CLCA2 Interactor EVA1 Is Required for Mammary Epithelial Cell Differentiation.

CLCA2 is a p53-, p63-inducible transmembrane protein that is frequently downregulated in breast cancer. It is induced during differentiation of human mammary epithelial cells, and its knockdown causes epithelial-to-mesenchymal transition (EMT). To determine how CLCA2 promotes epithelial differentiation, we searched for interactors using membrane dihybrid screening. We discovered a strong interaction with the cell junctional protein EVA1 (Epithelial V-like Antigen 1) and confirmed it by co-immunoprecipitation. Like CLCA2, EVA1 is a type I transmembrane protein that is regulated by p53 and p63. It is thought to mediate homophilic cell-cell adhesion in diverse epithelial tissues. We found that EVA1 is frequently downregulated in breast tumors and breast cancer cell lines, especially those of mesenchymal phenotype. Moreover, knockdown of EVA1 in immortalized human mammary epithelial cells (HMEC) caused EMT, implying that EVA1 is essential for epithelial differentiation. Both EVA1 and CLCA2 co-localized with E-cadherin at cell-cell junctions. The interacting domains were delimited by deletion analysis, revealing the site of interaction to be the transmembrane segment (TMS). The primary sequence of the CLCA2 TMS was found to be conserved in CLCA2 orthologs throughout mammals, suggesting that its interaction with EVA1 co-evolved with the mammary gland. A screen for other junctional interactors revealed that CLCA2 was involved in two different complexes, one with EVA1 and ZO-1, the other with beta catenin. Overexpression of CLCA2 caused downregulation of beta catenin and beta catenin-activated genes. Thus, CLCA2 links a junctional adhesion molecule to cytosolic signaling proteins that modulate proliferation and differentiation. These results may explain how attenuation of CLCA2 causes EMT and why CLCA2 and EVA1 are frequently downregulated in metastatic breast cancer cell lines

Measuring movement fluency during the sit-to-walk task

Restoring movement fluency is a key focus for physical rehabilitation; it's measurement, however, lacks objectivity. The purpose of this study was to find whether measurable movement fluency variables differed between groups of adults with different movement abilities whilst performing the sit-to-walk (STW) movement. The movement fluency variables were: (1) hesitation during movement (reduction in forward velocity of the centre of mass; CoM), (2) coordination (percentage of temporal overlap of joint rotations) and (3) smoothness (number of inflections in the CoM jerk signal)

Two-cluster bifurcations in systems of globally pulse-coupled oscillators

For a system of globally pulse-coupled phase-oscillators, we derive conditions for stability of the completely synchronous state and all possible two-cluster states and explain how the different states are naturally connected via bifurcations. The coupling is modeled using the phase-response-curve (PRC), which measures the sensitivity of each oscillator's phase to perturbations. For large systems with a PRC, which turns to zero at the spiking threshold, we are able to find the parameter regions where multiple stable two-cluster states coexist and illustrate this by an example. In addition, we explain how a locally unstable one-cluster state may form an attractor together will its homoclinic connections. This leads to the phenomenon of intermittent, asymptotic synchronization with abating beats away from the perfect synchrony.Comment: 12 pages. 6 figure

Parallelizing the dual revised simplex method

This paper introduces the design and implementation of two parallel dual simplex solvers for general large scale sparse linear programming problems. One approach, called PAMI, extends a relatively unknown pivoting strategy called suboptimization and exploits parallelism across multiple iterations. The other, called SIP, exploits purely single iteration parallelism by overlapping computational components when possible. Computational results show that the performance of PAMI is superior to that of the leading open-source simplex solver, and that SIP complements PAMI in achieving speedup when PAMI results in slowdown. One of the authors has implemented the techniques underlying PAMI within the FICO Xpress simplex solver and this paper presents computational results demonstrating their value. In developing the first parallel revised simplex solver of general utility, this work represents a significant achievement in computational optimization

Torpedoes in Parkinson's disease, Alzheimer's disease, essential tremor, and control brains

Purkinje cell axonal swellings ("torpedoes"), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions

Using Portable Transducers to Measure Tremor Severity

Background: Portable motion transducers, suitable for measuring tremor, are now available at a reasonable cost. The use of these transducers requires knowledge of their limitations and data analysis. The purpose of this review is to provide a practical overview and example software for using portable motion transducers in the quantification of tremor. Methods: Medline was searched via PubMed.gov in December 2015 using the Boolean expression “tremor AND (accelerometer OR accelerometry OR gyroscope OR inertial measurement unit OR digitizing tablet OR transducer).” Abstracts of 419 papers dating back to 1964 were reviewed for relevant portable transducers and methods of tremor analysis, and 105 papers written in English were reviewed in detail. Results: Accelerometers, gyroscopes, and digitizing tablets are used most commonly, but few are sold for the purpose of measuring tremor. Consequently, most software for tremor analysis is developed by the user. Wearable transducers are capable of recording tremor continuously, in the absence of a clinician. Tremor amplitude, frequency, and occurrence (percentage of time with tremor) can be computed. Tremor amplitude and occurrence correlate strongly with clinical ratings of tremor severity. Discussion: Transducers provide measurements of tremor amplitude that are objective, precise, and valid, but the precision and accuracy of transducers are mitigated by natural variability in tremor amplitude. This variability is so great that the minimum detectable change in amplitude, exceeding random variability, is comparable for scales and transducers. Research is needed to determine the feasibility of detecting smaller change using averaged data from continuous long-term recordings with wearable transducers

Effect of Three Cueing Devices for People with Parkinson’s disease with Gait Initiation Difficulties

Background: Freezing of gait (FOG) remains one of the most common debilitating aspects of Parkinson’s disease and has been linked to injuries, falls and reduced quality of life. Although commercially available portable cueing devices exist claiming to assist with overcoming freezing; their immediate effectiveness in overcoming gait initiation failure currently unknown. This study investigated the effects of three different types of cueing device in people with Parkinson’s disease who experience freezing. Methods: Twenty participants with idiopathic Parkinson’s disease who experienced freezing during gait but who were able to walk short distances indoors independently were recruited. At least three attempts at gait initiation were recorded using a ten camera Qualisys motion analysis system and four force platforms. Test conditions were: laser cane, sound metronome, vibrating metronome, walking stick and no intervention. Results: During testing 12 of the 20 participants had freezing episodes, from these participants 100 freezing and 91 non-freezing trials were recorded. Clear differences in the movement patterns were seen between freezing and non-freezing episodes. The laser cane was most effective cueing device at improving the forwards/backwards and side to side movement and had the least number of freezing episodes. The walking stick also showed significant improvements compared to the other conditions. The vibration metronome appeared to disrupt movement compared to the sound metronome at the same beat frequency. Conclusion: This study identified differences in the movement patterns between freezing episodes and non-freezing episodes, and identified immediate improvements during gait initiation when using the laser cane over the other interventions

Slow Orthostatic Tremor and the Case for Routine Electrophysiological Evaluation of All Tremors

In this issue of the journal, Hassan and Caviness reviewed the controversial topic of slow orthostatic tremor (OT). Based on their review of the relevant literature, Hassan and Caviness concluded that “multiple lines of evidence separate slow OT from classical OT,” but they also noted that “clinical and electrophysiologic overlap may occur.” We were invited to discuss the significance of this overlap within the context of tremor classification

Real-Time Estimation of Pathological Tremor Parameters from Gyroscope Data

This paper presents a two stage algorithm for real-time estimation of instantaneous tremor parameters from gyroscope recordings. Gyroscopes possess the advantage of providing directly joint rotational speed, overcoming the limitations of traditional tremor recording based on accelerometers. The proposed algorithm first extracts tremor patterns from raw angular data, and afterwards estimates its instantaneous amplitude and frequency. Real-time separation of voluntary and tremorous motion relies on their different frequency contents, whereas tremor modelling is based on an adaptive LMS algorithm and a Kalman filter. Tremor parameters will be employed to drive a neuroprosthesis for tremor suppression based on biomechanical loading