432 research outputs found
Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development.
During embryonic life, the initially paired pharyngeal arch arteries (PAAs) follow a precisely orchestrated program of persistence and regression that leads to the formation of the mature aortic arch and great vessels. When this program fails, specific cardiovascular defects arise that may be life threatening or mild, according to the identity of the affected artery. Fourth PAA-derived cardiovascular defects occur commonly in DiGeorge syndrome and velocardiofacial syndrome (22q11DS), and in Tbx1(+/-) mice that model the 22q11DS cardiovascular phenotype. Tbx1 is expressed in pharyngeal mesoderm, endoderm and ectoderm, and, in addition, we show that it is expressed in precursors of the endothelial cells that line the PAAs, thus expanding the number of tissues in which Tbx1 is potentially required for fourth PAA development. In this study, we have used cell fate mapping and tissue-specific gene deletion, driven by six different Cre lines, to explore Tbx1 gene-dosage requirements in the embryonic pharynx for fourth PAA development. Through this approach, we have resolved the spatial requirements for Tbx1 in this process, and we show pharyngeal epithelia to be a critical tissue. We also thereby demonstrate conclusively that the role of Tbx1 in fourth PAA development is cell non-autonomous
FRA2A is a CGG repeat expansion associated with silencing of AFF3
Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship
PLA2G6-associated neurodegeneration (PLAN): Further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease
Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy' is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features. © 2014 Elsevier Inc
Inter-individual variability contrasts with regional homogeneity in the human brain DNA methylome
The possibility that alterations in DNA methylation are mechanistic drivers of development, aging and susceptibility to disease is widely acknowledged, but evidence remains patchy or inconclusive. Of partic-ular interest in this regard is the brain, where it has been reported that DNA methylation impacts on neu-ronal activity, learning and memory, drug addiction and neurodegeneration. Until recently, however, lit-tle was known about the ‘landscape ’ of the human brain methylome. Here we assay 1.9 million CpGs in each of 43 brain samples representing different individuals and brain regions. The cerebellum was a consistent outlier compared to all other regions, and showed over 16 000 differentially methylated re-gions (DMRs). Unexpectedly, the sequence charac-teristics of hypo- and hypermethylated domains in cerebellum were distinct. In contrast, very few DMRs distinguished regions of the cortex, limbic system and brain stem. Inter-individual DMRs were readily detectable in these regions. These results lead to the surprising conclusion that, with the exception of cerebellum, DNA methylation patterns are more ho-mogeneous between different brain regions from the same individual, than they are for a single brain re-gion between different individuals. This finding sug-gests that DNA sequence composition, not develop-mental status, is the principal determinant of the hu-man brain DNA methylome
Rapid Evolution in the Most Luminous Galaxies During the First 900 Million Years
The first 900 million years (Myr) to redshift z~6 (the first seven per cent
of the age of the Universe) remains largely unexplored for the formation of
galaxies. Large samples of galaxies have been found at z~6, but detections at
earlier times are uncertain and unreliable. It is not at all clear how galaxies
built up from the first stars when the Universe was ~300 Myr old (z~12-15) to
z~6, just 600 Myr later. Here we report the results of a search for galaxies at
z~7-8, about 700 Myr after the Big Bang, using the deepest near-infrared and
optical images ever taken. Under conservative selection criteria we find only
one candidate galaxy at z~7-8, where ten would be expected if there were no
evolution in the galaxy population between z~7-8 and z~6. Using less
conservative criteria, there are four candidates, where 17 would be expected
with no evolution. This demonstrates that very luminous galaxies are quite rare
700 Myr after the Big Bang. The simplest explanation is that the Universe is
just too young to have built up many luminous galaxies at z~7-8 by the
hierarchical merging of small galaxies.Comment: Accepted for publication in Nature, 20 pages, 5 figures, 2 tables
(includes Supplementary Information), replaced to match version in pres
Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline
The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline
Self-medication for infants with colic in Lagos, Nigeria
<p>Abstract</p> <p>Background</p> <p>Infantile colic is a self-limiting condition that is distributed worldwide. It is often misdiagnosed as an organic disease for which an infant is admitted to the hospital. Many studies have described the aetiopathogenesis, pharmacologic and non-pharmacologic management of colic but none has evaluated self-medication for infants with colic. The aim of this study was therefore to determine the knowledge of Nigerian mothers about colic, their home-based management, extent of self-medication for the infants with colic and the types of medicines involved.</p> <p>Methods</p> <p>It is a prospective study conducted at the vaccination clinics of 20 primary health care centres, each from different Local Government Areas in Lagos, Nigeria. Eight hundred mothers that brought their infants for vaccination between April and September, 2006 were interviewed with open-and close-ended questionnaire.</p> <p>Results</p> <p>Six hundred and eighty three (85.4%) mothers claimed they had a good knowledge of colic. Incessant and excessive cry was the main clinical feature of colic identified by 430(62.9%) mothers. Three hundred and seventy eight (67.7%) infants were treated by self-medication, 157 (28.1%) sought medical intervention and 17 (3.1%) were treated at a traditional birth attendant home. Herbal medicines constituted 51.8% of the self-medicated medicines, of which 48 (26.2%) were "Ororo Ogiri". Nospamin<sup>® </sup>(49.5%) and Gripe water<sup>® </sup>(43.0%) were the two frequently prescribed and self-medicated medicines for infants with colic.</p> <p>Conclusion</p> <p>Nigerian mothers are deficient in their knowledge of colic. Self-medication was the most frequently used home-based intervention. Health education would appear necessary to improve parental management of this self-limiting condition.</p
Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom
Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. / Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. / Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6–89] months; median weight: 7.86 [range, 3.2–20.2] kg; duration of follow-up: 3–22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged 100 U/L (95% CI, 2.3–223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2–209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. / Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. / Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services
Ratio of the Isolated Photon Cross Sections at \sqrt{s} = 630 and 1800 GeV
The inclusive cross section for production of isolated photons has been
measured in \pbarp collisions at GeV with the \D0 detector at
the Fermilab Tevatron Collider. The photons span a transverse energy ()
range from 7-49 GeV and have pseudorapidity . This measurement is
combined with to previous \D0 result at GeV to form a ratio
of the cross sections. Comparison of next-to-leading order QCD with the
measured cross section at 630 GeV and ratio of cross sections show satisfactory
agreement in most of the range.Comment: 7 pages. Published in Phys. Rev. Lett. 87, 251805, (2001
Direct Search for Charged Higgs Bosons in Decays of Top Quarks
We present a search for charged Higgs bosons in decays of pair-produced top
quarks in pbar p collisions at sqrt(s) = 1.8 TeV using 62.2 pb^-1 of data
recorded by the D0 detector at the Fermilab Tevatron collider. No evidence is
found for signal, and we exclude at 95% confidence most regions of the (M
higgs, tan beta) parameter space where the decay t->H b has a branching
fraction greater than 0.36 and B(H -> tau nu) is large.Comment: 11 pages, 4 figures, submitted to Phys. Rev. Let
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