CONTROL OF MOTOR UNITS DURING VOLUNTARY FORCE-PRODUCTION: IMPLICATIONS FOR EXERCISE

We have recently developed a technology that enables studies of the firing properties of a large set (typically 30 to 40) of concurrently active motor units during isometric voluntary contractions ranging from low force levels to maximal voluntary contractions (MVC). With this technology we have executed studies to investigate the behavior of the firing rates of motor units as a function of their recruitment properties during contractions at various force levels. We found that the firing rates have a hierarchical structure wherein the firing rate value of motor units is inversely related to their recruitment threshold, with earlier recruited motor units having greater firing rates at any time and any force level during a contraction. This relationship does not support the opposite notion that has been generally held for the past five decades. Knowing the structure of the firing behavior of motor units during voluntary contractions provides guidance for understanding the performance of muscles during exercise and sports

A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases - An initial report.

Indications and treatment goals for SRS have changed since the publication of RTOG 90-05. We present initial retrospective outcomes from a new dose selection algorithm in use at our institution felt to be more contemporary with doses being used in the radiosurgery community today and report our local control and toxicity outcomes. This dose selection algorithm will be subject to a forthcoming prospective phase 2 trial.To evaluate safety and efficacy of an institutional dose selection algorithm in the treatment of brain metastases (BM) with single fraction radio-surgery (SRS).The medical records of 65 patients with ≤10 BM treated with GK at our institution between April 2012 and October 2012 were reviewed retrospectively. The prescription doses used in this study ranged from 16-22Gy and were based upon RTOG 90-05 guideline doses subsequently modified at our institution depending on lesion number, lesion volume, institutional experience and prior history of whole brain radiation therapy (WBRT). Primary endpoint was local recurrence (LR) with additional outcomes measured including distant intracranial recurrence (DIR), death without local recurrence (DWLR) and alive and disease free (ADF). Fine Gray competing risk analysis was used to examine factors affecting local recurrence.Median follow up was 8.9 months (range 1.0-29.6months) and 12 month overall survival was 37% (95% CI 24.9-49.1%). Overall local recurrence rate was 7.7%. On competing risks regression analysis, no variable was significantly associated with local recurrence, including previous whole brain radiotherapy (WBRT), (SHR 1.21 [95%CI 0.13-11.5], p=0.87 and radioresistant versus radiosensitive histology (SHR 0.51 [95% CI 0.06-7.73], p=0.55). No patient developed grade 3 or higher neurotoxicity at 12 months following GK.Initial local control and toxicity results from our institutional dose selection algorithm are reported here. Comparison of our results with RTOG 90-05 is difficult due to significant differences in the patient population and their treatments. The applicability of this algorithm merits further investigation across multiple centers for the purpose of treatment and clinical trial standardization in single fraction SRS and will be the subject of a forthcoming phase 2 prospective study within our own institution

Ability-Based Methods for Personalized Keyboard Generation

This study introduces an ability-based method for personalized keyboard generation, wherein an individual's own movement and human-computer interaction data are used to automatically compute a personalized virtual keyboard layout. Our approach integrates a multidirectional point-select task to characterize cursor control over time, distance, and direction. The characterization is automatically employed to develop a computationally efficient keyboard layout that prioritizes each user's movement abilities through capturing directional constraints and preferences. We evaluated our approach in a study involving 16 participants using inertial sensing and facial electromyography as an access method, resulting in significantly increased communication rates using the personalized keyboard (52.0 bits/min) when compared to a generically optimized keyboard (47.9 bits/min). Our results demonstrate the ability to effectively characterize an individual's movement abilities to design a personalized keyboard for improved communication. This work underscores the importance of integrating a user's motor abilities when designing virtual interfaces.Comment: 20 pages, 7 figure

Assessing the Cultural Appropriateness of UPLIFT for African Americans With Epilepsy: A Community Engaged Approach

Background: In trials of Project UPLIFT, a distance-delivered, mindfulness-based cognitive therapy intervention, there was improvement in the mental health of people with epilepsy/seizure disorder. In these trials, however, African Americans have been few. Thus, as this program is disseminated, it is desirable to ensure that it is culturally appropriate for minority populations. Methods: To determine the appropriateness of Project UPLIFT for African Americans, we engaged in three main research activities: 1) the formation and involvement of an epilepsy community advisory board; 2) qualitative interviews with healthcare providers who serve this community; and 3) focus groups with African American adults living with epilepsy or seizure disorder and main support persons of African American adults living with epilepsy or seizure disorder. Results: The epilepsy community advisory board provided recommendations for the most appropriate language to use when engaging and recruiting the target population. Healthcare providers indicated that psychosocial concerns of African American persons living with epilepsy seemed to be different from those among patients of other racial groups. They indicated that Project UPLIFT might be useful for this group. Focus groups revealed experiences of living with and supporting someone with epilepsy and provided favorable feedback on the UPLIFT intervention. Conclusions: Formative feedback indicates that Project UPLIFT may be useful for African Americans with epilepsy. These data will be used to guide a forthcoming randomized, controlled trial to assess the acceptability and feasibility of the intervention with this group

