A model for mesoscale patterns in motile populations

Experimental observations of cell migration often describe the presence of mesoscale patterns within motile cell populations. These patterns can take the form of cells moving as aggregates or in chain-like formation. Here we present a discrete model capable of producing mesoscale patterns. These patterns are formed by biasing movements to favor a particular configuration of agent–agent attachments using a binding function f(K), where K is the scaled local coordination number. This discrete model is related to a nonlinear diffusion equation, where we relate the nonlinear diffusivity D(C) to the binding function f. The nonlinear diffusion equation supports a range of solutions which can be either smooth or discontinuous. Aggregation patterns can be produced with the discrete model, and we show that there is a transition between the presence and absence of aggregation depending on the sign of D(C). A combination of simulation and analysis shows that both the existence of mesoscale patterns and the validity of the continuum model depend on the form of f. Our results suggest that there may be no formal continuum description of a motile system with strong mesoscale patterns.

Remaining useful life prediction using elliptical basis function network and Markov Chain

This paper presents a novel method for remaining useful life prediction using the Elliptical Basis Function (EBF) network and a Markov chain. The EBF structure is trained by a modified Expectation-Maximization (EM) algorithm in order to take into account the missing covariate set. No explicit extrapolation is needed for internal covariates while a Markov chain is constructed to represent the evolution of external covariates in the study. The estimated external and the unknown internal covariates constitute an incomplete covariate set which are then used and analyzed by the EBF network to provide survival information of the asset. It is shown in the case study that the method slightly underestimates the remaining useful life of an asset which is a desirable result for early maintenance decision and resource planning.

