CD73 and CD29 concurrently mediate the mechanically induced decrease of migratory capacity of mesenchymal stromal cells

The assumption that mesenchymal stromal cell (MSC)-based therapies are capable of augmenting physiological regeneration processes has fostered intensive basic and clinical research activities. However, to achieve sustained therapeutic success in vivo, not only the biological, but also the mechanical microenvironment of MSCs during these regeneration processes needs to be taken into account. This is especially important for e.g., bone fracture repair, since MSCs present at the fracture site undergo significant biomechanical stimulation. This study has therefore investigated cellular characteristics and the functional behaviour of MSCs in response to mechanical loading. Our results demonstrated a reduced expression of MSC surface markers CD73 (ecto-5’-nucleotidase) and CD29 (integrin β1) after loading. On the functional level, loading led to a reduced migration of MSCs. Both effects persisted for a week after the removal of the loading stimulus. Specifi c inhibition of CD73/CD29 demonstrated their substrate dependent involvement in MSC migration after loading. These results were supported by scanning electron microscopy images and phalloidin staining of actin fi laments displaying less cell spreading, lamellipodia formation and actin accumulations. Moreover, focal adhesion kinase and Src-family kinases were identified as candidate downstream targets of CD73/CD29 that might contribute to the mechanically induced decrease in MSC migration. These results suggest that MSC migration is controlled by CD73 CD29, which in turn are regulated by mechanical stimulation of cells. We therefore speculate that MSCs migrate into the fracture site, become mechanically entrapped, and thereby accumulate to fulfil their regenerative functions.

Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the post-illumination pupil response and circadian rhythm

Intrinsically photosensitive retinal ganglion cells (ipRGCs) in the eye transmit the environmental light level, projecting to the suprachiasmatic nucleus (SCN) (Berson, Dunn & Takao, 2002; Hattar, Liao, Takao, Berson & Yau, 2002), the location of the circadian biological clock, and the olivary pretectal nucleus (OPN) of the pretectum, the start of the pupil reflex pathway (Hattar, Liao, Takao, Berson & Yau, 2002; Dacey, Liao, Peterson, Robinson, Smith, Pokorny, Yau & Gamlin, 2005). The SCN synchronizes the circadian rhythm, a cycle of biological processes coordinated to the solar day, and drives the sleep/wake cycle by controlling the release of melatonin from the pineal gland (Claustrat, Brun & Chazot, 2005). Encoded photic input from ipRGCs to the OPN also contributes to the pupil light reflex (PLR), the constriction and recovery of the pupil in response to light. IpRGCs control the post-illumination component of the PLR, the partial pupil constriction maintained for > 30 sec after a stimulus offset (Gamlin, McDougal, Pokorny, Smith, Yau & Dacey, 2007; Kankipati, Girkin & Gamlin, 2010; Markwell, Feigl & Zele, 2010). It is unknown if intrinsic ipRGC and cone-mediated inputs to ipRGCs show circadian variation in their photon-counting activity under constant illumination. If ipRGCs demonstrate circadian variation of the pupil response under constant illumination in vivo, when in vitro ipRGC activity does not (Weng, Wong & Berson, 2009), this would support central control of the ipRGC circadian activity. A preliminary experiment was conducted to determine the spectral sensitivity of the ipRGC post-illumination pupil response under the experimental conditions, confirming the successful isolation of the ipRGC response (Gamlin, et al., 2007) for the circadian experiment. In this main experiment, we demonstrate that ipRGC photon-counting activity has a circadian rhythm under constant experimental conditions, while direct rod and cone contributions to the PLR do not. Intrinsic ipRGC contributions to the post-illumination pupil response decreased 2:46 h prior to melatonin onset for our group model, with the peak ipRGC attenuation occurring 1:25 h after melatonin onset. Our results suggest a centrally controlled evening decrease in ipRGC activity, independent of environmental light, which is temporally synchronized (demonstrates a temporal phase-advanced relationship) to the SCN mediated release of melatonin. In the future the ipRGC post-illumination pupil response could be developed as a fast, non-invasive measure of circadian rhythm. This study establishes a basis for future investigation of cortical feedback mechanisms that modulate ipRGC activity.

