410 research outputs found
A bifurcated circular waveguide problem
No full textThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in IMA Journal of Applied Mathematics following peer review. The definitive publisher-authenticated version A D Rawlins. A bifurcated circular waveguide problem. J.I.M.A. 54 (1995) 59-81. Oxford University press is available online at: http://imamat.oxfordjournals.org/cgi/reprint/54/1/59.pdfA rigorous and exact solution is obtained for the problem of the radiation of sound from a semi-infinite rigid duct inserted axially into a larger acoustically lined tube of infinite length. The solution to this problem is obtained by the Wiener-Hopf technique. The transmission and reflection coefficients, when the fundamental mode propagates in the semi-infinite tube, are obtained. The present results could be of use for exhaust design, and as a possible instrument for impedance measurement
A note on Wiener-Hopf matrix factorisation
No full textThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Quarterly Journal of Mechanics and Applied Mathematics following peer review. The definitive publisher-authenticated version Rawlins, A D (1985). A note on Wiener-Hopf matrix factorisation. Quarterly Journal of Mechanics and Applied Mathematics. 38 (3) 433-437 is available online at: http://qjmam.oxfordjournals.org/cgi/reprint/38/3/433.pdfIn this paper the most general class of 2 x 2 matrices is determined which permit a
Wiener-Hopf factorization by the procedure of Rawlins and Williams (1). According
to this procedure, the factorization problem is reduced to a matrix Hilbert problem
on a half-line, where the matrix involved in the Hilbert problem is required to have
zero diagonal elements
Investigating the genetic basis of hereditary spastic paraplegia and cerebellar Ataxia in Pakistani families
No full textBACKGROUND: Hereditary Spastic Paraplegias (HSPs) and Hereditary Cerebellar Ataxias (HCAs) are progressive neurodegenerative disorders encompassing a spectrum of neurogenetic conditions with significant overlaps of clinical features. Spastic ataxias are a group of conditions that have features of both cerebellar ataxia and spasticity, and these conditions are frequently clinically challenging to distinguish. Accurate genetic diagnosis is crucial but challenging, particularly in resource-limited settings. This study aims to investigate the genetic basis of HSPs and HCAs in Pakistani families. METHODS: Families from Khyber Pakhtunkhwa with at least two members showing HSP or HCA phenotypes, and who had not previously been analyzed genetically, were included. Families were referred for genetic analysis by local neurologists based on the proband's clinical features and signs of a potential genetic neurodegenerative disorder. Whole Exome Sequencing (WES) and Sanger sequencing were then used to identify and validate genetic variants, and to analyze variant segregation within families to determine inheritance patterns. The mean age of onset and standard deviation were calculated to assess variability among affected individuals, and the success rate was compared with literature reports using differences in proportions and Cohen's h. RESULTS: Pathogenic variants associated with these conditions were identified in five of eight families, segregating according to autosomal recessive inheritance. These variants included previously reported SACS c.2182 C > T, p.(Arg728*), FA2H c.159_176del, p.(Arg53_Ile58del) and SPG11 c.2146 C > T, p.(Gln716*) variants, and two previously unreported variants in SACS c.2229del, p.(Phe743Leufs*8) and ZFYVE26 c.1926_1941del, p.(Tyr643Metfs*2). Additionally, FA2H and SPG11 variants were found to have recurrent occurrences, suggesting a potential founder effect within the Pakistani population. Onset age among affected individuals ranged from 1 to 14 years (M = 6.23, SD = 3.96). The diagnostic success rate was 62.5%, with moderate effect sizes compared to previous studies. CONCLUSIONS: The findings of this study expand the genotypic and phenotypic spectrum of HSPs and HCAs in Pakistan and emphasize the importance of utilizing exome/genome sequencing for accurate diagnosis or support accurate differential diagnosis. This approach can improve genetic counseling and clinical management, addressing the challenges of diagnosing neurodegenerative disorders in resource-limited settings.This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Mutational spectrum associated with oculocutaneous albinism and Hermansky-Pudlak syndrome in nine Pakistani families
