site turnover.” CAED of all APP orthologues and homologues are predicted to bind metal ions including Amyloid-like protein 1 (APLP1) and Amyloid-like protein 2 (APLP2). Our results suggest that HDs on the CAEDs are most probably key components of metal-binding domains, which facilitate and/or regulate inter- or intra-molecular interactions in a metal ion-dependent or metal ion concentration-dependent manner. The involvement of naturally occurring mutations of HD (Tottori (D7N) and English (H6R) mutations) in early onset Alzheimer's disease gives additional support to our finding that HD has an evolutionary preserved function on APPOs

Effects of dietary carotenoids on mouse lung genomic profiles and their modulatory effects on short-term cigarette smoke exposures

Male C57BL/6 mice were fed diets supplemented with either β-carotene (BC) or lycopene (LY) that were formulated for human consumption. Four weeks of dietary supplementations results in plasma and lung carotenoid (CAR) concentrations that approximated the levels detected in humans. Bioactivity of the CARs was determined by assaying their effects on the activity of the lung transcriptome (~8,500 mRNAs). Both CARs activated the cytochrome P450 1A1 gene but only BC induced the retinol dehydrogenase gene. The contrasting effects of the two CARs on the lung transcriptome were further uncovered in mice exposed to cigarette smoke (CS) for 3 days; only LY activated ~50 genes detected in the lungs of CS-exposed mice. These genes encoded inflammatory-immune proteins. Our data suggest that mice offer a viable in vivo model for studying bioactivities of dietary CARs and their modulatory effects on lung genomic expression in both health and after exposure to CS toxicants