An examination of monotony and hypovigilance, independent of fatigue : relevance to road safety

Driving is a vigilance task, requiring sustained attention to maintain performance and avoid crashes. Hypovigilance (i.e., marked reduction in vigilance) while driving manifests as poor driving performance and is commonly attributed to fatigue (Dinges, 1995). However, poor driving performance has been found to be more frequent when driving in monotonous road environments, suggesting that monotony plays a role in generating hypovigilance (Thiffault & Bergeron, 2003b). Research to date has tended to conceptualise monotony as a uni-dimensional task characteristic, typically used over a prolonged period of time to facilitate other factors under investigation, most notably fatigue. However, more often than not, more than one exogenous factor relating to the task or operating environment is manipulated to vary or generate monotony (Mascord & Heath, 1992). Here we aimed to explore whether monotony is a multi-dimensional construct that is determined by characteristics of both the task proper and the task environment. The general assumption that monotony is a task characteristic used solely to elicit hypovigilance or poor performance related to fatigue appears to have led to there being little rigorous investigation into the exact nature of the relationship. While the two concepts are undoubtedly linked, the independent effect of monotony on hypovigilance remains largely ignored. Notwithstanding, there is evidence that monotony effects can emerge very early in vigilance tasks and are not necessarily accompanied by fatigue (see Meuter, Rakotonirainy, Johns, & Wagner, 2005). This phenomenon raises a largely untested, empirical question explored in two studies: Can hypovigilance emerge as a consequence of task and/or environmental monotony, independent of time on task and fatigue? In Study 1, using a short computerised vigilance task requiring responses to be withheld to infrequent targets, we explored the differential impacts of stimuli and task demand manipulations on the development of a monotonous context and the associated effects on vigilance performance (as indexed by respone errors and response times), independent of fatigue and time on task. The role of individual differences (sensation seeking, extroversion and cognitive failures) in moderating monotony effects was also considered. The results indicate that monotony affects sustained attention, with hypovigilance and associated performance worse in monotonous than in non-monotonous contexts. Critically, performance decrements emerged early in the task (within 4.3 minutes) and remained consistent over the course of the experiment (21.5 minutes), suggesting that monotony effects can operate independent of time on task and fatigue. A combination of low task demands and low stimulus variability form a monotonous context characterised by hypovigilance and poor task performance. Variations to task demand and stimulus variability were also found to independently affect performance, suggesting that monotony is a multi-dimensional construct relating to both task monotony (associated with the task itself) and environmental monotony (related to characteristics of the stimulus). Consequently, it can be concluded that monotony is multi-dimensional and is characterised by low variability in stimuli and/or task demands. The proposition that individual differences emerge under conditions of varying monotony with high sensation seekers and/or extroverts performing worse in monotonous contexts was only partially supported. Using a driving simulator, the findings of Study 1 were extended to a driving context to identify the behavioural and psychophysiological indices of monotony-related hypovigilance associated with variations to road design and road side scenery (Study 2). Supporting the proposition that monotony is a multi-dimensional construct, road design variability emerged as a key moderating characteristic of environmental monotony, resulting in poor driving performance indexed by decrements in steering wheel measures (mean lateral position). Sensation seeking also emerged as a moderating factor, where participants high in sensation seeking tendencies displayed worse driving behaviour in monotonous conditions. Importantly, impaired driving performance was observed within 8 minutes of commencing the driving task characterised by environmental monotony (low variability in road design) and was not accompanied by a decline in psychophysiological arousal. In addition, no subjective declines in alertness were reported. With fatigue effects associated with prolonged driving (van der Hulst, Meijman, & Rothengatter, 2001) and indexed by drowsiness, this pattern of results indicates that monotony can affect driver vigilance, independent of time on task and fatigue. Perceptual load theory (Lavie, 1995, 2005) and mindlessness theory (Robertson, Manly, Andrade, Baddley, & Yiend, 1997) provide useful theoretical frameworks for explaining and predicting monotony effects by positing that the low load (of task and/or stimuli) associated with a monotonous task results in spare attentional capacity which spills over involuntarily, resulting in the processing of task-irrelevant stimuli or task unrelated thoughts. That is, individuals – even when not fatigued - become easily distracted when performing a highly monotonous task, resulting in hypovigilance and impaired performance. The implications for road safety, including the likely effectiveness of fatigue countermeasures to mitigate monotony-related driver hypovigilance are discussed.

Right to the city, desire for the suburb?

The 2000s have been a lively decade for cities. The Worldwatch Institute estimated that 2007 was the first year in human history that more people worldwide lived in cities than the countryside. Globalisation and new digital media technologies have generated the seemingly paradoxical outcome that spatial location came to be more rather than less important, as combinations of firms, industries, cultural activities and creative talents have increasingly clustered around a select node of what have been termed “creative cities,” that are in turn highly networked into global circuits of economic capital, political power and entertainment media. Intellectually, the period has seen what the UCLA geographer Ed Soja refers to as the spatial turn in social theory, where “whatever your interests may be, they can be significantly advanced by adopting a critical spatial perspective”. This is related to the dynamic properties of socially constructed space itself, or what Soja terms “the powerful forces that arise from socially produced spaces such as urban agglomerations and cohesive regional economies,” with the result that “what can be called the stimulus of socio-spatial agglomeration is today being assertively described as the primary cause of economic development, technological innovation, and cultural creativity”

The effect of ocular surface conditions on blink rate and completeness

A healthy human would be expected to show periodic blinks, making a brief closure of the eyelids. Most blinks are spontaneous, occurring regularly with no external stimulus. However a reflex blink can occur in response to external stimuli such as a bright light, a sudden loud noise, or an object approaching toward the eyes. A voluntary or forced blink is another type of blink in which the person deliberately closes the eyes and the lower eyelid raises to meet the upper eyelid. A complete blink, in which the upper eyelid touches the lower eyelid, contributes to the health of ocular surface by providing a fresh layer of tears as well as maintaining optical integrity by providing a smooth tear film over the cornea. The rate of blinking and its completeness vary depending on the task undertaken during blink assessment, the direction of gaze, the emotional state of the subjects and the method under which the blink was measured. It is also well known that wearing contact lenses (both rigid and soft lenses) can induce significant changes in blink rate and completeness. It is been established that efficient blinking plays an important role in ocular surface health during contact lens wear and for improving contact lens performance and comfort. Inefficient blinking during contact lens wear may be related to a low blink rate or incomplete blinking and can often be a reason for dry eye symptoms or ocular surface staining. It has previously been shown that upward gaze can affect blink rate, causing it to become faster. In the first experiment, it was decided to expand on previous studies in this area by examining the effect of various gaze directions (i.e. upward gaze, primary gaze, downward gaze and lateral gaze) as well as head angle (recumbent position) on normal subjects’ blink rate and completeness through the use of filming with a high-speed camera. The results of this experiment showed that as the open palpebral aperture (and exposed ocular surface area) increased from downward gaze to upward gaze, the number of blinks significantly increased (p<0.04). Also, the size of closed palpebral aperture significantly increased from downward gaze to upward gaze (p<0.005). A weak positive correlation (R² = 0.18) between the blink rate and ocular surface area was found in this study. Also, it was found that the subjects showed 81% complete blinks, 19% incomplete blinks and 2% of twitch blinks in primary gaze, consistent with previous studies. The difference in the percentage of incomplete blinks between upward gaze and downward gaze was significant (p<0.004), showing more incomplete blinks in upward gaze. The findings of this experiment suggest that while blink rate becomes slower in downward gaze, the completeness of blinking is typically better, thereby potentially reducing the risk of tear instability. On the other hand, in upward gaze while the completeness of blinking becomes worse, this is potentially offset by increased blink frequency. In addition, blink rate and completeness were not affected by lateral gaze or head angle, possibly because these conditions have similar size of the open palpebral aperture compared with primary gaze. In the second experiment, an investigation into the changes in blink rate and completeness was carried out in primary gaze and downward gaze with soft and rigid contact lenses in unadapted wearers. Not surprisingly, rigid lens wear caused a significant increase in the blink rate in both primary (p<0.001) and downward gaze (p<0.02). After fitting rigid contact lenses, the closed palpebral aperture (blink completeness) did not show any changes but the open palpebral aperture showed a significant narrowing (p<0.04). This might occur from the subjects’ attempt to avoid interaction between the upper eyelid and the edge of the lens to minimize discomfort. After applying topical anaesthetic eye drops in the eye fitted with rigid lenses, the increased blink rate dropped to values similar to that before lens insertion and the open palpebral aperture returned to baseline values, suggesting that corneal and/or lid margin sensitivity was mediating the increased blink rate and narrowed palpebral aperture. We also investigated the changes in the blink rate and completeness with soft contact lenses including a soft sphere, double slab-off toric design and periballast toric design. Soft contact lenses did not cause any significant changes in the blink rate, closed palpebral aperture, open palpebral aperture and the percentage of incomplete blinks in either primary gaze or downward gaze. After applying anaesthetic eye drops, the blink rate reduced in both primary gaze and downward gaze, however this difference was not statistically significant. The size of the closed palpebral aperture and open palpebral aperture did not show any significant changes after applying anaesthetic eye drops. However it should be noted that the effects of rigid and soft contact lenses that we observed in these studies were only the immediate reaction to contact lenses and in the longer term, it is likely that these responses will vary as the eye adapts to the presence of the lenses.

