Interpretation of Brain Morphology in Association to Alzheimer's Disease Dementia Classification Using Graph Convolutional Networks on Triangulated Meshes

We propose a mesh-based technique to aid in the classification of Alzheimer's disease dementia (ADD) using mesh representations of the cortex and subcortical structures. Deep learning methods for classification tasks that utilize structural neuroimaging often require extensive learning parameters to optimize. Frequently, these approaches for automated medical diagnosis also lack visual interpretability for areas in the brain involved in making a diagnosis. This work: (a) analyzes brain shape using surface information of the cortex and subcortical structures, (b) proposes a residual learning framework for state-of-the-art graph convolutional networks which offer a significant reduction in learnable parameters, and (c) offers visual interpretability of the network via class-specific gradient information that localizes important regions of interest in our inputs. With our proposed method leveraging the use of cortical and subcortical surface information, we outperform other machine learning methods with a 96.35% testing accuracy for the ADD vs. healthy control problem. We confirm the validity of our model by observing its performance in a 25-trial Monte Carlo cross-validation. The generated visualization maps in our study show correspondences with current knowledge regarding the structural localization of pathological changes in the brain associated to dementia of the Alzheimer's type.Comment: Accepted for the Shape in Medical Imaging (ShapeMI) workshop at MICCAI International Conference 202

Gene Expression Profiles of Sporadic Canine Hemangiosarcoma Are Uniquely Associated with Breed

The role an individual's genetic background plays on phenotype and biological behavior of sporadic tumors remains incompletely understood. We showed previously that lymphomas from Golden Retrievers harbor defined, recurrent chromosomal aberrations that occur less frequently in lymphomas from other dog breeds, suggesting spontaneous canine tumors provide suitable models to define how heritable traits influence cancer genotypes. Here, we report a complementary approach using gene expression profiling in a naturally occurring endothelial sarcoma of dogs (hemangiosarcoma). Naturally occurring hemangiosarcomas of Golden Retrievers clustered separately from those of non-Golden Retrievers, with contributions from transcription factors, survival factors, and from pro-inflammatory and angiogenic genes, and which were exclusively present in hemangiosarcoma and not in other tumors or normal cells (i.e., they were not due simply to variation in these genes among breeds). Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) was among genes preferentially enriched within known pathways derived from gene set enrichment analysis when characterizing tumors from Golden Retrievers versus other breeds. Heightened VEGFR1 expression in these tumors also was apparent at the protein level and targeted inhibition of VEGFR1 increased proliferation of hemangiosarcoma cells derived from tumors of Golden Retrievers, but not from other breeds. Our results suggest heritable factors mold gene expression phenotypes, and consequently biological behavior in sporadic, naturally occurring tumors

Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma

<p>Abstract</p> <p>Background</p> <p>The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease.</p> <p>Methods</p> <p>We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR.</p> <p>Results</p> <p>Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma).</p> <p>Conclusions</p> <p>The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells.</p

Moving to capture children’s attention: developing a methodology for measuring visuomotor attention

Attention underpins many activities integral to a child’s development. However, methodological limitations currently make large-scale assessment of children’s attentional skill impractical, costly and lacking in ecological validity. Consequently we developed a measure of ‘Visual Motor Attention’ (VMA) - a construct defined as the ability to sustain and adapt visuomotor behaviour in response to task-relevant visual information. In a series of experiments, we evaluated the capability of our method to measure attentional processes and their contributions in guiding visuomotor behaviour. Experiment 1 established the method’s core features (ability to track stimuli moving on a tablet-computer screen with a hand-held stylus) and demonstrated its sensitivity to principled manipulations in adults’ attentional load. Experiment 2 standardised a format suitable for use with children and showed construct validity by capturing developmental changes in executive attention processes. Experiment 3 tested the hypothesis that children with and without coordination difficulties would show qualitatively different response patterns, finding an interaction between the cognitive and motor factors underpinning responses. Experiment 4 identified associations between VMA performance and existing standardised attention assessments and thereby confirmed convergent validity. These results establish a novel approach to measuring childhood attention that can produce meaningful functional assessments that capture how attention operates in an ecologically valid context (i.e. attention's specific contribution to visuomanual action)

