Pathology - Research Publications
Now showing items 1-12 of 379
Fast Principal Component Analysis of Large-Scale Genome-Wide Data
(PUBLIC LIBRARY SCIENCE, 2014)
Principal component analysis (PCA) is routinely used to analyze genome-wide single-nucleotide polymorphism (SNP) data, for detecting population structure and potential outliers. However, the size of SNP datasets has increased immensely in recent years and PCA of large datasets has become a time consuming task. We have developed flashpca, a highly efficient PCA implementation based on randomized algorithms, which delivers identical accuracy in extracting the top principal components compared with existing tools, in substantially less time. We demonstrate the utility of flashpca on both HapMap3 and on a large Immunochip dataset. For the latter, flashpca performed PCA of 15,000 individuals up to 125 times faster than existing tools, with identical results, and PCA of 150,000 individuals using flashpca completed in 4 hours. The increasing size of SNP datasets will make tools such as flashpca essential as traditional approaches will not adequately scale. This approach will also help to scale other applications that leverage PCA or eigen-decomposition to substantially larger datasets.
Analysis of the regulatory and catalytic domains of PTEN-induced kinase-1 (PINK1)
Mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene can cause early-onset familial Parkinson disease (PD). PINK1 encodes a neuroprotective protein kinase localized at the mitochondria, and its involvement in regulating mitochondrial dynamics, trafficking, structure, and function is well documented. Owing to the lack of information on structure and biochemical properties for PINK1, exactly how PINK1 exerts its neuroprotective function and how the PD-causative mutations impact on PINK1 structure and function remain unclear. As an approach to address these questions, we conducted bioinformatic analyses of the mitochondrial targeting, the transmembrane, and kinase domains of PINK1 to predict the motifs governing its regulation and function. Our report sheds light on how PINK1 is targeted to the mitochondria and how PINK1 is cleaved by mitochondrial peptidases. Moreover, it includes a potential optimal phosphorylation sequence preferred by the PINK1 kinase domain. On the basis of the results of our analyses, we predict how the PD-causative mutations affect processing of PINK1 in the mitochondria, PINK1 kinase activity, and substrate specificity. In summary, our results provide a conceptual framework for future investigation of the structural and biochemical basis of regulation and the neuroprotective mechanism of PINK1.
Prediction of the repeat domain structures and impact of parkinsonism-associated variations on structure and function of all functional domains of Leucine-rich repeat kinase 2 (LRRK2)
Genetic variations of leucine-rich repeat kinase 2 (LRRK2) are the major cause of dominantly inherited Parkinson disease (PD). LRRK2 protein contains seven predicted domains: a tandem Ras-like GTPase (ROC) domain and C-terminal of Roc (COR) domain, a protein kinase domain and four repeat domains. PD-causative variations arise in all domains, suggesting that aberrant functioning of any domain can contribute to neurotoxic mechanisms of LRRK2. Determination of the three-dimensional structure of LRRK2 is one of the best avenues to decipher its neurotoxic mechanism. However, with the exception of the Roc domain, the three-dimensional structures of the functional domains of LRRK2 have yet to be determined. Based upon the known three-dimensional structures of repeat domains of other proteins, the tandem Roc-COR domains of the C. tepidum Rab family protein, and the kinase domain of the D. discoideum Roco4 protein, we predicted (i) the motifs essential for protein-protein interactions in all domains, (ii) the motifs critical for catalysis and substrate recognition in the tandem Roc-COR and kinase domains, and (iii) the effects of some PD-associated missense variations on the neurotoxic action of LRRK2. Results of our analysis provide a conceptual framework for future investigation into the regulation and the neurotoxic mechanism of LRRK2.
Can we detect altered disease state in early stage Huntington’s Disease using acoustic markers of speech?
(Causal Productions, 2012)
Altered prosody has been described in symptomatic Huntington’s Disease (HD) individuals, however, the extent to which acoustic analysis of speech is sensitive to gene positive pre-manifest (PreHD) individuals is unknown. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue, counted from 1-20 and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. Tasks were compared to determine their relative sensitivity to disease state. Tasks with greater cognitive demand appeared more suitable for detecting Huntington’s disease compared to tasks with high levels of automaticity.