The effects of muscle fatigue on knee function during landing

The human knee acts as a sophisticated shock absorber during landing movements. The ability of the knee to perform this function in the real world is remarkable given that the context of the landing movement may vary widely between performances. For this reason, humans must be capable of rapidly adjusting the mechanical properties of the knee under impact load in order to satisfy many competing demands. However, the processes involved in regulating these properties in response to changing constraints remain poorly understood. In particular, the effects of muscle fatigue on knee function during step landing are yet to be fully explored. Fatigue of the knee muscles is significant for 2 reasons. First, it is thought to have detrimental effects on the ability of the knee to act as a shock absorber and is considered a risk factor for knee injury. Second, fatigue of knee muscles provides a unique opportunity to examine the mechanisms by which healthy individuals alter knee function. A review of the literature revealed that the effect of fatigue on knee function during landing has been assessed by comparing pre and postfatigue measurements, with fatigue induced by a voluntary exercise protocol. The information is limited by inconsistent results with key measures, such as knee stiffness, showing varying results following fatigue, including increased stiffness, decreased stiffness or failure to detect any change in some experiments. Further consideration of the literature questions the validity of the models used to induce and measure fatigue, as well as the pre-post study design, which may explain the lack of consensus in the results. These limitations cast doubt on the usefulness of the available information and identify a need to investigate alternative approaches. Based on the results of this review, the aims of this thesis were to: • evaluate the methodological procedures used in validation of a fatigue model • investigate the adaptation and regulation of post-impact knee mechanics during repeated step landings • use this new information to test the effects of fatigue on knee function during a step-landing task. To address the aims of the thesis, 3 related experiments were conducted that collected kinetic, kinematic and electromyographic data from 3 separate samples of healthy male participants. The methodologies involved optoelectronic motion capture (VICON), isokinetic dynamometry (System3 Pro, BIODEX) and wireless surface electromyography (Zerowire, Aurion, Italy). Fatigue indicators and knee function measures used in each experiment were derived from the data. Study 1 compared the validity and reliability of repetitive stepping and isokinetic contractions with respect to fatigue of the quadriceps and hamstrings. Fifteen participants performed 50 repetitions of each exercise twice in randomised order, over 4 sessions. Sessions were separated by a minimum of 1 week’s rest, to ensure full recovery. Validity and reliability depended on a complex interaction between the exercise protocol, the fatigue indicator, the individual and the muscle of interest. Nevertheless, differences between exercise protocols indicated that stepping was less effective in eliciting valid and reliable changes in peak power and spectral compression, compared with isokinetic exercise. A key finding was that fatigue progressed in a biphasic pattern during both exercises. The point separating the 2 phases, known as the transition point, demonstrated superior between-test reliability during the isokinetic protocol, compared with stepping. However, a correction factor should be used to accurately apply this technique to the study of fatigue during landing. Study 2 examined alterations in knee function during repeated landings, with a different sample (N =12) performing 60 consecutive step landing trials. Each landing trial was separated by 1-minute rest periods. The results provided new information in relation to the pre-post study design in the context of detecting adjustments in knee function during landing. First, participants significantly increased or decreased pre-impact muscle activity or post-impact mechanics despite environmental and task constraints remaining unchanged. This is the 1st study to demonstrate this effect in healthy individuals without external feedback on performance. Second, single-subject analysis was more effective in detecting alterations in knee function compared to group-level analysis. Finally, repeated landing trials did not reduce inter-trial variability of knee function in some participants, contrary to assumptions underpinning previous studies. The results of studies 1 and 2 were used to modify the design of Study 3 relative to previous research. These alterations included a modified isokinetic fatigue protocol, multiple pre-fatigue measurements and singlesubject analysis to detect fatigue-related changes in knee function. The study design incorporated new analytical approaches to investigate fatiguerelated alterations in knee function during landing. Participants (N = 16) were measured during multiple pre-fatigue baseline trial blocks prior to the fatigue model. A final block of landing trials was recorded once the participant met the operational fatigue definition that was identified in Study 1. The analysis revealed that the effects of fatigue in this context are heavily dependent on the compensatory response of the individual. A continuum of responses was observed within the sample for each knee function measure. Overall, preimpact preparation and post-impact mechanics of the knee were altered with highly individualised patterns. Moreover, participants used a range of active or passive pre-impact strategies to adapt post-impact mechanics in response to quadriceps fatigue. The unique patterns identified in the data represented an optimisation of knee function based on priorities of the individual. The findings of these studies explain the lack of consensus within the literature regarding the effects of fatigue on knee function during landing. First, functional fatigue protocols lack validity in inducing fatigue-related changes in mechanical output and spectral compression of surface electromyography (sEMG) signals, compared with isokinetic exercise. Second, fatigue-related changes in knee function during landing are confounded by inter-individual variation, which limits the sensitivity of group-level analysis. By addressing these limitations, the 3rd study demonstrated the efficacies of new experimental and analytical approaches to observe fatigue-related alterations in knee function during landing. Consequently, this thesis provides new perspectives into the effects of fatigue in knee function during landing. In conclusion: • The effects of fatigue on knee function during landing depend on the response of the individual, with considerable variation present between study participants, despite similar physical characteristics. • In healthy males, adaptation of pre-impact muscle activity and postimpact knee mechanics is unique to the individual and reflects their own optimisation of demands such as energy expenditure, joint stability, sensory information and loading of knee structures. • The results of these studies should guide future exploration of adaptations in knee function to fatigue. However, research in this area should continue with reduced emphasis on the directional response of the population and a greater focus on individual adaptations of knee function.

