130,370 research outputs found
Genetic studies of rare skeletal disorders : to solve the unsolved
No full textCongenital skeletal disorders, also called skeletal dysplasias, constitute a diverse group of rare genetic conditions that occur in approximately 1 per 3000-5000 births. Skeletal dysplasias exhibit both clinical and molecular heterogeneity, with the phenotype of the affected individuals varying based on the severity of the disease. While skeletal dysplasias primarily affect cartilage and bone, they often include extraskeletal manifestations, including internal organ abnormalities. Diagnosis of skeletal disorders includes clinical characterization, radiographic pattern recognition, and genetic testing. Despite the advancements in genome sequencing technologies, there remains a gap in understanding the genetic and phenotypic characteristics of some of the skeletal disorders, and new types of skeletal dysplasias continue to be identified.The work in this thesis focused on identifying genetic causes and molecular mechanisms of rare skeletal disorders. Using genome sequencing the objective was to identify new genes or novel variants and improve the clinical and genetic characterization in the individuals with skeletal disease of unknown genetic background. The research goals were achieved through four constituent studies included in this thesis.Study I identified TOMM7 as a novel disease-causing gene in a patient with syndromic short stature and developmental delay. The molecular pathogenesis of TOMM7 (c.73T>C, p.Trp25Arg) variant was studied in a mouse model. Tomm7 mutant mice showed growth restriction, reduced chondrocyte proliferation, and lipoatrophy caused by mitochondrial dysfunction. Study II identified ADAMTSL2 as a genetic cause of previously genetically uncharacterized skeletal dysplasia cortical dysostosis Al-Gazali type and connected it to the spectrum of ADAMTSL2-related disorders. This study included a cohort of nine individuals characterized by intrauterine growth restriction, distinct radiological patterns, and early mortality. Using primary dermal fibroblasts from the affected individual, we showed abnormal organization of the fibrillin-1 microfibrils. Study III identified disease-causing variants in the RAB34 gene in a fetus with complex malformations, including skeletal abnormalities consistent with shortrib thoracic dysplasia, and a combination of rarely occurring pre- and postaxial polydactyly. Study IV focused on investigating gene dosage abnormalities in type I collagen genes COL1A1 and COL1A2 in eight patients from five unrelated families with Osteogenesis Imperfecta (OI). A complex structural variant, including deletion and duplication in COL1A2, was resolved by long-read genome sequencing in a patient with progressively deforming OI, characterized by multiple fractures and short stature.This thesis has contributed to the field by broadening the genetic and phenotypic understanding of several congenital skeletal disorders. Two genes previously not associated with human phenotype, TOMM7 and RAB34, were described. Furthermore, a genetic cause was identified for the previously unresolved Al-Gazali skeletal dysplasia. Genome sequencing serves as a first-tier research tool for identifying novel candidate genes and variants; however, linking these variants to specific diseases depends on a range of factors, including knowledge of gene and protein function and detailed phenotypic characterization of patient groups.List of scientific papersI. A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay. Young C, Batkovskyte D, Kitamura M, Shvedova M, Mihara Y, Akiba J, Zhou W, Hammarsjö A, Nishimura G, Yatsuga S, Grigelioniene G, Kobayashi T. HGG Advances. 2022 Oct 4;4(1):100148. doi: 10.1016/j.xhgg.2022.100148. PMID: 36299998. https://doi.org/10.1016/j.xhgg.2022.100148 II. Al-Gazali skeletal dysplasia constitutes the lethal end of ADAMTSL2-related disorders. Batkovskyte D, McKenzie F, Taylan F, Simsek-Kiper PO, Nikkel SM, Ohashi H, Stevenson RE, Ha T, Cavalcanti DP, Miyahara H, Skinner SA, Aguirre MA, Akçören Z, Utine GE, Chiu T, Shimizu K, Hammarsjö A, Boduroglu K, Moore HW, Louie RJ, Arts P, Merrihew AN, Babic M, Jackson MR, Papadogiannakis N, Lindstrand A, Nordgren A, Barnett CP, Scott HS, Chagin AS, Nishimura G, Grigelioniene G. Journal of Bone and Mineral Research. 2023 May;38(5):692-706. doi: 10.1002/jbmr.4799. Epub 2023 Mar 27. PMID: 36896612. https://doi.org/10.1002/jbmr.4799 III. Compound heterozygous variants in RAB34 in a rare skeletal ciliopathy syndrome. Batkovskyte D, Komatsu M, Hammarsjö A, Pooh R, Shimokawa O, Ikegawa S, Grigelioniene G, Nishimura G, Yamada T. Clinical Genetics. 2024 Jan;105(1):87-91. doi: 10.1111/cge.14419. Epub 2023 Aug 24. PMID: 37619988. https://doi.org/10.1111/cge.14419 IV. Structural variants in COL1A1 and COL1A2 in Osteogenesis Imperfecta. Batkovskyte D, Swolin-Eide D, Hammarsjö A, Bilgrav Sæther K, Thunström S, Lundin J, Eisfeldt J, Lindstrand A, Nordgren A, Åström E, Grigelioniene G. 2024. [Manuscript]</p
MeSH term explosion and author rank improve expert recommendations
No full textInformation overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Scholarly Communication and Publishing Lunch and Learn Talk #11: The ULS Open Access Author Fee Fund
No full textAt the May 2014 talk, you will learn about the ULS Open Access Author Fee Fund--what it is, why we do it, how it works, and how the program is going so far
The R&D Tax Incentives
No full textThis article sets out some background information and reflections of the author on the R&D tax incentive schemes included in the Common Corporate Tax Base (CCTB) Proposal. In particular the author analyzes the stimulus to private R&D through ad hoc tax incentives included in the CCTB Proposal and dives into the actual provisions included in the Proposal highlighting the most relevant issues connected with their design and interpretation. Moreover, the author explores the interaction between the CCTB Proposal and the granting by Member States of domestic R&D tax incentives
Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis
No full textMutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in presymptomatic CTSD knockout (Ctsd) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (mEPSCs) with no effect on paired-pulse modulation of the evoked excitatory post synaptic potentials in the hippocampus of Ctsd mice. The reduced mEPSCs frequency was observed before the appearance of epilepsy or any morphologic sign of synaptic degeneration. Taken together, these data indicate that CTSD is required for normal synaptic function and that a failure in synaptic trafficking or recycling may bean early and important pathologic mechanism in Ctsd mice; these presynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss
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