Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins.

Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. Spy1/RINGO (Spy1) proteins bind and activate Cdk but are resistant to canonical regulatory mechanisms that establish cell-cycle checkpoints. Cancer cells exploit Spy1 to stimulate proliferation through inappropriate activation of Cdks, yet the mechanism is unknown. We have determined crystal structures of the Cdk2-Spy1 and p27-Cdk2-Spy1 complexes that reveal how Spy1 activates Cdk. We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. Our structural description of Spy1 provides important mechanistic insights that may be utilized for targeting upregulated Spy1 in cancer.

Predicting Fall Counts Using Wearable Sensors: A Novel Digital Biomarker for Parkinson's Disease.

People with Parkinson's disease (PD) experience significant impairments to gait and balance; as a result, the rate of falls in people with Parkinson's disease is much greater than that of the general population. Falls can have a catastrophic impact on quality of life, often resulting in serious injury and even death. The number (or rate) of falls is often used as a primary outcome in clinical trials on PD. However, falls data can be unreliable, expensive and time-consuming to collect. We sought to validate and test a novel digital biomarker for PD that uses wearable sensor data obtained during the Timed Up and Go (TUG) test to predict the number of falls that will be experienced by a person with PD. Three datasets, containing a total of 1057 (671 female) participants, including 71 previously diagnosed with PD, were included in the analysis. Two statistical approaches were considered in predicting falls counts: the first based on a previously reported falls risk assessment algorithm, and the second based on elastic net and ensemble regression models. A predictive model for falls counts in PD showed a mean R2 value of 0.43, mean error of 0.42 and a mean correlation of 30% when the results were averaged across two independent sets of PD data. The results also suggest a strong association between falls counts and a previously reported inertial sensor-based falls risk estimate. In addition, significant associations were observed between falls counts and a number of individual gait and mobility parameters. Our preliminary research suggests that the falls counts predicted from the inertial sensor data obtained during a simple walking task have the potential to be developed as a novel digital biomarker for PD, and this deserves further validation in the targeted clinical population.

The Feasibility of Equine Field-Based Postural Sway Analysis Using a Single Inertial Sensor.

(1) Background: Postural sway is frequently used to quantify human postural control, balance, injury, and neurological deficits. However, there is considerably less research investigating the value of the metric in horses. Much of the existing equine postural sway research uses force or pressure plates to examine the centre of pressure, inferring change at the centre of mass (COM). This study looks at the inverse, using an inertial measurement unit (IMU) on the withers to investigate change at the COM, exploring the potential of postural sway evaluation in the applied domain. (2) Methods: The lipopolysaccharide model was used to induce transient bilateral lameness in seven equines. Horses were monitored intermittently by a withers fixed IMU over seven days. (3) Results: There was a significant effect of time on total protein, carpal circumference, and white blood cell count in the horses, indicating the presence of, and recovery from, inflammation. There was a greater amplitude of displacement in the craniocaudal (CC) versus the mediolateral (ML) direction. A significant difference was observed in the amplitude of displacement in the ML direction between 4-12 h and 168 h. (4) Conclusions: The significant reduction in ML displacement during the acute inflammation period alongside greater overall CC displacement may be a compensatory behaviour for bilateral lameness.

Effect of External Counterpulsation on Exercise Recovery in Team Sport Athletes.

External counterpulsation (ECP), an electrocardiogram-led sequential compression of lower limbs, has been recently proposed for sports recovery, but research is scant. This study examined the effects of an ECP session upon neuromuscular function (vertical jump and torque/velocity characteristics), biochemical responses (creatine kinase, cortisol, testosterone, alpha-amylase and immunoglobulin-A), and muscle soreness (visual analogue scale) following high-intensity exercise. Twenty-one male team sport athletes (age: 21.6±3.4 yrs; height: 182.7±7.3 cm; body mass: 82.7±9.3 kg) recovered from the fatiguing exercise using either ECP or rest. Data collection was conducted at three separate time points: upon arrival (Pre), post-recovery (Post), and 24 h post-recovery (24hPost). Significant main effects for time were observed for increased torque/velocity slope and for decreased isometric extension peak torque (p<0.001). Significant main effects for time were observed for increased creatine kinase, testosterone, alpha-amylase, and muscle soreness (all p<0.001). Significant interaction effects were observed at post-testing following ECP: Cortisol release and the related decline in testosterone/cortisol ratio were attenuated, and immunoglobulin-A was increased following ECP in comparison to the control (all p<0.05). Following high-intensity exercise, ECP has potentially beneficial effects upon biomarkers of recovery, without affecting the neuromuscular function.