No full textBACKGROUND: Oculocutaneous albinism (OCA) is a genetically heterogeneous condition that is associated with reduced or absent melanin pigment in the skin, hair, and eyes, resulting in reduced vision, high sensitivity to light, and rapid and uncontrolled eye movements. To date, seventeen genes have been associated with OCA including syndromic and non-syndromic forms of the condition. METHODS: Whole exome sequencing (WES) was performed to identify pathogenic variants in nine Pakistani families with OCA, with validation and segregation of candidate variants performed using Sanger sequencing. Furthermore, the pathogenicity of the identified variants was assessed using various in-silico tools and 3D protein structural analysis software. RESULTS: WES identified biallelic variants in three genes explaining the OCA in these families, including four variants in TYR, three in OCA2, and two in HPS1, including two novel variants c.667C > T: p.(Gln223*) in TYR, and c.2009 T > C: p.(Leu670Pro) in HPS1. CONCLUSIONS: Overall, this study adds further knowledge of the genetic basis of OCA in Pakistani communities and facilitates improved management and counselling services for families suffering from severe genetic diseases in Pakistan.Published version, accepted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Delineating the clinical, genetic and molecular characteristics of neurodevelopmental disorders in a community setting
No full textInherited neurodevelopmental disorders are a large group of clinically and genetically heterogeneous conditions affecting the development, structure and functioning of the central nervous system, and are frequently associated with extremes of brain growth. Whilst specific neurodevelopmental disorders are typically individually rare, as a group these conditions comprise a significant healthcare burden globally. A significant contribution to our understanding of neurodevelopmental disorders has been made by the study of autosomal recessive conditions, which are rare in the general population but occur at increased frequency in certain genetically isolated communities due to founder gene variants. The studies described in this thesis entail clinical, genetic and functional studies of inherited single gene disorders of brain growth identified in North American Amish and rural Pakistani communities, leading to investigations in other families globally.
Chapter three describes the identification of a microcephalic neurodevelopmental disorder resulting from biallelic variants in the TRAPPC10 gene, encoding a transport protein particle (TRAPP) complex subunit involved in membrane trafficking and other cellular processes. This study, stemming from genetic findings in two Pakistani families harbouring distinct TRAPPC10 variants, entailed comprehensive clinical, genomic, mouse and functional studies to confirm TRAPPC10-related disorder as a novel TRAPPopathy. This chapter also describes preliminary clinical and genetic studies identifying or consolidating five further TRAPPopathy disorders.
KPTN-related megalencephalic neurodevelopmental disorder was first identified by our research group in 2014. Chapter four documents the most detailed phenotypic description of the condition to date, alongside genetic findings of 36 affected individuals identified through international collaboration. This work enabled preliminary genotype-phenotype correlations to be drawn and patient management guidelines to be developed. Additionally, detailed comparisons with a Kptn-/- knock-out mouse model that closely recapitulates the human disease, alongside cell studies, provided fundamental new insights into the condition. Together, this enabled KPTN-related disorder to be confirmed as a new mTORopathy, highlighting the potential of mTOR inhibitors as a candidate therapeutic option for the condition.
Chapter five details extensive clinical and genetic datasets to consolidate and more comprehensively define two previously poorly described causes of autosomal recessive disorders of brain growth and development. These involve variants in CEP55 associated with a severe lethal fetal disorder characterised by a variable spectrum of brain and kidney abnormalities, and INPP4A associated with a variable neurodevelopmental disorder with features of severe cognitive impairment, seizures, muscle weakness, cerebellar signs, spasticity and behavioural abnormalities.
The clinical, genetic and molecular delineation of rare neurodevelopmental disorders facilitates accurate diagnosis and management of these conditions. The work described in this thesis also provides invaluable insights into disease pathogenesis and improves the scientific understanding of the subcellular processes underlying neurodevelopment. This knowledge is crucial to ultimately enable the discovery and delivery of potential new therapeutic avenues to treat these disorders
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