Acoustic analysis of the effects of 24 hours of sustained wakefulness
(Causal Productions, 2010)
The effect of 24 hours of sustained wakefulness on the speech of healthy adults is poorly documented. Therefore, speech samples were systematically acquired (e.g., every four hours) from 18 healthy adults over 24 hours. Stimuli included automated and extemporaneous tasks, sustained vowel and a read passage. Measures of timing and frequency were derived acoustically using Praat and significant changes were observed on all tasks. The effect of fatigue on speech was found to be strongest just before dawn (after 22 hours). Key features of timing (e.g., mean pause length), frequency (e.g., F4 variation) and power (alpha ratio) changed as a function of increasing levels of fatigue.
Dysphagia and swallowing-related quality of life in Friedreich ataxia
Dysphagia in Friedreich ataxia (FRDA) and its impact on quality of life is not adequately understood. The objective of this study was to characterise dysphagia in FRDA and to determine the impact of swallowing dysfunction on activities, participation, and sense of well-being. Thirty-six individuals with a confirmed diagnosis of FRDA were assessed via a clinical bedside examination (CBE), the Royal Brisbane Hospital outcome measure for swallowing, an oral-motor examination and the Australian therapy outcome measures for speech and swallowing (AusTOMS). Data on swallowing function, diet modification and swallowing strategies were collated. Thirty-three (91.67 %) participants exhibited clinical signs of dysphagia according to the CBE, and all participants received ratings indicating swallowing difficulties on at least one other measure. Dysphagia in FRDA is characterised by oral and pharyngeal stage impairment relating to incoordination, weakness and spasticity. A significant positive correlation was found between the severity of impairment, activity, participation and distress/well-being on the AusTOMS, suggesting that swallowing function decreases with overall reductions in quality of life. A significant correlation was found between activity on the AusTOMS and disease duration (r = −0.283, p = 0.012). No significant correlations were found between dysphagia severity and GAA repeat length, age of onset or disease severity. Participants employing diet modification and swallowing strategies demonstrated higher dysphagia severity, activity limitations and participation restrictions. These data advocate a holistic approach to dysphagia management in FRDA. Early detection of swallowing impairment and consideration of the potential impact dysphagia has on quality of life should be key aspects in disease management.
Primary cutaneous CD4/CD56 hematodermic neoplasm (blastic NK-cell lymphoma): a report of five cases
(Ferrata Storti, 2006)
CD4/CD56hematodermic neoplasm (WHO- EORTC) or blastic NK-cell lymphoma (WHO) is a rare aggressive CD4+CD56+lin- skin-tropic lymphoma of putative early-plasmacytoid dendritic cell origin. We present five cases to highlight the need for greater awareness of this entity amongst pathologists such that aggressive treatment be considered given the generally poor prognosis.
The sensitivity of CD138 immunostaining of bone marrow trephine specimens for quantifying marrow involvement in MGUS and myeloma,including samples with a low percentage of plasma cells
(European Hematology Association, 2006)
Accurate quantification of plasma cells in bone marrow samples is essential for the diagnosis, classification and prognosis of plasma-cell dyscrasias. Published comparisons between aspirate/trephine morphology, flow cytometry and immunohistochemistry are lacking. Bone marrow plasma cells from 100 patients with plasma cell myeloma or monoclonal gammopathy of undetermined significance were quantified by a 500-cell differential count on Romanowsky-stained aspirate slides, flow-cytometry gating of CD38bright+/CD138+cells,hematoxylin and eosin trephine section examination and CD138 trephine immunohistology. The results of quantification by the different methods were compared. Compared to other methods, CD138 trephine immunohistology consistently demonstrated greater plasma-cell infiltration. Immunohistology is the most sensitive method for assessment of plasma-cell infiltration at diagnosis or post-therapy,especially in patients with minimal bone marrow involvement.