The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1

The Epstein-Barr virus (EBV) latent-lytic switch is mediated by the BZLF1 immediate-early protein. EBV is normally latent in memory B cells, but cellular factors which promote viral latency specifically in B cells have not been identified. In this report, we demonstrate that the B-cell specific transcription factor, Oct-2, inhibits the function of the viral immediate-early protein, BZLF1, and prevents lytic viral reactivation. Co-transfected Oct-2 reduces the ability of BZLF1 to activate lytic gene expression in two different latently infected nasopharyngeal carcinoma cell lines. Furthermore, Oct-2 inhibits BZLF1 activation of lytic EBV promoters in reporter gene assays, and attenuates BZLF1 binding to lytic viral promoters in vivo. Oct-2 interacts directly with BZLF1, and this interaction requires the DNA-binding/dimerization domain of BZLF1 and the POU domain of Oct-2. An Oct-2 mutant (Δ262–302) deficient for interaction with BZLF1 is unable to inhibit BZLF1-mediated lytic reactivation. However, an Oct-2 mutant defective for DNA-binding (Q221A) retains the ability to inhibit BZLF1 transcriptional effects and DNA-binding. Importantly, shRNA-mediated knockdown of endogenous Oct-2 expression in several EBV-positive Burkitt lymphoma and lymphoblastoid cell lines increases the level of lytic EBV gene expression, while decreasing EBNA1 expression. Moreover, treatments which induce EBV lytic reactivation, such as anti-IgG cross-linking and chemical inducers, also decrease the level of Oct-2 protein expression at the transcriptional level. We conclude that Oct-2 potentiates establishment of EBV latency in B cells

Protocol for a randomized controlled study of Iyengar yoga for youth with irritable bowel syndrome

<p>Abstract</p> <p>Introduction</p> <p>Irritable bowel syndrome affects as many as 14% of high school-aged students. Symptoms include discomfort in the abdomen, along with diarrhea and/or constipation and other gastroenterological symptoms that can significantly impact quality of life and daily functioning. Emotional stress appears to exacerbate irritable bowel syndrome symptoms suggesting that mind-body interventions reducing arousal may prove beneficial. For many sufferers, symptoms can be traced to childhood and adolescence, making the early manifestation of irritable bowel syndrome important to understand. The current study will focus on young people aged 14-26 years with irritable bowel syndrome. The study will test the potential benefits of Iyengar yoga on clinical symptoms, psychospiritual functioning and visceral sensitivity. Yoga is thought to bring physical, psychological and spiritual benefits to practitioners and has been associated with reduced stress and pain. Through its focus on restoration and use of props, Iyengar yoga is especially designed to decrease arousal and promote psychospiritual resources in physically compromised individuals. An extensive and standardized teacher-training program support Iyengar yoga's reliability and safety. It is hypothesized that yoga will be feasible with less than 20% attrition; and the yoga group will demonstrate significantly improved outcomes compared to controls, with physiological and psychospiritual mechanisms contributing to improvements.</p> <p>Methods/Design</p> <p>Sixty irritable bowel syndrome patients aged 14-26 will be randomly assigned to a standardized 6-week twice weekly Iyengar yoga group-based program or a wait-list usual care control group. The groups will be compared on the primary clinical outcomes of irritable bowel syndrome symptoms, quality of life and global improvement at post-treatment and 2-month follow-up. Secondary outcomes will include visceral pain sensitivity assessed with a standardized laboratory task (water load task), functional disability and psychospiritual variables including catastrophizing, self-efficacy, mood, acceptance and mindfulness. Mechanisms of action involved in the proposed beneficial effects of yoga upon clinical outcomes will be explored, and include the mediating effects of visceral sensitivity, increased psychospiritual resources, regulated autonomic nervous system responses and regulated hormonal stress response assessed via salivary cortisol.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01107977">NCT01107977</a>.</p