17 research outputs found
Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity
BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"
Twenty-four miles around Nelungaloo : the history and importance of cinema exhibition in pre-television times to a country area of central-western New South Wales
Little research into historical, architectural and social significance of the picture theatre in pre-television rural Australian society has been undertaken. Taking a New South Wales country area (to represent a microcosm), this thesis records the picture venues and qualitative research material from past patrons and theatre staff. The study 1/. establishes the environment created by a picture theatre 2/. shows that New South Wales was typical of Australia in film attendance before the 1960s 3/. introduces the Central-West subject area, and describes how data was gathered from available records 4/. shows the development of the picture venues within the subject areas 5/. gives 'life' to the occasion formerly associated with going to the pictures 6/. suggests the success ot the rural picture shows was a happy co-incidence: the exhibitors' desire to make money and the patrons' desire for a social experience (and entertainment). A recommendation is made that one of the venues discovered during the course of research should be investigated for heritage listing. It is important that we should acknowledge the vital part that going to the pictures once played in pre-television days, especially in rural area
The forces that shaped the Irish Regional Technical College buildings
The paper charts the early development of environmental thinking in Architecture up to the radical
paradigm shift of modernism and brutalism. The resulting emphasis on proportional grammar over
the technical performance of the interior environment would be common threads in Educational
architecture leading up to the design of the Regional Technical Colleges (RTCs) in 1967. Changes
in technology, materials and skills shortages led to the development of post war steel frame
Hertfordshire Schools which greatly influenced the future direction of Technological School and
College design. Financial rationalisation saw a movement away from the steel frame CLASP models to
concrete frame Intergrid systems, which would directly influence a key precedent of the RTC design,
the M&M building at the University of Birmingham. The intelligence of the building design by ARUP
would be compromised by the Modernist emphasis on plastic over glazed facades, which lacked
shading suffered from great heat loss. The movement away from quality materiality and exposed grid
structure, resulted in a loss of delight and a greater level of brutalism
Study on Street Children in Four Selected Towns in Ethiopia
The child is the most precious asset and the focal point of development for any country. However, unless children are brought up in a stimulating and conducive environment getting the best possible care and protection, their physical, mental, emotional and social development is susceptible to permanent damage. Ethiopia, being one of the least developed countries of the world due to interrelated and complex socio-economic factors including man-made and natural calamities, a large portion of our population - especially children - are victimized by social evils like famine, disease, poverty, mass displacement, lack of education and family instability. Owing to the fact that children are the most vulnerable group among the whole society and also because they constitute half of the population it is evident that a considerable number of Ethiopian children are living under difficult circumstances. Therefore, as in a number of other third world countries there are many poor, displaced, unaccompanied and orphaned children in our country. A considerable proportion of these children work on the street with some even totally living on the street without any adult care and protection. These children are forced to the streets in their tight for survival. They supplement their parents meagre income or support themselves with the small incomes they earn doing menial jobs. In doing this, street children face the danger of getting into accidents and violence, they get exploited and abused, many are forced to drop out of school or never get the chance to be enroled at all and some drift into begging or petty crime. This study is undertaken mainly for updating the findings of previous studies, monitoring changing trends, examining new facts of the problem and getting a better understanding of the phenomenon in the country by covering at least some of the major centres where the problem is acute. Thus, the outcome of this research can be useful in the formation of tne social welfare programme of the country. Finally, in recognition of the urgency of the problem and the limited resources available, the Ministry of Labour and Social Affairs expresses appreciation to all agencies engaged in the rehabilitation of street children and prevention of the problem. The Ministry also calls for more co-operation and support between concerned governmental and non-governmental organizations in their efforts for improving the situation of street children and in curbing the overwhelming nature of the problem
Strategy for Breakpoint Cluster Region Analysis in Chronic Myelocytic Leukemia in a Routine Clinical Laboratory
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The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.
Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents