Complex temporal patterns in molecular dynamics:a direct measure of the phase-space exploration by the trajectory at macroscopic time scales

Computer simulated trajectories of bulk water molecules form complex spatiotemporal structures at the picosecond time scale. This intrinsic complexity, which underlies the formation of molecular structures at longer time scales, has been quantified using a measure of statistical complexity. The method estimates the information contained in the molecular trajectory by detecting and quantifying temporal patterns present in the simulated data (velocity time series). Two types of temporal patterns are found. The first, defined by the short-time correlations corresponding to the velocity autocorrelation decay times (â‰0.1â€ps), remains asymptotically stable for time intervals longer than several tens of nanoseconds. The second is caused by previously unknown longer-time correlations (found at longer than the nanoseconds time scales) leading to a value of statistical complexity that slowly increases with time. A direct measure based on the notion of statistical complexity that describes how the trajectory explores the phase space and independent from the particular molecular signal used as the observed time series is introduced. © 2008 The American Physical Society.

Visualising and controlling the flow in biomolecular systems at and between multiple scales:from atoms to hydrodynamics at different locations in time and space

A novel framework for modelling biomolecular systems at multiple scales in space and time simultaneously is described. The atomistic molecular dynamics representation is smoothly connected with a statistical continuum hydrodynamics description. The system behaves correctly at the limits of pure molecular dynamics (hydrodynamics) and at the intermediate regimes when the atoms move partly as atomistic particles, and at the same time follow the hydrodynamic flows. The corresponding contributions are controlled by a parameter, which is defined as an arbitrary function of space and time, thus, allowing an effective separation of the atomistic 'core' and continuum 'environment'. To fill the scale gap between the atomistic and the continuum representations our special purpose computer for molecular dynamics, MDGRAPE-4, as well as GPU-based computing were used for developing the framework. These hardware developments also include interactive molecular dynamics simulations that allow intervention of the modelling through force-feedback devices.

Spatial patterns of asynuclein positive glial cytoplasmic inclusions in multiple system atrophy

In cases of multiple system atrophy (MSA), glial cytoplasmic inclusions (GCI) were distributed randomly or present in large diffuse clusters (>1,600 μm in diameter) in most areas studied. These spatial patterns contrast with those reported for filamentous neuronal inclusions in the tauopathies and α-synucleinopathies. © 2003 Movement Disorder Society.

Clustering of neuronal inclusions in "dementia with neurofilament inclusions"

Dementia with neurofilament inclusions (DNI) is a new disorder characterized clinically by early-onset dementia and histologically by the presence of intraneural inclusions immunopositive for neurofilament antigens but lacking tau and α-synuclein reactivity. We studied the clustering patterns of the neurofilament inclusions (NI) in regions of the temporal lobe in three cases of DNI to determine whether they have the same spatial patterns as inclusions in the tauopathies and α-synucleinopathies. The NI exhibited a clustered distribution (mean size of clusters 400 μm, range 50-800 μm, SD 687.8) in 24/28 of the areas studied. In 22 of these areas, the clusters exhibited a regular distribution along the tissue parallel to the pia mater or alveus. In 3 cortical areas, there was evidence of a more complex pattern in which the NI clusters were aggregated into larger superclusters. In 6 cortical areas, the size of the clusters approximated to those of the cells of origin of the cortico-cortical pathways but in the remaining areas cluster size was smaller than 400 μm. Despite the unique molecular profile of the NI, their spatial patterns are similar to those shown by filamentous neuronal inclusions in the tauopathies and α-synucleinopathies.

Product variety and just-in-time conflict and challenge

This paper addresses the question of how just-in-time can be implemented within high variety manufacture. To illustrate some of the principles in relation to the high variety-low volume situation the case of a computer manufacturer is considered in detail. For contrast the paper also considers the case of the manufacture of highly-configured four wheel drive vehicles where both variety and volumes are high. The most important issue in high variety/low volume production is that JIT operation should be seen in terms of the tactical holding of inventory in upstream buffers within the supply chain so that value is not added to work in progress prematurely. Tactical buffers ensure that service levels are maintained and the risk of stock-outs is minimized. In high variety/high volume production schedule integrity is the key factor, unreliable schedules being a major inhibitor to the introduction of JIT.

