136 research outputs found
Mouse Models of Genomic Syndromes as Tools for Understanding the Basis of Complex Traits: An Example with the Smith-Magenis and the Potocki-Lupski Syndromes
Each human's genome is distinguished by extra and missing DNA that can be “benign” or powerfully impact everything from development to disease. In the case of genomic disorders DNA rearrangements, such as deletions or duplications, correlate with a clinical specific phenotype. The clinical presentations of genomic disorders were thought to result from altered gene copy number of physically linked dosage sensitive genes. Genomic disorders are frequent diseases (~1 per 1,000 births). Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders, associated with a deletion and a duplication, of 3.7 Mb respectively, within chromosome 17 band p11.2. This region includes 23 genes. Both syndromes have complex and distinctive phenotypes including multiple congenital and neurobehavioral abnormalities. Human chromosome 17p11.2 is syntenic to the 32-34 cM region of murine chromosome 11. The number and order of the genes are highly conserved. In this review, we will exemplify how genomic disorders can be modeled in mice and the advantages that such models can give in the study of genomic disorders in particular and gene copy number variation (CNV) in general. The contributions of the SMS and PTLS animal models in several aspects ranging from more specific ones, as the definition of the clinical aspects of the human clinical spectrum, the identification of dosage sensitive genes related to the human syndromes, to the more general contributions as the definition of genetic locus impacting obesity and behavior and the elucidation of general mechanisms related to the pathogenesis of gene CNV are discussed
Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki-Lupski syndrome
The Potocki-Lupski syndrome (PTLS) is associated with a microduplication of 17p11.2. Clinical features include multiple congenital and neurobehavioral abnormalities and autistic features. We have generated a PTLS mouse model, Dp(11)17/+, that recapitulates some of the physical and neurobehavioral phenotypes present in patients. Here, we investigated the social behavior and gene expression pattern of this mouse model in a pure C57BL/6-Tyrc-Brd genetic background. Dp(11)17/+ male mice displayed normal home-cage behavior but increased anxiety and increased dominant behavior in specific tests. A subtle impairment in the preference for a social target versus an inanimate target and abnormal preference for social novelty (the preference to explore an unfamiliar mouse versus a familiar one) was also observed. Our results indicate that these animals could provide a valuable model to identify the specific gene(s) that confer abnormal social behaviors and that map within this delimited genomic deletion interval. In a first attempt to identify candidate genes and for elucidating the mechanisms of regulation of these important phenotypes, we directly assessed the relative transcription of genes within and around this genomic interval. In this mouse model, we found that candidates genes include not only most of the duplicated genes, but also normal-copy genes that flank the engineered interval; both categories of genes showed altered expression levels in the hippocampus of Dp(11)17/+ mic
Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome
<p>Abstract</p> <p>Background</p> <p>Smith-Magenis Syndrome is a contiguous gene syndrome in which the dosage sensitive gene has been identified: the Retinoic Acid Induced 1 (<it>RAI1</it>). Little is known about the function of human RAI1.</p> <p>Results</p> <p>We generated the full-length cDNA of the wild type protein and five mutated forms: <it>RAI1-HA </it>2687delC, <it>RAI1-HA </it>3103delC, <it>RAI1 </it>R960X, <it>RAI1-HA </it>Q1562R, and <it>RAI1-HA </it>S1808N. Four of them have been previously associated with SMS clinical phenotype. Molecular weight, subcellular localization and transcription factor activity of the wild type and mutant forms were studied by western blot, immunofluorescence and luciferase assays respectively. The wild type protein and the two missense mutations presented a higher molecular weight than expected, localized to the nucleus and activated transcription of a reporter gene. The frameshift mutations generated a truncated polypeptide with transcription factor activity but abnormal subcellular localization, and the same was true for the 1-960aa N-terminal half of RAI1. Two different C-terminal halves of the RAI1 protein (1038aa-end and 1229aa-end) were able to localize into the nucleus but had no transactivation activity.</p> <p>Conclusion</p> <p>Our results indicate that transcription factor activity and subcellular localization signals reside in two separate domains of the protein and both are essential for the correct functionality of RAI1. The pathogenic outcome of some of the mutated forms can be explained by the dissociation of these two domains.</p
Exocomet signatures around the A-shell star Leo?
We present an intensive monitoring of high-resolution spectra of the Ca {\sc
ii} K line in the A7IV shell star Leo at very short (minutes, hours),
short (night to night), and medium (weeks, months) timescales. The spectra show
remarkable variable absorptions on timescales of hours, days, and months. The
characteristics of these sporadic events are very similar to most that are
observed toward the debris disk host star Pic, which are commonly
interpreted as signs of the evaporation of solid, comet-like bodies grazing or
falling onto the star. Therefore, our results suggest the presence of solid
bodies around Leo. To our knowledge, with the exception of Pic,
our monitoring has the best time resolution at the mentioned timescales for a
star with events attributed to exocomets. Assuming the cometary scenario and
considering the timescales of our monitoring, our results indicate that
Leo presents the richest environment with comet-like events known to date,
second only to Pic.Comment: A&A letters, proof-correcte
The mass ratio and formation mechanisms of Herbig Ae/Be star binary systems
We present B and R band spectroastrometry of a sample of 45 Herbig Ae/Be
stars in order to study their binary properties. All but one of the targets
known to be binary systems with a separation of ~0.1-2.0 arcsec are detected by
a distinctive spectroastrometric signature. Some objects in the sample exhibit
spectroastrometric features that do not appear attributable to a binary system.