The relationship between the golf swing plane and ball impact characteristics using trajectory ellipse fitting.

The trajectory of the clubhead close to ball impact during the golf swing has previously been shown to be planar. However, the relationship between the plane orientation and the orientation characteristics of the clubhead at ball impact has yet to be defined. Fifty-two male golfers (27 high skilled, 25 intermediate skilled) hit 40 drives each in an indoor biomechanics laboratory. This study successfully fitted the trajectory of the clubhead near impact to an ellipse for each swing for players of different skill levels to help better explain this relationship. Additionally, the eccentricities of the ellipses were investigated for links to skill level. The trajectory of the clubhead was found to fit to an ellipse with RMSE of 1.2 mm. The eccentricity of the ellipse was found to be greater in the high-skilled golfers. The club path and angle of attack generated from the ellipse fitted clubhead trajectory were found to have a normalised bias-corrected RMSE of 2% and 3%, respectively. A set of "rule of thumb" values for the relationship between the club path, angle of attack and delivery plane angle was generated for use by coaches.

Stability of daily home-based measures of postural control over an 8-week period in highly functioning older adults.

PURPOSE: The focus of this study was to monitor daily objective measures of standing postural control over an 8-week period, recorded in a person's home, in a population of healthy older adults. Establishing natural patterns of variation in the day-to-day signal, occurring in the relative absence of functional decline or disease, would enable us to determine thresholds for changes in postural control from baseline that could be considered clinically important. METHODS: Eighteen community-dwelling older adults (3 M, 15 F, 72 ± 6 years) participated in a home-based trial where each day they were asked to complete a technology-enabled routine consisting of a short questionnaire, as well as a quiet standing balance trial. Centre of pressure (COP) excursions were calculated over the course of each daily balance trial to generate variables such as postural sway length and mean sway frequency. RESULTS: The data demonstrated large differences between subjects in centre of pressure measures (coefficients of variation ranging 37-107 %, depending on the variable). Each participant also exhibited variations in their day-to-day trials (e.g. coefficients of variation across 8 weeks ranging ~17-56 %, within person for mean COP distance). Inter- and intra-subject differences were not strongly related to functional tests, suggesting that these variations were not necessarily aberrant movement patterns, but are seemingly representative of natural movement variability. CONCLUSIONS: The idea of applying a group-focused approach at an individual level may result in misclassifying important changes for a particular individual. Early detection of deterioration can only be achieved through the creation of individual trajectories for each person, that are inherently self referential.

Responsiveness of respiratory function in Parkinson's Disease to an integrative exercise programme: A prospective cohort study.

INTRODUCTION: Respiratory disorders are the most common cause of death in Parkinson's Disease (PD). Conflicting data exist on the aetiology of respiratory dysfunction in PD and few studies examine the effects of exercise-based interventions on respiratory measures. This study was conducted to better understand respiratory dysfunction in PD and to identify measures of dysfunction responsive to an integrative exercise programme. OBJECTIVES: The objectives were to compare baseline respiratory measures with matched, published population norms and to examine immediate and longer-term effects of a 12-week integrated exercise programme on these measures. DESIGN: Twenty-three people with mild PD (median Hoehn & Yahr = 2) self-selected to participate in this exploratory prospective cohort study. Evaluation of participants occurred at three time points: at baseline; following the 12-week exercise programme and at 4-month follow-up. OUTCOME MEASURES: Outcome measures included: Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second (FEV1), FEV1/FVC ratio, Peak Expiratory Flow (PEF), Inspiratory Muscle Strength (MIP), Expiratory Muscle Strength (MEP), Peak Cough Flow (PCF), and Cardiovascular Fitness measures of estimated VO2 max and 6-Minute Walk Test (6MWT). RESULTS: Compared to published norms, participants had impaired cough, reduced respiratory muscle strength, FEV, FVC, PEF and cardiovascular fitness. Post exercise intervention, statistically significant improvements were noted in MEP, cardiovascular fitness, and PEF. However only gains in PEF were maintained at 4-month follow-up. CONCLUSIONS: Significant respiratory dysfunction exists, even in the early stages of PD. Metrics of respiratory muscle strength, peak expiratory flow and cardiovascular fitness appear responsive to an integrative exercise programme.