Laminar distribution of ballooned neurons and tau positive neurons with inclusions in patients with corticobasal degeneration

The laminar distribution of ballooned neurons (BN) and tau positive neurons with inclusions (tau+ neurons) was studied in the frontal and temporal cortex in twelve patients with corticobasal degeneration (CBD). In the majority of brain areas, the density of BN and tau+ neurons was maximal in the lower and upper cortical laminae respectively. The densities of tau+ neurons in the upper and lower cortex were positively correlated. In the majority of brain areas, however, no correlations were observed between the densities of BN and tau+ neurons. The laminar distribution of the BN may reflect the degeneration of the feedback cortico-cortical and/or the efferent cortical pathways. By contrast, the distribution of the tau+ neurons may reflect the degeneration of the feed-forward cortico-cortical pathways. In addition, BN and tau+ neurons may arise as a result of distinct pathological processes.

A morphometric study of the spatial patterns of TDP-43 immunoreactive neuronal inclusions in frontotemporal lobar degeneration (FTLD) with progranulin (GRN) mutation

Mutations of the progranulin (GRN) gene are a major cause of familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). We studied the spatial patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and neuronal intranuclear inclusions (NII) in histological sections of the frontal and temporal lobe in eight cases of FTLD-TDP with GRN mutation using morphometric methods and spatial pattern analysis. In neocortical regions, the NCI were clustered and the clusters were regularly distributed parallel to the pia mater; 58% of regions analysed exhibiting this pattern. The NII were present in regularly distributed clusters in 35% of regions but also randomly distributed in many areas. In neocortical regions, the sizes of the regular clusters of NCI and NII were 400-800 µm, approximating to the size of the modular columns of the cortico-cortical projections, in 31% and 36% of regions respectively. The NCI and NII also exhibited regularly spaced clustering in sectors CA1/2 of the hippocampus and in the dentate gyrus. The clusters of NCI and NII were not spatially correlated. The data suggest degeneration of the cortico-cortical and cortico-hippocampal pathways in FTLD-TDP with GRN mutation, the NCI and NII affecting different clusters of neurons.

The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of familial amyotrophic lateral sclerosis with FUS mutation, NIFID, basophilic inclusion body disease, and atypical FTLD with ubiquitin-immunoreactive inclusions (aFTLD-U). To further characterize FUS proteinopathy in NIFID, and to determine whether the pathology revealed by FUS immunohistochemistry (IHC) is more extensive than a-internexin, we have undertaken a quantitative assessment of ten clinically and neuropathologically well-characterized cases using FUS IHC. The densities of NCI were greatest in the dentate gyrus (DG) and in sectors CA1/2 of the hippocampus. Anti-FUS antibodies also labeled glial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN). Vacuolation was extensive across upper and lower cortical layers. Significantly greater densities of abnormally enlarged neurons and glial cell nuclei were present in the lower compared with the upper cortical laminae. FUS IHC revealed significantly greater numbers of NCI in all brain regions especially the DG. Our data suggest: (1) significant densities of FUS-immunoreactive NCI in NIFID especially in the DG and CA1/2; (2) infrequent FUS-immunoreactive GI, NII, and DN; (3) widely distributed vacuolation across the cortex, and (4) significantly more NCI revealed by FUS than a-internexin IHC.

Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease:a comparative study of eight disorders

Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer's disease, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the 'fused in sarcoma' (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400-800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders. © 2012 Springer-Verlag.

Impact of just-in-time on job content, employee attitudes and well-being:a longitudinal study

Just-in-time (JIT) production systems are increasingly being seen as a vital way for manufacturing organizations to enhance their competitiveness. A number of commentators have suggested that this will simplify jobs and reduce employee well-being. This paper presents a conceptual framework for interpreting the effects of JIT and reports findings from a study of the impact of JIT on the content of workers'jobs and on job satisfaction and psychological strain. The introduction of JIT led to a reduction in control over work timing, an increase in production pressure, and a drop in job satisfaction. Contrary to claims in the literature, no changes were found in control over work methods, other aspects of cognitive demands and skill use, and in psychological strain. The study shows that JIT can be implemented without radical changes in job content or adverse impact in terms of employee strain, and the implications of these findings are discussed.