Learning styles of medical students, general surgery residents, and general surgeons: implications for surgical education

Abstract Background Surgical education is evolving under the dual pressures of an enlarging body of knowledge required during residency and mounting work-hour restrictions. Changes in surgical residency training need to be based on available educational models and research to ensure successful training of surgeons. Experiential learning theory, developed by David Kolb, demonstrates the importance of individual learning styles in improving learning. This study helps elucidate the way in which medical students, surgical residents, and surgical faculty learn. Methods The Kolb Learning Style Inventory, which divides individual learning styles into Accommodating, Diverging, Converging, and Assimilating categories, was administered to the second year undergraduate medical students, general surgery resident body, and general surgery faculty at the University of Alberta. Results A total of 241 faculty, residents, and students were surveyed with an overall response rate of 73%. The predominant learning style of the medical students was assimilating and this was statistically significant (p Conclusions We conclude that medical students have a significantly different learning style from general surgical trainees and general surgeons. This has important implications in the education of general surgery residents.</p

Oligosaccharyltransferase Inhibition Induces Senescence in RTK-Driven Tumor Cells

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high throughput screen and lead compound optimization campaign that delivered a cell permeable inhibitor (NGI-1). NGI-1 targets the oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small cell lung cancer cells NGI-1 blocks cell surface localization and signaling of the EGFR glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or FGFR) for survival. In these cell lines OST inhibition causes cell cycle arrest accompanied by induction of p21, autofluorescence, and changes in cell morphology; all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor tyrosine kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells

Overexpression of c-erbB2 is a negative prognostic factor in anaplastic astrocytomas

The epidermal growth factor receptor (EGFR) family, consisting of four tyrosine kinase receptors, c-erbB1-4, seems to be influential in gliomagenesis. The aim of this study was to investigate EGFR gene amplification and expression of c-erbB1-4 receptor proteins in human anaplastic astrocytomas. Formalin-fixed and paraffin-embedded sections from 31 cases were investigated by standard immunohistochemical procedures for expression of c-erbB1-4 receptor proteins using commercial antibodies. EGFR gene amplification was studied by fluorescence in situ hybridization using paraffin-embedded tissues. Two monoclonal antibodies, NCL-EGFR-384 and NCL-EGFR, were used for EGFR detection and they displayed positive immunoreactivity in 97% and 71%, respectively. For c-erbB2 detection three monoclonal antibodies, CB11, 3B5, and 5A2, were applied and they displayed positive immunoreactivity in 45%, 100%, and 52%, respectively. Positive immunostaining for c-erbB3 and c-erbB4 was encountered in 97% and 74%, respectively. The EGFR gene was amplified in 9 out of 31 tumors (29%). After adjusting for age, Karnofsky performance status, and extent of surgical resection, Cox multiple regression analysis with overall survival as the dependent variable revealed that c-erbB2 overexpression detected by the monoclonal antibody clone CB11 was a statistically significant poor prognostic factor (P = 0.004). This study shows the convenience and feasibility of immunohistochemistry when determining the expression of receptor proteins in tissue sections of human astrocytomas. The synchronous overexpression of c-erbB1-4 proteins in anaplastic astrocytomas supports their role in the pathogenesis of these tumors. Further, c-erbB2 overexpression seems to predict aggressive behaviour

Proteome-Wide Analysis of Single-Nucleotide Variations in the N-Glycosylation Sequon of Human Genes

N-linked glycosylation is one of the most frequent post-translational modifications of proteins with a profound impact on their biological function. Besides other functions, N-linked glycosylation assists in protein folding, determines protein orientation at the cell surface, or protects proteins from proteases. The N-linked glycans attach to asparagines in the sequence context Asn-X-Ser/Thr, where X is any amino acid except proline. Any variation (e.g. non-synonymous single nucleotide polymorphism or mutation) that abolishes the N-glycosylation sequence motif will lead to the loss of a glycosylation site. On the other hand, variations causing a substitution that creates a new N-glycosylation sequence motif can result in the gain of glycosylation. Although the general importance of glycosylation is well known and acknowledged, the effect of variation on the actual glycoproteome of an organism is still mostly unknown. In this study, we focus on a comprehensive analysis of non-synonymous single nucleotide variations (nsSNV) that lead to either loss or gain of the N-glycosylation motif. We find that 1091 proteins have modified N-glycosylation sequons due to nsSNVs in the genome. Based on analysis of proteins that have a solved 3D structure at the site of variation, we find that 48% of the variations that lead to changes in glycosylation sites occur at the loop and bend regions of the proteins. Pathway and function enrichment analysis show that a significant number of proteins that gained or lost the glycosylation motif are involved in kinase activity, immune response, and blood coagulation. A structure-function analysis of a blood coagulation protein, antithrombin III and a protease, cathepsin D, showcases how a comprehensive study followed by structural analysis can help better understand the functional impact of the nsSNVs