A comparison of algorithms for body-worn sensor-based spatiotemporal gait parameters to the GAITRite electronic walkway.

This study compares the performance of algorithms for body-worn sensors used with a spatiotemporal gait analysis platform to the GAITRite electronic walkway. The mean error in detection time (true error) for heel strike and toe-off was 33.9 ± 10.4 ms and 3.8 ± 28.7 ms, respectively. The ICC for temporal parameters step, stride, swing and stance time was found to be greater than 0.84, indicating good agreement. Similarly, for spatial gait parameters--stride length and velocity--the ICC was found to be greater than 0.88. Results show good to excellent concurrent validity in spatiotemporal gait parameters, at three different walking speeds (best agreement observed at normal walking speed). The reported algorithms for body-worn sensors are comparable to the GAITRite electronic walkway for measurement of spatiotemporal gait parameters in healthy subjects.

Irish Equine Industry Stakeholder Perspectives of Objective Technology for Biomechanical Analyses in the Field.

Wearable sensing technologies are increasingly used in human and equine gait research to improve ecological validity of research findings. It is unclear how these tools have penetrated the equine industry or what perspectives industry stakeholders' hold in relation to these relatively new devices. Semi-structured interviews were conducted with Irish equine industry stakeholders to understand their perception of objective tools for biomechanical analysis in the field. The study participants came from professional/elite backgrounds in both the sport horse (n = 6) and thoroughbred (n = 6) sectors. The interview data were analysed using thematic analysis, resulting in four analytical themes. The first theme conveys the importance of tacit knowledge and experience in the holistic analysis of a horse. Theme two highlights that the perfect horse does not exist therefore, equine athlete management is complex and requires a multi-layered problem-solving approach. Theme three describes an awareness among stakeholders of technologies, however they are sceptical of their value. The final theme identified that one of the key barriers to technology adoption is the economic value of the horse and the cost of implementing technology herd-wide. Our findings highlight the need for a user-centred design in this domain, which requires greater consultation and learning between technology developers and equine stakeholders to develop fit-for-purpose analysis and monitoring tools.

Impact of Exercise Intervention in Parkinson's Disease can be Quantified Using Inertial Sensor Data and Clinical Tests.

Parkinson's Disease (PD) has the second-highest prevalence rate of all neurodegenerative disorders. It effects approximately 1% of the population over the age of 60, with this proportion rising further, in more elderly cohorts. PD manifests as several motor and non-motor disfunctions, which develop progressively over time. Gait and mobility problems are amongst the most debilitating symptoms for people with PD. They severely affect a person's ability to carry out daily activities of living and can lead to a decreased quality of life. However, recent research has shown exercise intervention to be effective in improving gait, and overall functional mobility, in persons with PD. In this paper, we study the effect of an exercise intervention, comprised of three separate methods of exercise - all which have been shown previously to be effective individually - on a cohort with early-to-moderate stage PD. We also examine the ability of the Timed Up and Go (TUG) test - instrumented with inertial sensors (QTUG) - and the Unified Parkinson's Disease Rating Scale (UPDRS) Part III in measuring the response to the exercise intervention. We found that TUG time and the QTUG-derived frailty index - along with many additional parameters derived from QTUG - showed a significant change between baseline and post-intervention, while the UPDRS Part III score did not. The direction of the changes in the QTUG parameters also align with the expected exercise effect from the literature. Our results suggest QTUG may be a more sensitive measure than UPDRS Part III for assessing the effect of exercise intervention on functional mobility in people with early-to-moderate stage PD.

