Trunk neuromuscular responses to a single whole-body vibration session in patients with chronic low back pain: a cross-sectional study.

OBJECTIVE: Whole-body vibration (WBV) exercise is progressively adopted as an alternative therapeutic modality for enhancing muscle force and muscle activity via neurogenic potentiation. So far, possible changes in the recruitment patterns of the trunk musculature after WBV remain undetermined. The main objective of this study was to evaluate the short-term effects of a single WBV session on trunk neuromuscular responses in patients with chronic low back pain (cLBP) and healthy participants. METHODS: Twenty patients with cLBP and 21 healthy participants performed 10 trunk flexion-extensions before and after a single WBV session consisting of five 1-minute vibration sets. Surface electromyography (EMG) of erector spinae at L2-L3 and L4-L5 and lumbopelvic kinematic variables were collected during the trials. Data were analyzed using 2-way mixed analysis of variance models. RESULTS: The WBV session led to increased lumbar EMG activity during the flexion and extension phases but yielded no change in the quiet standing and fully flexed phases. Kinematic data showed a decreased contribution to the movement of the lumbar region in the second extension quartile. These effects were not different between patients with cLBP and healthy participants. CONCLUSIONS: Increased lumbar EMG activity after a single WBV session most probably results from potentiation effects of WBV on lumbar muscles reflex responses. Decreased EMG activity in full trunk flexion, usually observed in healthy individuals, was still present after WBV, suggesting that the ability of the spine stabilizing mechanisms to transfer the extension torque from muscles to passive structures was not affected.

Leadership and individual differences: at the cusp of a renaissance

In this introductory editorial, we provide a brief overview of the history of individual difference research in leadership. We explain the major challenges that trait research faced, and why it was revived primarily because of methodological advancements. Next, we argue that leadership individual difference research is at a cusp of a renaissance. We explain why we are at this cusp and what researchers should do reify the renaissance in terms of theoretical extensions of trait models, the application of robust methodological advancements, and the development of process models linking distal (i.e., traits) predictors to proximal predictors (e.g., behaviors, skills, attitudes), and the latter to leader outcomes. We then summarize the papers we accepted for the special issue, and conclude with an optimistic note for leadership individual difference research.

The final N-terminal trimming of a subaminoterminal proline-containing HLA class I-restricted antigenic peptide in the cytosol is mediated by two peptidases.

The proteasome produces MHC class I-restricted antigenic peptides carrying N-terminal extensions, which are trimmed by other peptidases in the cytosol or within the endoplasmic reticulum. In this study, we show that the N-terminal editing of an antigenic peptide with a predicted low TAP affinity can occur in the cytosol. Using proteomics, we identified two cytosolic peptidases, tripeptidyl peptidase II and puromycin-sensitive aminopeptidase, that trimmed the N-terminal extensions of the precursors produced by the proteasome, and led to a transient enrichment of the final antigenic peptide. These peptidases acted either sequentially or redundantly, depending on the extension remaining at the N terminus of the peptides released from the proteasome. Inhibition of these peptidases abolished the CTL-mediated recognition of Ag-expressing cells. Although we observed some proteolytic activity in fractions enriched in endoplasmic reticulum, it could not compensate for the loss of tripeptidyl peptidase II/puromycin-sensitive aminopeptidase activities.

Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling.

To investigate their role in receptor coupling to G(q), we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the alpha(1b)-adrenergic receptor (AR). The wild type and mutated receptors were expressed in COS-7 cells and characterized for their ligand binding properties and ability to increase inositol phosphate accumulation. The experimental results have been interpreted in the context of both an ab initio model of the alpha(1b)-AR and of a new homology model built on the recently solved crystal structure of rhodopsin. Among the twenty-three basic amino acids mutated only mutations of three, Arg(254) and Lys(258) in the third intracellular loop and Lys(291) at the cytosolic extension of helix 6, markedly impaired the receptor-mediated inositol phosphate production. Additionally, mutations of two conserved hydrophobic residues, Val(147) and Leu(151) in the second intracellular loop had significant effects on receptor function. The functional analysis of the receptor mutants in conjunction with the predictions of molecular modeling supports the hypothesis that Arg(254), Lys(258), as well as Leu(151) are directly involved in receptor-G protein interaction and/or receptor-mediated activation of the G protein. In contrast, the residues belonging to the cytosolic extensions of helices 3 and 6 play a predominant role in the activation process of the alpha(1b)-AR. These findings contribute to the delineation of the molecular determinants of the alpha(1b)-AR/G(q) interface.