Experiments in time:exploring the components of motor timing behaviour in dyslexia

This investigation aimed to pinpoint the elements of motor timing control that are responsible for the increased variability commonly found in children with developmental dyslexia on paced or unpaced motor timing tasks (Chapter 3). Such temporal processing abilities are thought to be important for developing the appropriate phonological representations required for the development of literacy skills. Similar temporal processing difficulties arise in other developmental disorders such as Attention Deficit Hyperactivity Disorder (ADHD). Motor timing behaviour in developmental populations was examined in the context of models of typical human timing behaviour, in particular the Wing-Kristofferson model, allowing estimation of the contribution of different timing control systems, namely timekeeper and implementation systems (Chapter 2 and Methods Chapters 4 and 5). Research examining timing in populations with dyslexia and ADHD has been inconsistent in the application of stimulus parameters and so the first investigation compared motor timing behaviour across different stimulus conditions (Chapter 6). The results question the suitability of visual timing tasks which produced greater performance variability than auditory or bimodal tasks. Following an examination of the validity of the Wing-Kristofferson model (Chapter 7) the model was applied to time series data from an auditory timing task completed by children with reading difficulties and matched control groups (Chapter 8). Expected group differences in timing performance were not found, however, associations between performance and measures of literacy and attention were present. Results also indicated that measures of attention and literacy dissociated in their relationships with components of timing, with literacy ability being correlated with timekeeper variance and attentional control with implementation variance. It is proposed that these timing deficits associated with reading difficulties are attributable to central timekeeping processes and so the contribution of error correction to timing performance was also investigated (Chapter 9). Children with lower scores on measures of literacy and attention were found to have a slower or failed correction response to phase errors in timing behaviour. Results from the series of studies suggest that the motor timing difficulty in poor reading children may stem from failures in the judgement of synchrony due to greater tolerance of uncertainty in the temporal processing system.

Cortical mechanisms of attention in time:neural correlates of the Lag-1-sparing phenomenon

If humans monitor streams of rapidly presented (approximately 100-ms intervals) visual stimuli, which are typically specific single letters of the alphabet, for two targets (T1 and T2), they often miss T2 if it follows T1 within an interval of 200-500 ms. If T2 follows T1 directly (within 100 ms; described as occurring at 'Lag 1'), however, performance is often excellent: the so-called 'Lag-1 sparing' phenomenon. Lag-1 sparing might result from the integration of the two targets into the same 'event representation', which fits with the observation that sparing is often accompanied by a loss of T1-T2 order information. Alternatively, this might point to competition between the two targets (implying a trade-off between performance on T1 and T2) and Lag-1 sparing might solely emerge from conditional data analysis (i.e. T2 performance given T1 correct). We investigated the neural correlates of Lag-1 sparing by carrying out magnetoencephalography (MEG) recordings during an attentional blink (AB) task, by presenting two targets with a temporal lag of either 1 or 2 and, in the case of Lag 2, with a nontarget or a blank intervening between T1 and T2. In contrast to Lag 2, where two distinct neural responses were observed, at Lag 1 the two targets produced one common neural response in the left temporo-parieto-frontal (TPF) area but not in the right TPF or prefrontal areas. We discuss the implications of this result with respect to competition and integration hypotheses, and with respect to the different functional roles of the cortical areas considered. We suggest that more than one target can be identified in parallel in left TPF, at least in the absence of intervening nontarget information (i.e. masks), yet identified targets are processed and consolidated as two separate events by other cortical areas (right TPF and PFC, respectively).

Accurate modelling of pulse transformation by adjustable-in-time medium parameters

A possibility of a strong change of an electromagnetic signal by a short sequence of time cycles of pulses that modulate the medium parameters is shown. The backward wave is demonstrated to be an inevitable result of the medium time change. Dependence of the relation between backward and forward waves on the parameters of the medium modulation is investigated. The finite statistical complexity of the electromagnetic signal transformed by a finite sequence of modulating cycles is calculated. Increase of the complexity with the number of cycles is shown.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.