Investigating normal day to day variations of postural control in a healthy young population using Wii balance boards.

The quantification of postural control (PC) provides the opportunity to understand the function and integration of the sensorimotor subsystems. The increased availability of portable sensing technology, such as Wii Balance Boards (WBB), has afforded the capacity to capture data pertaining to motor function, outside of the laboratory and clinical setting. However, prior to its use in long-term monitoring, it is crucial to understand natural daily PC variation. Twenty-four young adults conducted repeated static PC assessments over 20 consecutive weekdays, using WBBs. 16/24 participants (eyes open) and 11/24 participants (eyes closed) exhibited statistically significant differences (p <; 0.05) between their initial `once-off' measure and their daily measures of PC. This study showed that variations in PC exist in a healthy population, a once-off measure may not be representative of true performance and this inherent variation should be considered when implementing long-term monitoring protocols.

Frontal-Plane Variability in Foot Orientation During Fatiguing Running Exercise in Individuals With Chronic Ankle Instability.

CONTEXT: Researchers have reported increased variability in frontal-plane movement at the ankle during jumping in individuals with chronic ankle instability (CAI), which may increase their risk of recurrent ankle sprain. It is not known if this behavior is present during running gait or how fatigue affects the amount of frontal-plane-movement variability in individuals with CAI. OBJECTIVE: To investigate the amount of roll-angle variability at the foot during a fatiguing exercise protocol in participants with CAI. DESIGN: Controlled laboratory study. SETTING: Motion-analysis research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 18 volunteers with CAI (10 men, 8 women; age = 29.8 ± 9.2 years, height = 175.8 ± 11.2 cm, mass = 75.4 ± 10.7 kg) and 17 volunteers serving as controls (8 men, 9 women; age = 28.2 ± 6.3 years, height = 172.3 ± 10.6 cm, mass = 68.8 ± 12.9 kg). INTERVENTION(S): Kinematic data for foot position were collected while participants performed a functional fatigue protocol based on shuttle runs. MAIN OUTCOME MEASURE(S): Variability (ie, standard deviation) of the roll angle of the foot about the x-axis, corresponding to inversion-eversion, was measured at 2 discrete times: 50 milliseconds before foot strike and 65% of stance. RESULTS: No differences in roll-angle range or variability were observed between limbs in either group. At 65% of stance, we found a main effect for time, whereby both groups demonstrated decreased roll-angle ranges at the end of the fatigue protocol ( P = .01). A between-groups effect in the roll-angle variability at 65% of stance was noted ( P = .04), with the CAI group exhibiting higher levels of variability. No between-groups differences were observed at 50 milliseconds before foot strike. CONCLUSIONS: Chronic ankle instability is a complex, multifactorial condition that can affect patients in diverse ways. Identifying excessive foot-position variability in particular situations could potentially inform targeted rehabilitation programs.

The influence of auditory-motor coupling on fractal dynamics in human gait.

Humans exhibit an innate ability to synchronize their movements to music. The field of gait rehabilitation has sought to capitalize on this phenomenon by invoking patients to walk in time to rhythmic auditory cues with a view to improving pathological gait. However, the temporal structure of the auditory cue, and hence the temporal structure of the target behavior has not been sufficiently explored. This study reveals the plasticity of auditory-motor coupling in human walking in relation to 'complex' auditory cues. The authors demonstrate that auditory-motor coupling can be driven by different coloured auditory noise signals (e.g. white, brown), shifting the fractal temporal structure of gait dynamics towards the statistical properties of the signals used. This adaptive capability observed in whole-body movement, could potentially be harnessed for targeted neuromuscular rehabilitation in patient groups, depending on the specific treatment goal.

A comparison of cross-sectional and prospective algorithms for falls risk assessment.