The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes.

Cellular directional migration in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC), in addition to its function of regulating sodium transport in kidney, has recently been found to modulate cell locomotory speed. Here we tested whether ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely blocks only galvanotaxis and does not decrease migration speed. Overexpression of ENaC is sufficient to drive galvanotaxis in otherwise unresponsive cells. Pharmacologic blockade or maintenance of the open state of ENaC also decreases or increases, respectively, galvanotaxis, suggesting that the channel open state is responsible for the response. Stable lamellipodial extensions formed at the cathodal sides of wild-type cells at the start of galvanotaxis; these were absent in the ENaC knockout keratinocytes, suggesting that ENaC mediates galvanotaxis by generating stable lamellipodia that steer cell migration. We provide evidence that ENaC is required for directional migration of keratinocytes in an electric field, supporting a role for ENaC in skin wound healing.

MADAP, a flexible clustering tool for the interpretation of one-dimensional genome annotation data.

A recurring task in the analysis of mass genome annotation data from high-throughput technologies is the identification of peaks or clusters in a noisy signal profile. Examples of such applications are the definition of promoters on the basis of transcription start site profiles, the mapping of transcription factor binding sites based on ChIP-chip data and the identification of quantitative trait loci (QTL) from whole genome SNP profiles. Input to such an analysis is a set of genome coordinates associated with counts or intensities. The output consists of a discrete number of peaks with respective volumes, extensions and center positions. We have developed for this purpose a flexible one-dimensional clustering tool, called MADAP, which we make available as a web server and as standalone program. A set of parameters enables the user to customize the procedure to a specific problem. The web server, which returns results in textual and graphical form, is useful for small to medium-scale applications, as well as for evaluation and parameter tuning in view of large-scale applications, requiring a local installation. The program written in C++ can be freely downloaded from ftp://ftp.epd.unil.ch/pub/software/unix/madap. The MADAP web server can be accessed at http://www.isrec.isb-sib.ch/madap/.

Adaptive tracking of EEG oscillations.

Neuronal oscillations are an important aspect of EEG recordings. These oscillations are supposed to be involved in several cognitive mechanisms. For instance, oscillatory activity is considered a key component for the top-down control of perception. However, measuring this activity and its influence requires precise extraction of frequency components. This processing is not straightforward. Particularly, difficulties with extracting oscillations arise due to their time-varying characteristics. Moreover, when phase information is needed, it is of the utmost importance to extract narrow-band signals. This paper presents a novel method using adaptive filters for tracking and extracting these time-varying oscillations. This scheme is designed to maximize the oscillatory behavior at the output of the adaptive filter. It is then capable of tracking an oscillation and describing its temporal evolution even during low amplitude time segments. Moreover, this method can be extended in order to track several oscillations simultaneously and to use multiple signals. These two extensions are particularly relevant in the framework of EEG data processing, where oscillations are active at the same time in different frequency bands and signals are recorded with multiple sensors. The presented tracking scheme is first tested with synthetic signals in order to highlight its capabilities. Then it is applied to data recorded during a visual shape discrimination experiment for assessing its usefulness during EEG processing and in detecting functionally relevant changes. This method is an interesting additional processing step for providing alternative information compared to classical time-frequency analyses and for improving the detection and analysis of cross-frequency couplings.

Rgtsp: a generalized top scoring pairs package for class prediction.

SUMMARY: A top scoring pair (TSP) classifier consists of a pair of variables whose relative ordering can be used for accurately predicting the class label of a sample. This classification rule has the advantage of being easily interpretable and more robust against technical variations in data, as those due to different microarray platforms. Here we describe a parallel implementation of this classifier which significantly reduces the training time, and a number of extensions, including a multi-class approach, which has the potential of improving the classification performance. AVAILABILITY AND IMPLEMENTATION: Full C++ source code and R package Rgtsp are freely available from http://lausanne.isb-sib.ch/~vpopovic/research/. The implementation relies on existing OpenMP libraries.

Long-Term Safety of Canakinumab in Patients with Gouty Arthritis.