Predictors of future falls in Parkinson disease

Background: Falls are a major health and injury problem for people with Parkinson disease (PD). Despite the severe consequences of falls, a major unresolved issue is the identification of factors that predict the risk of falls in individual patients with PD. The primary aim of this study was to prospectively determine an optimal combination of functional and disease-specific tests to predict falls in individuals with PD. ----- ----- Methods: A total of 101 people with early-stage PD undertook a battery of neurologic and functional tests in their optimally medicated state. The tests included Tinetti, Berg, Timed Up and Go, Functional Reach, and the Physiological Profile Assessment of Falls Risk; the latter assessment includes physiologic tests of visual function, proprioception, strength, cutaneous sensitivity, reaction time, and postural sway. Falls were recorded prospectively over 6 months. ----- ----- Results: Forty-eight percent of participants reported a fall and 24% more than 1 fall. In the multivariate model, a combination of the Unified Parkinson's Disease Rating Scale (UPDRS) total score, total freezing of gait score, occurrence of symptomatic postural orthostasis, Tinetti total score, and extent of postural sway in the anterior-posterior direction produced the best sensitivity (78%) and specificity (84%) for predicting falls. From the UPDRS items, only the rapid alternating task category was an independent predictor of falls. Reduced peripheral sensation and knee extension strength in fallers contributed to increased postural instability. ----- ----- Conclusions: Falls are a significant problem in optimally medicated early-stage PD. A combination of both disease-specific and balance- and mobility-related measures can accurately predict falls in individuals with PD.

Simulated cataract and low contrast stimuli impair cognitive performance in older adults : implications for neuropsychological assessment and everyday function

Objective: To investigate how age-related declines in vision (particularly contrast sensitivity), simulated using cataract-goggles and low-contrast stimuli, influence the accuracy and speed of cognitive test performance in older adults. An additional aim was to investigate whether declines in vision differentially affect secondary more than primary memory. Method: Using a fully within-subjects design, 50 older drivers aged 66-87 years completed two tests of cognitive performance - letter matching (perceptual speed) and symbol recall (short-term memory) - under different viewing conditions that degraded visual input (low-contrast stimuli, cataract-goggles, and low-contrast stimuli combined with cataract-goggles, compared with normal viewing). However, presentation time was also manipulated for letter matching. Visual function, as measured using standard charts, was taken into account in statistical analyses. Results: Accuracy and speed for cognitive tasks were significantly impaired when visual input was degraded. Furthermore, cognitive performance was positively associated with contrast sensitivity. Presentation time did not influence cognitive performance, and visual gradation did not differentially influence primary and secondary memory. Conclusion: Age-related declines in visual function can impact on the accuracy and speed of cognitive performance, and therefore the cognitive abilities of older adults may be underestimated in neuropsychological testing. It is thus critical that visual function be assessed prior to testing, and that stimuli be adapted to older adults' sensory capabilities (e.g., by maximising stimuli contrast).

Are Active Australia physical activity questions valid for older adults?

Objective The Active Australia Survey (AAS) is used for physical activity (PA) surveillance in the general Australian adult population, but its validity in older adults has not been evaluated. Our aim was to examine the convergent validity of the AAS questions in older adults. Design The AAS was validated against pedometer step counts as an objective measure of PA, self-reported physical function, and a step-test to assess cardiorespiratory fitness. Method Participants were community-dwelling adults, aged 65-89 y, with the ability to walk 100 m. They completed a self-administered AAS and the step-test in one interview. One week earlier, they completed the Short Form-36 physical function subscale. Between these two interviews, they each wore a YAMAX Digiwalker SW200 pedometer and recorded daily steps. Using the AAS data, daily walking minutes and total PA minutes (walking, moderate-intensity PA and vigorous-intensity PA) were compared with the validity measures using Spearman rank-order correlations. Fifty-three adults completed the study. Results Median daily walking minutes were 34.2 (interquartile range [IQR] 17.1, 60.0), and median daily total PA minutes were 68.6 (IQR 31.4, 113.6). Walking and total PA minutes were both moderately correlated with pedometer steps (Spearman correlation r=0.42, p=0.003, for each) but not with step-test seconds to completion (r=-0.11, p=0.44; r=-0.25, p=0.08, respectively). Total PA minutes were significantly correlated with physical function scores (r=0.39, p=0.004), but walking minutes were not (r=0.15, p=0.29). Conclusions This initial examination of the psychometric properties of the AAS for older adults suggests that this surveillance tool has acceptable convergent validity for ambulatory, community-dwelling older adults.