Falls are the most common cause of injury and hospitalization and one of the principal causes of death and disability in older adults worldwide. Accurate identification of patients at risk of falls could lead to timely medical intervention, reducing the incidence of falls related injuries along with associated costs. The current best practice for studies of falls and falls risk recommends the use of prospective follow-up data. However, the majority of studies reporting sensor based methods for assessment of falls risk employ cross-sectional falls data (falls history). The purpose of this study was to compare the performance of sensor based falls risk assessment algorithms derived from cross-sectional (N=909) and prospective (N=259) datasets in terms of false positive rate. The utility of any classification algorithm is clearly limited by a high false positive rate. An estimate of the false positive rate for both cross-sectional and prospective algorithms was determined using an inertial sensor data set of 611 TUG tests from 55 healthy control subjects, with no history of falls. We aimed to determine which falls risk assessment algorithm is more effective at classifying falls risk in healthy control subjects. The cross-sectional algorithm correctly classified 94.11% of tests, while the prospective algorithm, correctly classified 79.38% of tests. Results suggest that sensor based falls risk assessment algorithms generated using cross-sectional falls data, may be more effective than those generated using prospective data in classifying healthy controls and reducing associated false positives.

Gait variability is altered in older adults when listening to auditory stimuli with differing temporal structures.

Gait variability in the context of a deterministic dynamical system may be quantified using nonlinear time series analyses that characterize the complexity of the system. Pathological gait exhibits altered gait variability. It can be either too periodic and predictable, or too random and disordered, as is the case with aging. While gait therapies often focus on restoration of linear measures such as gait speed or stride length, we propose that the goal of gait therapy should be to restore optimal gait variability, which exhibits chaotic fluctuations and is the balance between predictability and complexity. In this context, our purpose was to investigate how listening to different auditory stimuli affects gait variability. Twenty-seven young and 27 elderly subjects walked on a treadmill for 5 min while listening to white noise, a chaotic rhythm, a metronome, and with no auditory stimulus. Stride length, step width, and stride intervals were calculated for all conditions. Detrended Fluctuation Analysis was then performed on these time series. A quadratic trend analysis determined that an idealized inverted-U shape described the relationship between gait variability and the structure of the auditory stimuli for the elderly group, but not for the young group. This proof-of-concept study shows that the gait of older adults may be manipulated using auditory stimuli. Future work will investigate which structures of auditory stimuli lead to improvements in functional status in older adults.

The appropriate use of approximate entropy and sample entropy with short data sets.

Approximate entropy (ApEn) and sample entropy (SampEn) are mathematical algorithms created to measure the repeatability or predictability within a time series. Both algorithms are extremely sensitive to their input parameters: m (length of the data segment being compared), r (similarity criterion), and N (length of data). There is no established consensus on parameter selection in short data sets, especially for biological data. Therefore, the purpose of this research was to examine the robustness of these two entropy algorithms by exploring the effect of changing parameter values on short data sets. Data with known theoretical entropy qualities as well as experimental data from both healthy young and older adults was utilized. Our results demonstrate that both ApEn and SampEn are extremely sensitive to parameter choices, especially for very short data sets, N ≤ 200. We suggest using N larger than 200, an m of 2 and examine several r values before selecting your parameters. Extreme caution should be used when choosing parameters for experimental studies with both algorithms. Based on our current findings, it appears that SampEn is more reliable for short data sets. SampEn was less sensitive to changes in data length and demonstrated fewer problems with relative consistency.

Effects of a low-volume, vigorous intensity step exercise program on functional mobility in middle-aged adults.