Background/Purpose: Gouty arthritis (GA) is a chronic inflammatory disease. Targeting the inflammatory pathway through IL-1_ inhibition with canakinumab (CAN) may provide significant long-term benefits. CAN safety versus triamcinolone acetonide (TA) over initial 24 weeks (blinded study) for patients (pts) with history of frequent attacks (_3 in year before baseline) was reported earlier from core (_-RELIEVED [_-REL] and _-REL-II) and first extension (E1) studies1. Herein we present full 18-month long-term CAN safety data, including open-label second extension (E2) studies. Methods: GA pts completing _-REL E1 and _-REL-II E1 studies1 were enrolled in these 1-year, open-label, E2 studies. All pts entering E2, whether randomized to CAN or TA, received CAN 150 mg sc on demand upon new attack. Data are presented only for pts randomized to CAN, and are reported cumulatively, i.e. including corresponding data from previously reported core and E1 studies. Long-term safety outcomes and safety upon re-treatment are presented as incidence rate per 100 patient-years (pyr) of study participation for AEs and SAEs. Deaths are reported for all pts (randomized to CAN or TA). Selected predefined notable laboratory abnormalities are shown (neutrophils, platelets, liver and renal function tests). Long-term attack rate per year is also provided. Results: In total, 69/115 (60%) and 72/112 (64.3%) of the pts randomized to CAN in the two core studies entered the two E2 studies, of which 68 and 64 pts, respectively completed the E2 studies. The 2 study populations had differing baseline comorbidity and geographic origin. Lab data (not time adjusted) for neutropenia appears worse after retreatment in _-REL E2, and deterioration of creatinine clearance appears worse after retreatment (Table 1). The time-adjusted incidence rates for AEs were 302.4/100 pyr and 360/100 pyr, and for SAEs were 27.9/100 pyr and 13.9/100 pyr in _-REL E2 and _-REL-II E2 respectively (Table 1). The time-adjusted incidence rates of any AEs, infection AEs, any SAEs, and selected SAEs before and after re-treatment are presented in Table 1. Incidence rates for AEs and SAEs declined after re-treatment, with the exception of SAEs in _-REL-II E2, which increased from 2.9/100 pyr to 10.9/100 pyr (no infection SAEs after retreatment in _-REL-II E2, and other SAEs fit no special pattern). In the total safety population (N_454, core and all extensions), there were 4 deaths, 2 in the core studies previously reported1 and 2 during the _-REL E2 study (one patient in the CAN group died from pneumonia; one patient in the TA group who never received CAN died of pneumococcal sepsis). None of the deaths was suspected by investigators to be study drug related. The mean rates of new attacks per year on CAN were 1.21 and 1.18 in _-REL E2 and in _-REL-II E2. Conclusion: The clinical safety profile of CAN upon re-treatment was maintained long-term with no new infection concerns

Neural networks as mechanisms to regulate division of labor.

Abstract In social insects, workers perform a multitude of tasks, such as foraging, nest construction, and brood rearing, without central control of how work is allocated among individuals. It has been suggested that workers choose a task by responding to stimuli gathered from the environment. Response-threshold models assume that individuals in a colony vary in the stimulus intensity (response threshold) at which they begin to perform the corresponding task. Here we highlight the limitations of these models with respect to colony performance in task allocation. First, we show with analysis and quantitative simulations that the deterministic response-threshold model constrains the workers' behavioral flexibility under some stimulus conditions. Next, we show that the probabilistic response-threshold model fails to explain precise colony responses to varying stimuli. Both of these limitations would be detrimental to colony performance when dynamic and precise task allocation is needed. To address these problems, we propose extensions of the response-threshold model by adding variables that weigh stimuli. We test the extended response-threshold model in a foraging scenario and show in simulations that it results in an efficient task allocation. Finally, we show that response-threshold models can be formulated as artificial neural networks, which consequently provide a comprehensive framework for modeling task allocation in social insects.

Evidential relevance in scene to offender transfer cases: development and analysis of a likelihood ratio for offence level propositions

The present paper focuses on the analysis and discussion of a likelihood ratio (LR) development for propositions at a hierarchical level known in the context as 'offence level'. Existing literature on the topic has considered LR developments for so-called offender to scene transfer cases. These settings involve-in their simplest form-a single stain found on a crime scene, but with possible uncertainty about the degree to which that stain is relevant (i.e. that it has been left by the offender). Extensions to multiple stains or multiple offenders have also been reported. The purpose of this paper is to discuss a development of a LR for offence level propositions when case settings involve potential transfer in the opposite direction, i.e. victim/scene to offender transfer. This setting has previously not yet been considered. The rationale behind the proposed LR is illustrated through graphical probability models (i.e. Bayesian networks). The role of various uncertain parameters is investigated through sensitivity analyses as well as simulations.