Patient education to prevent falls among older hospital inpatients : a randomized controlled trial

Background Falls are a common adverse event during hospitalization of older adults, and few interventions have been shown to prevent then. Methods This study was a 3-group randomized trial to evaluate the efficacy of 2 forms of multimedia patient education compared with usual care for the prevention of in-hospital falls. Older hospital patients (n = 1206) admitted to a mixture of acute (orthopedic, respiratory, and medical) and subacute (geriatric and neurorehabilitation) hospital wards at 2 Australian hospitals were recruited between January 2008 and April 2009. The interventions were a multimedia patient education program based on the health-belief model combined with trained health professional follow-up (complete program), multi-media patient education materials alone (materials only), and usual care (control). Falls data were collected by blinded research assistants by reviewing hospital incident reports, hand searching medical records, and conducting weekly patient interviews. Results Rates of falls per 1000 patient-days did not differ significantly between groups (control, 9.27; materials only, 8.61; and complete program, 7.63). However, there was a significant interaction between the intervention and presence of cognitive impairment. Falls were less frequent among cognitively intact patients in the complete program group (4.01 per 1000 patient-days) than among cognitively intact patients in the materials-only group (8.18 per 1000 patient-days) (adjusted hazard ratio, 0.51; 95% confidence interval, 0.28-0.93]) and control group (8.72 per 1000 patient-days) (adjusted hazard ratio, 0.43; 95% confidence interval, 0.24-0.78). Conclusion Multimedia patient education with trained health professional follow-up reduced falls among patients with intact cognitive function admitted to a range of hospital wards.

Executive function effects and numerical development in children : behavioural and ERP evidence from a numerical Stroop paradigm

Most research on numerical development in children is behavioural, focusing on accuracy and response time in different problem formats. However, Temple and Posner (1998) used ERPs and the numerical distance task with 5-year-olds to show that the development of numerical representations is difficult to disentangle from the development of the executive components of response organization and execution. Here we use the numerical Stroop paradigm (NSP) and ERPs to study possible executive interference in numerical processing tasks in 6–8-year-old children. In the NSP, the numerical magnitude of the digits is task-relevant and the physical size of the digits is task-irrelevant. We show that younger children are highly susceptible to interference from irrelevant physical information such as digit size, but that access to the numerical representation is almost as fast in young children as in adults. We argue that the developmental trajectories for executive function and numerical processing may act together to determine numerical development in young children.

Physical function and health-related quality of life of older adults undergoing hospital rehabilitation : how strong is the association?

The purpose of this research is to report preliminary empirical evidence regarding the association between common physical performance measures and health-related quality of life (HRQoL) of hospitalized older adults recovering from illness and injury. Frequently, these patients do not return to premorbid levels of independence and physical ability. Rehabilitation for this population often focuses on improving physical functioning and mobility with the intention of maximizing their HRQoL for discharge and thereafter. For this reason, longitudinal use of physical performance measures as an indicator of improvement in physical functioning (and thus HRQoL) is common. Although this is a logical approach, there have been mixed results from previous investigations into the association between common measures of physical function and HRQoL amongst other adult patient populations.1,2 There has been no previous investigation reporting the association between HRQoL and a variety of common physical performance measures in hospitalized older adults.

Implementation results of efficient trajectories on a testbed AUV

In this paper we consider the implementation of time and energy efficient trajectories onto a test-bed autonomous underwater vehicle. The trajectories are losely connected to the results of the application of the maximum principle to the controlled mechanical system. We use a numerical algorithm to compute efficient trajectories designed using geometric control theory to optimize a given cost function. Experimental results are shown for the time minimization problem.

Cognitive skills required in contemporary workplaces

This paper discusses some of the changes occurring in contemporary workplace practices, and the implications these have for the types of knowledge and skills required to work in such environments. Increasingly, workers need to be multi-skilled to function effectively in contemporary work environments. The nature of multi-skilling is explained in terms of cross-skilling, up-skilling and higher-order thinking skills, and the relevance of multi-skilling in today's workplaces is examined. Finally, the paper explores some factors affecting the acquisition of these desired skills in light of current work practices.