Aging-related decline in functional mobility is associated with loss of independence. This decline may be mitigated through programs of physical activity. Despite reports of aging-related mobility impairment in middle-aged adults, this age group has been largely overlooked in terms of exercise programs that target functional mobility and the preservation of independence in older age. A method to quantitatively assess changes in functional mobility could direct rehabilitation in a proactive rather than reactive manner. Thirty-three healthy but sedentary middle-aged adults participated in a four week low-volume, vigorous intensity stepping exercise program. Two baseline testing sessions and one post-training testing session were conducted. Functional mobility was assessed using the timed up and go (TUG) test, with its constituent sit-to-walk and walk-to-sit phases examined using a novel inertial sensor-based method. Additionally, semi-tandem balance and knee extensor muscle isometric torque were assessed. Trunk acceleration during walk-to-sit reduced significantly post-training, suggesting altered movement control due to the exercise program. No significant training-induced changes in sit-to-walk acceleration, TUG time, balance or torque were observed. The novel method of functional mobility assessment presented provides a reliable means to quantify subtle changes in mobility during postural transitions. Over time, this exercise program may improve functional mobility.

Cks confers specificity to phosphorylation-dependent CDK signaling pathways.

Cks is an evolutionarily conserved protein that regulates cyclin-dependent kinase (CDK) activity. Clarifying the underlying mechanisms and cellular contexts of Cks function is critical because Cks is essential for proper cell growth, and its overexpression has been linked to cancer. We observe that budding-yeast Cks associates with select phosphorylated sequences in cell cycle-regulatory proteins. We characterize the molecular interactions responsible for this specificity and demonstrate that Cks enhances CDK activity in response to specific priming phosphosites. Identification of the binding consensus sequence allows us to identify putative Cks-directed CDK substrates and binding partners. We characterize new Cks-binding sites in the mitotic regulator Wee1 and discover a new role for Cks in regulating CDK activity at mitotic entry. Together, our results portray Cks as a multifunctional phosphoadaptor that serves as a specificity factor for CDK activity.

Peripheral arterial disease affects the frequency response of ground reaction forces during walking.

BACKGROUND: Walking is problematic for patients with peripheral arterial disease. The purpose of this study was to investigate the frequency domain of the ground reaction forces during walking to further elucidate the ambulatory impairment of these patients. METHODS: Nineteen bilateral peripheral arterial disease patients and nineteen controls were included in this study. Subjects were matched for age and gait speed. Participants walked over a force plate sampling at 600 Hz. PAD patients were tested before (pain-free condition) after the onset of claudication symptoms (pain). We calculated median frequency, frequency bandwidth, and frequency containing 99.5% of the signal for the vertical and anterior-posterior ground reaction forces. FINDINGS: Our results showed reduced median frequency in the vertical and anterior-posterior components of the ground reaction forces between the control group and both peripheral arterial disease conditions. We found reduced frequency bandwidth in the anterior-posterior direction between controls and the peripheral arterial disease pain-free condition. There were no differences in median frequency or bandwidth between peripheral arterial disease pain-free and pain conditions, but an increase in the frequency content for 99.5% of the signal was observed in the pain condition. INTERPRETATION: Reduced frequency phenomena during gait in peripheral arterial disease patients compared to velocity-matched controls suggests more sluggish activity within the neuromotor system. Increased frequency phenomena due to pain in these patients suggest a more erratic application of propulsive forces when walking. Frequency domain analysis thus offers new insights into the gait impairments associated with this patient population.

Displacement of centre of mass during quiet standing assessed using accelerometry in older fallers and non-fallers.

Postural sway during quiet standing is associated with falls risk in older adults. The aim of this study was to investigate the utility of a range of accelerometer-derived parameters of centre of mass (COM) displacement in identifying older adults at risk of falling. A series of instrumented standing balance trials were performed to investigate postural control in a group of older adults, categorised as fallers or non-fallers. During each trial, participants were asked to stand as still as possible under two conditions: comfortable stance (six repetitions) and semi-tandem stance (three repetitions). A tri-axial accelerometer was secured to the lower back during the trials. Accelerometer data were twice integrated to estimate COM displacement during the trials, with numerical techniques used to reduce integration error. Anterior-posterior (AP) and medial-lateral (ML) sway range, sway length and sway velocity were examined, along with root mean squared (RMS) acceleration. All derived parameters significantly discriminated fallers from non-fallers during both comfortable and semi-tandem stance. Results indicate that these accelerometer-based estimates of COM displacement may improve the discriminative power of quiet standing falls risk assessments, with potential for use in unsupervised balance assessment.