Characterisation of APC localisation, dynamics and functions at the centrosome

Adenomatous polyposis coli (APC) is a tumour suppressor protein and regulator of the wnt signalling pathway. APC is mutated in >90% of colorectal tumours and these mutations often translate a shorter truncated protein. Truncated APC has now been linked to mitotic spindle dysfunction. Mitotic spindles are nucleated from centrosomes and in cells expressing cancer mutant forms of APC cause aberrant spindle attachments leading to an increased rate of chromosome instability. Both full-length and mutant APC persistently localise to the centrosome throughout the cell cycle, however its role at interphase centrosomes are ill-defined. In this thesis, using a combination of immunofluorescence microscopy, retention assays and fluorescence recovery after photobleaching (FRAP) techniques, both wild-type and mutant forms of APC were found to be highly dynamic at the interphase centrosome, but highly retained at the mitotic centrosome, and targeted by the Armadillo domain of APC. Using various centrosome functional assays, APC was found to contribute to microtubule nucleation, but was not involved in centrosome amplification or separation. Using protein interaction methods, several novel APC binding partners ranging from protein regulators of the centrosome to microtubule-associated proteins were also discovered

"Developing Writers": The Multiple Identities of an Embedded Tutor In the Developmental Writing Classroom

In her essay “When Basic Writers Come to College,” Patricia Bizzell explains that writers placed in developmental courses “are asked to join an academic community ... united almost entirely by its language” (296). Specifically, students are asked to learn “new dialect and discourse conventions ... [and] the outcome of such learning is the acquisition of a whole new world view” (297), which requires not only a different way of writing and communicating but a different way of thinking. This is no small task. Therefore, some of the problems that developmental writers face “are best understood as stemming from the initial distance between their world views and the academic world view” (297). James Paul Gee further defines these communities as “Discourses” where students can create an “‘identity kit,’ which comes complete with the appropriate costume and instructions on how to act, talk, and often write, so as to take on a particular role that others will recognize” (7). Many of us would agree that most writing center tutors have successfully negotiated these different communities and Discourses, adapted alternative viewpoints, and even created various identities through their work in our centers, which results in tremendous change and growth. As Hughes, Gillespie, and Kail have demonstrated through the Peer Writing Tutor Alumni Research Project, the work of tutoring has a profound impact, changing the way tutors perceive writing, learn critical thinking, value the power of collaborative learning, and develop a new-found sense of personal confidence.University Writing Cente

The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells

Background: Although GATA1 is one of the most extensively studied haematopoietic transcription factors little is currently known about the physiological functions of its naturally occurring isoforms GATA1s and GATA1FL in humans—particularly whether the isoforms have distinct roles in different lineages and whether they have non-redundant roles in haematopoietic differentiation. As well as being of general interest to understanding of haematopoiesis, GATA1 isoform biology is important for children with Down syndrome associated acute megakaryoblastic leukaemia (DS-AMKL) where GATA1FL mutations are an essential driver for disease pathogenesis. <p/>Methods: Human primary cells and cell lines were analyzed using GATA1 isoform specific PCR. K562 cells expressing GATA1s or GATA1FL transgenes were used to model the effects of the two isoforms on in vitro haematopoietic differentiation. <p/>Results: We found no evidence for lineage specific use of GATA1 isoforms; however GATA1s transcripts, but not GATA1FL transcripts, are down-regulated during in vitro induction of terminal megakaryocytic and erythroid differentiation in the cell line K562. In addition, transgenic K562-GATA1s and K562-GATA1FL cells have distinct gene expression profiles both in steady state and during terminal erythroid differentiation, with GATA1s expression characterised by lack of repression of MYB, CCND2 and SKI. <p/>Conclusions: These findings support the theory that the GATA1s isoform plays a role in the maintenance of proliferative multipotent megakaryocyte-erythroid precursor cells and must be down-regulated prior to terminal differentiation. In addition our data suggest that SKI may be a potential therapeutic target for the treatment of children with DS-AMKL

Power grip, pinch grip, manual muscle testing or thenar atrophy - which should be assessed as a motor outcome after carpal tunnel decompression? A systematic review