Knowing about the English language: “a wrinkle in time”

Beryl & Gael discuss the ‘new’ metalanguage for knowledge about language presented in the Australian Curriculum English (ACARA, 2010). Their discussion connects to practice by recounting how one teacher scaffolds her students through detailed understandings of noun and adjective groups in reading activities. The stimulus text is the novel ‘A wrinkle in time’ (L’Engle, 1962, reproduced 2007) and the purpose is to build students’ understandings so they can work towards ‘expressing and developing ideas’ in written text (ACARA, 2010).

Sequential Monte Carlo for Bayesian sequentially designed experiments for discrete data

In this paper we present a sequential Monte Carlo algorithm for Bayesian sequential experimental design applied to generalised non-linear models for discrete data. The approach is computationally convenient in that the information of newly observed data can be incorporated through a simple re-weighting step. We also consider a flexible parametric model for the stimulus-response relationship together with a newly developed hybrid design utility that can produce more robust estimates of the target stimulus in the presence of substantial model and parameter uncertainty. The algorithm is applied to hypothetical clinical trial or bioassay scenarios. In the discussion, potential generalisations of the algorithm are suggested to possibly extend its applicability to a wide variety of scenarios

Understanding evaluation of learning support in mathematics and statistics

With rapid and continuing growth of learning support initiatives in mathematics and statistics found in many parts of the world, and with the likelihood that this trend will continue, there is a need to ensure that robust and coherent measures are in place to evaluate the effectiveness of these initiatives. The nature of learning support brings challenges for measurement and analysis of its effects. After briefly reviewing the purpose, rationale for, and extent of current provision, this article provides a framework for those working in learning support to think about how their efforts can be evaluated. It provides references and specific examples of how workers in this field are collecting, analysing and reporting their findings. The framework is used to structure evaluation in terms of usage of facilities, resources and services provided, and also in terms of improvements in performance of the students and staff who engage with them. Very recent developments have started to address the effects of learning support on the development of deeper approaches to learning, the affective domain and the development of communities of practice of both learners and teachers. This article intends to be a stimulus to those who work in mathematics and statistics support to gather even richer, more valuable, forms of data. It provides a 'toolkit' for those interested in evaluation of learning support and closes by referring to an on-line resource being developed to archive the growing body of evidence. © 2011 Taylor & Francis.

The effect of emotional and attentional load on attentional startle modulation

The interactive effects of emotion and attention on attentional startle modulation were investigated in two experiments. Participants performed a discrimination and counting task with two visual stimuli during which acoustic eyeblink startle-eliciting probes were presented at long lead intervals. In Experiment 1, this task was combined with aversive Pavlovian conditioning. In Group Attend CS+, the attended stimulus was followed by an aversive unconditional stimulus (US) and the ignored stimulus was presented alone whereas the ignored stimulus was paired with the US in Group Attend CS−. In Experiment 2, a non-aversive reaction time task US replaced the aversive US. Regardless of the conditioning manipulation and consistent with a modality non-specific account of attentional startle modulation, startle magnitude was larger during attended than ignored stimuli in both experiments. Blink latency shortening was differentially affected by the conditioning manipulations suggesting additive effects of conditioning and discrimination and counting task on blink startle.