The connectome viewer toolkit: an open source framework to manage, analyze, and visualize connectomes.

Advanced neuroinformatics tools are required for methods of connectome mapping, analysis, and visualization. The inherent multi-modality of connectome datasets poses new challenges for data organization, integration, and sharing. We have designed and implemented the Connectome Viewer Toolkit - a set of free and extensible open source neuroimaging tools written in Python. The key components of the toolkit are as follows: (1) The Connectome File Format is an XML-based container format to standardize multi-modal data integration and structured metadata annotation. (2) The Connectome File Format Library enables management and sharing of connectome files. (3) The Connectome Viewer is an integrated research and development environment for visualization and analysis of multi-modal connectome data. The Connectome Viewer's plugin architecture supports extensions with network analysis packages and an interactive scripting shell, to enable easy development and community contributions. Integration with tools from the scientific Python community allows the leveraging of numerous existing libraries for powerful connectome data mining, exploration, and comparison. We demonstrate the applicability of the Connectome Viewer Toolkit using Diffusion MRI datasets processed by the Connectome Mapper. The Connectome Viewer Toolkit is available from http://www.cmtk.org/

Precision and scaling in morphogen gradient read-out.

Morphogen gradients infer cell fate as a function of cellular position. Experiments in Drosophila embryos have shown that the Bicoid (Bcd) gradient is precise and exhibits some degree of scaling. We present experimental results on the precision of Bcd target genes for embryos with a single, double or quadruple dose of bicoid demonstrating that precision is highest at mid-embryo and position dependent, rather than gene dependent. This confirms that the major contribution to precision is achieved already at the Bcd gradient formation. Modeling this dynamic process, we investigate precision for inter-embryo fluctuations in different parameters affecting gradient formation. Within our modeling framework, the observed precision can only be achieved by a transient Bcd profile. Studying different extensions of our modeling framework reveals that scaling is generally position dependent and decreases toward the posterior pole. Our measurements confirm this trend, indicating almost perfect scaling except for anterior most expression domains, which overcompensate fluctuations in embryo length.

Value of positron emission tomography in full-thickness chest wall resections for malignancies.

Preoperative imaging for resection of chest wall malignancies is generally performed by computed tomography (CT). We evaluated the role of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in planning full-thickness chest wall resections for malignancies. We retrospectively included 18 consecutive patients operated from 2004 to 2006 at our institution. Tumor extent was measured by CT and PET, using the two largest perpendicular tumor extensions in the chest wall plane to compute the tumor surface assuming an elliptical shape. Imaging measurements were compared to histopathology assessment of tumor borders. CT assessment consistently overestimated the tumor size as compared to PET (+64% vs. +1%, P<0.001). Moreover, PET was significantly better than CT at defining the size of lesions >24 cm(2) corresponding to a mean diameter >5.5 cm or an ellipse of >4 cm x 7.6 cm (positive predictive value 80% vs. 44% and specificity 93% vs. 64%, respectively). Metabolic PET imaging was superior to CT for defining the extent of chest wall tumors, particularly for tumors with a diameter >5.5 cm. PET can complement CT in planning full-thickness chest wall resection for malignancies, but its true value remains to be determined in larger, prospective studies.

Computer-Aided Business Model Design

There is a lack of dedicated tools for business model design at a strategic level. However, in today's economic world the need to be able to quickly reinvent a company's business model is essential to stay competitive. This research focused on identifying the functionalities that are necessary in a computer-aided design (CAD) tool for the design of business models in a strategic context. Using design science research methodology a series of techniques and prototypes have been designed and evaluated to offer solutions to the problem. The work is a collection of articles which can be grouped into three parts: First establishing the context of how the Business Model Canvas (BMC) is used to design business models and explore the way in which CAD can contribute to the design activity. The second part extends on this by proposing new technics and tools which support elicitation, evaluation (assessment) and evolution of business models design with CAD. This includes features such as multi-color tagging to easily connect elements, rules to validate coherence of business models and features that are adapted to the correct business model proficiency level of its users. A new way to describe and visualize multiple versions of a business model and thereby help in addressing the business model as a dynamic object was also researched. The third part explores extensions to the business model canvas such as an intermediary model which helps IT alignment by connecting business model and enterprise architecture. And a business model pattern for privacy in a mobile environment, using privacy as a key value proposition. The prototyped techniques and proposition for using CAD tools in business model modeling will allow commercial CAD developers to create tools that are better suited to the needs of practitioners.