<p>Abstract</p> <p>Background</p> <p>Objective assessment of motor function is frequently used to evaluate outcome after surgical treatment of carpal tunnel syndrome (CTS). However a range of outcome measures are used and there appears to be no consensus on which measure of motor function effectively captures change. The purpose of this systematic review was to identify the methods used to assess motor function in randomized controlled trials of surgical interventions for CTS. A secondary aim was to evaluate which instruments reflect clinical change and are psychometrically robust.</p> <p>Methods</p> <p>The bibliographic databases Medline, AMED and CINAHL were searched for randomized controlled trials of surgical interventions for CTS. Data on instruments used, methods of assessment and results of tests of motor function was extracted by two independent reviewers.</p> <p>Results</p> <p>Twenty-two studies were retrieved which included performance based assessments of motor function. Nineteen studies assessed power grip dynamometry, fourteen studies used both power and pinch grip dynamometry, eight used manual muscle testing and five assessed the presence or absence of thenar atrophy. Several studies used multiple tests of motor function. Two studies included both power and pinch strength and reported descriptive statistics enabling calculation of effect sizes to compare the relative responsiveness of grip and pinch strength within study samples. The study findings suggest that tip pinch is more responsive than lateral pinch or power grip up to 12 weeks following surgery for CTS.</p> <p>Conclusion</p> <p>Although used most frequently and known to be reliable, power and key pinch dynamometry are not the most valid or responsive tools for assessing motor outcome up to 12 weeks following surgery for CTS. Tip pinch dynamometry more specifically targets the thenar musculature and appears to be more responsive. Manual muscle testing, which in theory is most specific to the thenar musculature, may be more sensitive if assessed using a hand held dynamometer – the Rotterdam Intrinsic Handheld Myometer. However further research is needed to evaluate its reliability and responsiveness and establish the most efficient and psychometrically robust method of evaluating motor function following surgery for CTS.</p

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Profile Prediction and Fabrication of Wet-Etched Gold Nanostructures for Localized Surface Plasmon Resonance

Dispersed nanosphere lithography can be employed to fabricate gold nanostructures for localized surface plasmon resonance, in which the gold film evaporated on the nanospheres is anisotropically dry etched to obtain gold nanostructures. This paper reports that by wet etching of the gold film, various kinds of gold nanostructures can be fabricated in a cost-effective way. The shape of the nanostructures is predicted by profile simulation, and the localized surface plasmon resonance spectrum is observed to be shifting its extinction peak with the etching time

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed

Long-term social skills group training for children and adolescents with autism spectrum disorder: a randomized controlled trial

Social skills group training (SSGT) is widely used for intellectually able children and adolescents with autism spectrum disorder (ASD). Previous studies indicate small to moderate effects on social communication capacities. The duration of most available programs is relatively short, and extended training might lead to further improvement. This randomized controlled trial compared an extended 24-week version of the SSGT program KONTAKT with standard care. The weekly sessions gradually shifted in content from acquisition of new skills to real-world application of the acquired skills. A total of 50 participants with ASD (15 females; 35 males) aged 8–17 years were included. The study was conducted at two child and adolescent psychiatry outpatient units in Sweden. The primary outcome was the Social Responsiveness Scale–Second Edition (SRS-2) rated by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and at 3-months follow-up. Parent-rated SRS-2 scores indicated large effects posttreatment [- 19.2; 95% CI - 29.9 to - 8.5; p &lt; .001, effect size (ES) = 0.76], which were maintained at follow-up (- 20.7; 95% CI - 31.7 to - 9.7; p &lt; .0001, ES = 0.82). These estimates indicate substantially larger improvement than previously reported for shorter SSGT. However, the effects on teacher-rated SRS-2 and most secondary outcomes did not reach statistical significance. Our results suggest added benefits of extended SSGT training, implying that service providers might reach better results by optimizing the delivery of SSGT

The role of tibialis posterior fatigue on foot kinematics during walking

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to investigate the effect of localised tibialis posterior muscle fatigue on foot kinematics during walking. It was hypothesised that following fatigue, subjects would demonstrate greater forefoot and rearfoot motion during walking. It was also postulated that the magnitude of the change in rearfoot motion would be associated with standing anatomical rearfoot posture.</p> <p>Methods</p> <p>Twenty-nine subjects underwent an exercise fatigue protocol aimed at reducing the force output of tibialis posterior. An eight camera motion analysis system was used to evaluate 3D foot kinematics during treadmill walking both pre- and post-fatigue. The anatomical rearfoot angle was measured during standing prior to the fatigue protocol using a goniometer.</p> <p>Results</p> <p>Peak rearfoot eversion remained unchanged following the fatigue protocol. Although increases in rearfoot eversion excursion were observed following fatigue, these changes were of a magnitude of questionable clinical significance (<1.0°). The magnitude of the change in rearfoot eversion due to fatigue was not associated with the anatomical measurement of standing rearfoot angle. No substantial changes in forefoot kinematics were observed following the fatigue protocol.</p> <p>Conclusions</p> <p>These data indicate that reduced force output of the tibialis posterior muscle did not alter rearfoot and forefoot motion during gait. The anatomical structure of the rearfoot was not associated with the dependence of muscular activity that an individual requires to maintain normal rearfoot kinematics during gait.</p