Epistasis and the sensitivity of phenotypic screens for beta thalassaemia

Genetic disorders of haemoglobin, particularly the sickle cell diseases and the alpha and beta thalassaemias, are the commonest inherited disorders worldwide. The majority of affected births occur in low-income and lower-middle income countries. Screening programmes are a vital tool to counter these haemoglobinopathies by: (i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene-frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive. One popular first-stage screening option to detect carriers of beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that interactions between the carrier states for beta thalassaemia and alpha thalassaemia, glucose-6-phosphate dehydrogenase deficiency and Southeast Asian Ovalocytosis have the potential to reduce the sensitivity of OTOFTs for beta thalassaemia heterozygosity to below 70%. Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur

Determination of Turbine Blade Life from Engine Field Data

It is probable that no two engine companies determine the life of their engines or their components in the same way or apply the same experience and safety factors to their designs. Knowing the failure mode that is most likely to occur minimizes the amount of uncertainty and simplifies failure and life analysis. Available data regarding failure mode for aircraft engine blades, while favoring low-cycle, thermal mechanical fatigue as the controlling mode of failure, are not definitive. Sixteen high-pressure turbine (HPT) T-1 blade sets were removed from commercial aircraft engines that had been commercially flown by a single airline and inspected for damage. Each set contained 82 blades. The damage was cataloged into three categories related to their mode of failure: (1) Thermal-mechanical fatigue, (2) Oxidation/Erosion, and (3) "Other." From these field data, the turbine blade life was determined as well as the lives related to individual blade failure modes using Johnson-Weibull analysis. A simplified formula for calculating turbine blade life and reliability was formulated. The L(sub 10) blade life was calculated to be 2427 cycles (11 077 hr). The resulting blade life attributed to oxidation/erosion equaled that attributed to thermal-mechanical fatigue. The category that contributed most to blade failure was Other. If there were there no blade failures attributed to oxidation/erosion and thermal-mechanical fatigue, the overall blade L(sub 10) life would increase approximately 11 to 17 percent

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management

Mutation update for the SATB2 gene

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120=42.5%) followed by missense variants (31/120=25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge on animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS

Gaia white dwarfs within 40 pc – III. Spectroscopic observations of new candidates in the Southern hemisphere

We present a spectroscopic survey of 248 white dwarf candidates within 40 pc of the Sun; of these 244 are in the Southern hemisphere. Observations were performed mostly with the Very Large Telescope (X-Shooter) and Southern Astrophysical Research Telescope. Almost all candidates were selected from Gaia Data Release 3 (DR3). We find a total of 246 confirmed white dwarfs, 209 of which had no previously published spectra, and two main-sequence star contaminants. Of these, 100 white dwarfs display hydrogen Balmer lines, 69 have featureless spectra, and two show only neutral helium lines. Additionally, 14 white dwarfs display traces of carbon, while 37 have traces of other elements that are heavier than helium. We observe 35 magnetic white dwarfs through the detection of Zeeman splitting of their hydrogen Balmer or metal spectral lines. High spectroscopic completeness (> 97 per cent) has now been reached, such that we have 1058 confirmed Gaia DR3 white dwarfs out of 1083 candidates within 40 pc of the Sun at all declinations

On evidence-based medicine

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Corrigendum To "morphometric Analysis Of Fetal Development Of Cavia Porcellus (linnaeus, 1758) By Ultrasonography-pilot Study" [theriogenology 81, (2014), 896-900]

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