Insulin-like growth factor-i : vitronectin complex-induced changes in gene expression effect breast cell survival and migration

Recent studies have demonstrated that IGF-I associates with VN through IGF-binding proteins (IGFBP) which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment and migration. Since IGFs play important roles in transformation and progression of breast tumours, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of PI3-K/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and PI3-K pathways confirms that both pathways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS-1). These changes were not detected when the IGF-I analogue (\[L24]\[A31]-IGF-I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of ECM and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression.

Chlamydial infection of immune cells : altered function and implications for disease

Chlamydia trachomatis is an obligate intracellular bacterial pathogen that infects the genital and ocular mucosa of humans, causing infections that can lead to pelvic inflammatory disease, infertility, and blinding trachoma. C. pneumoniae is a respiratory pathogen that is the cause of 12–15% of community-acquired pneumonia. Both chlamydial species were believed to be restricted to the epithelia of the genital, ocular, and respiratory mucosa; however, increasing evidence suggests that both these pathogens can be isolated from peripheral blood of both healthy individuals and patients with inflammatory conditions such as coronary artery disease and asthma. Chlamydia can also be isolated from brain tissues of patients with degenerative neurological disorders such as Alzheimer’s disease and multiple sclerosis, and also from certain lymphomas. An increasing number of in vitro studies suggest that some chlamydial species can infect immune cells, at least at low levels. These infections may alter immune cell function in a way that promotes chlamydial persistence in the host and contributes to the progression of several chronic inflammatory diseases. In this paper, we review the evidence for the growth of Chlamydia in immune cells, particularly monocytes/macrophages and dendritic cells, and describe how infection may affect the function of these cells.

ATM mediated phosphorylation of CHD4 contributes to genome maintenance

Background: In order to maintain cellular viability and genetic integrity cells must respond quickly following the induction of cytotoxic double strand DNA breaks (DSB). This response requires a number of processes including stabilisation of the DSB, signalling of the break and repair. It is becoming increasingly apparent that one key step in this process is chromatin remodelling. Results: Here we describe the chromodomain helicase DNA-binding protein (CHD4) as a target of ATM kinase. We show that ionising radiation (IR)-induced phosphorylation of CHD4 affects its intranuclear organization resulting in increased chromatin binding/retention. We also show assembly of phosphorylated CHD4 foci at sites of DNA damage, which might be required to fulfil its function in the regulation of DNA repair. Consistent with this, cells overexpressing a phospho-mutant version of CHD4 that cannot be phosphorylated by ATM fail to show enhanced chromatin retention after DSBs and display high rates of spontaneous damage. Conclusion: These results provide insight into how CHD4 phosphorylation might be required to remodel chromatin around DNA breaks allowing efficient DNA repair to occur.

Spatiotemporal investigations of DNA damage repair using microbeams

Cellular response to radiation damage is made by a complex network of pathways and feedback loops whose spatiotemporal organisation is still unclear despite its decisive role in determining the fate of the damaged cell. Revealing the dynamic sequence of the repair proteins is therefore critical in understanding how the DNA repair mechanisms work. There are also still open questions regarding the possible movement of damaged chromatin domains and its role as trigger for lesion recognition and signalling in the DNA repair context. The single-cell approach and the high spatial resolution offered by microbeams provide the perfect tool to study and quantify the dynamic processes associated with the induction and repair of DNA damage. We have followed the development of radiation-induced foci for three DNA damage markers (i.e. γ-H2AX, 53BP1 and hSSB1) using normal fibroblasts (AG01522), human breast adenocarcinoma cells (MCF7) and human fibrosarcoma cells (HT1080) stably transfected with yellow fluorescent protein fusion proteins following irradiation with the QUB X-ray microbeam (carbon X-rays <2 µm spot). The size and intensity of the foci has been analysed as a function of dose and time post-irradiation to investigate the dynamics of the above-mentioned DNA repair processes and monitor the remodelling of chromatin structure that the cell undergoes to deal with DNA damage.