We find that these may be due to light reflected from dusty halos or material
entrained in winds. We present 8 new binary detections and 4 detections of an
unknown component in previously discovered binary systems. The data confirm
previous reports that Herbig Ae/Be stars have a high binary fraction, 74+/-6
per cent in the sample presented here. We use a spectroastrometric
deconvolution technique to separate the spatially unresolved binary spectra
into the individual constituent spectra. The separated spectra allow us to
ascertain the spectral type of the individual binary components, which in turn
allows the mass ratio of these systems to be determined. In addition, we
appraise the method used and the effects of contaminant sources of flux. We
find that the distribution of system mass ratios is inconsistent with random
pairing from the Initial Mass Function, and that this appears robust despite a
detection bias. Instead, the mass ratio distribution is broadly consistent with
the scenario of binary formation via disk fragmentation.Comment: Accepted for publication in MNRAS, minor changes made in proof stag
NEXT-100 Technical Design Report (TDR). Executive Summary
In this Technical Design Report (TDR) we describe the NEXT-100 detector that
will search for neutrinoless double beta decay (bbonu) in Xe-136 at the
Laboratorio Subterraneo de Canfranc (LSC), in Spain. The document formalizes
the design presented in our Conceptual Design Report (CDR): an
electroluminescence time projection chamber, with separate readout planes for
calorimetry and tracking, located, respectively, behind cathode and anode. The
detector is designed to hold a maximum of about 150 kg of xenon at 15 bar, or
100 kg at 10 bar. This option builds in the capability to increase the total
isotope mass by 50% while keeping the operating pressure at a manageable level.
The readout plane performing the energy measurement is composed of Hamamatsu
R11410-10 photomultipliers, specially designed for operation in low-background,
xenon-based detectors. Each individual PMT will be isolated from the gas by an
individual, pressure resistant enclosure and will be coupled to the sensitive
volume through a sapphire window. The tracking plane consists in an array of
Hamamatsu S10362-11-050P MPPCs used as tracking pixels. They will be arranged
in square boards holding 64 sensors (8 times8) with a 1-cm pitch. The inner
walls of the TPC, the sapphire windows and the boards holding the MPPCs will be
coated with tetraphenyl butadiene (TPB), a wavelength shifter, to improve the
light collection.Comment: 32 pages, 22 figures, 5 table
A prognostic DNA methylation signature for stage I non-small-cell lung cancer
Purpose Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard. Patients and Methods A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC. Results Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high-and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001). Conclusion The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging. (C) 2013 by American Society of Clinical Oncology
The co-existence of hot and cold gas in debris discs
Context. Debris discs have often been described as gas-poor discs as the gas-to-dust ratio is expected to be considerably lower than in primordial, protoplanetary discs. However, recent observations have confirmed the presence of a non-negligible amount of cold gas in the circumstellar (CS) debris discs around young main-sequence stars. This cold gas has been suggested to be related to the outgassing of planetesimals and cometary-like objects. Aims. The goal of this paper is to investigate the presence of hot gas in the immediate surroundings of the cold-gas-bearing debris-disc central stars. Methods. High-resolution optical spectra of all currently known cold-gas-bearing debris-disc systems, with the exception of β Pic and Fomalhaut, have been obtained from La Palma (Spain), La Silla (Chile), and La Luz (Mexico) observatories. To verify the presence of hot gas around the sample of stars, we have analysed the Ca II H&K and the Na I D lines searching for non-photospheric absorptions of CS origin, usually attributed to cometary-like activity. Results. Narrow, stable Ca II and/or Na I absorption features have been detected superimposed to the photospheric lines in 10 out of the 15 observed cold-gas-bearing debris-disc stars. Features are found at the radial velocity of the stars, or slightly blue- or red-shifted, and/or at the velocity of the local interstellar medium (ISM). Some stars also present transient variable events or absorptions extended towards red wavelengths (red wings). These are the first detections of such Ca II features in 7 out of the 15 observed stars. Although an ISM origin cannot categorically be excluded, the results suggest that the stable and variable absorptions arise from relatively hot gas located in the CS close-in environment of the stars. This hot gas is detected in at least ~80%, of edge-on cold-gas-bearing debris discs, while in only ~10% of the discs seen close to face-on. We interpret this result as a geometrical effect, and suggest that the non-detection of hot gas absorptions in some face-on systems is due to the disc inclination and likely not to the absence of the hot-gas component. This gas is likely released in physical processes related in some way to the evaporation of exocomets, evaporation of dust grains, or grain-grain collisions close to the central star
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