Can creativity be taught? And why should it be?

CreativityMoneyLove has an important question at its core – ‘what does the education and skills system need to look like in order for people to lead fulfilled creative lives, and in order for the creative and cultural industries in the UK to thrive?’ It is a question that is currently being asked by politicians and policy makers in different ways, in respect to different sections of industry, as they search for levers to economic growth. The aim of this publication is to give creative practitioners, employers and key thinkers a platform to express their views. Creativity as a concept is not an isolated part of the education system. It has the potential to underpin the entire way we learn, in order to build more imaginative, innovative and thoughtful people who can prosper in a rapidly changing world. It is vital therefore that we ask those at the forefront of their fields how they think the system could and should be changing. We have asked people to consider education in the broadest sense, from the school curriculum to vocational training, from university teaching to informal learning. The opinions expressed here are not our own. Many are overtly political, controversial, inspirational, and contradictory. We wanted to capture those views here, at this particular moment in time, when some key decisions are being made about the future of education in the UK. As two agencies that are in a position to take some of the ideas forward, this is an important part of the process of our own strategic thinking for the future. For A New Direction and Creative & Cultural Skills, the content generated through CreativityMoneyLove will provide the stimulus for a range of conversations, interventions, projects and discussions with young people, policy makers, employers, educators and creative practitioners. The dialogue has started at www.creativitymoneylove.co.uk, where all the pieces are also published online, and the bank of opinion can be added to. Spread the word, and add your own article on the subject.

Binocular summation improves performance to defocus-induced blur

PURPOSE. To assess whether there are any advantages of binocular over monocular vision under blur conditions. METHODS. We measured the effect of defocus, induced by positive lenses, on the pattern reversal Visual Evoked Potential (VEP) and on visual acuity (VA). Monocular (dominant eye) and binocular VEPs were recorded from thirteen volunteers (average age: 28±5 years, average spherical equivalent: -0.25±0.73 D) for defocus up to 2.00 D using positive powered lenses. VEPs were elicited using reversing 10 arcmin checks at a rate of 4 reversals/second. The stimulus subtended a circular field of 7 degrees with 100% contrast and mean luminance 30 cd/m2. VA was measured under the same conditions using ETDRS charts. All measurements were performed at 1m viewing distance with best spectacle sphero-cylindrical correction and natural pupils. RESULTS. With binocular stimulation, amplitudes and implicit times of the P100 component of the VEPs were greater and shorter, respectively, in all cases than for monocular stimulation. Mean binocular enhancement ratio in the P100 amplitude was 2.1 in-focus, increasing linearly with defocus to be 3.1 at +2.00 D defocus. Mean peak latency was 2.9 ms shorter in-focus with binocular than for monocular stimulation, with the difference increasing with defocus to 8.8 ms at +2.00 D. As for the VEP amplitude, VA was always better with binocular than with monocular vision, with the difference being greater for higher retinal blur. CONCLUSIONS. Both subjective and electrophysiological results show that binocular vision ameliorates the effect of defocus. The increased binocular facilitation observed with retinal blur may be due to the activation of a larger population of neurons at close-to-threshold detection under binocular stimulation.

Influence of field size on pupil diameter under photopic and mesopic light levels

Purpose: We investigated the interaction between adapting field size and luminance on pupil diameter when cones alone (photopic) or rods and cones (mesopic) were active. Method: Circular achromatic targets (1o to 24o diameter) were presented to eight young participants on a rectangular projector screen. The accommodative influence on pupil diameter was minimized using cycloplegia in the fixing right eye and the consensual pupil reflex was measured in the left eye. Target luminance was adjusted for each stimulus such that corneal flux density (product of field area and luminance) was constant at 3600 cd.deg2m-2 (photopic condition) and 1.49 cd.deg2m-2 (mesopic condition). Results: There were no statistically significant effects of adaptive field size on pupil diameter for either condition. Conclusion: If corneal flux density is kept constant, there will be no change in pupil diameter as the size of the stimulus field increases at either mesopic or photopic lighting levels up to at least 24°.

Visual backward masking performance in young adult emmetropes and myopes

Purpose. To investigate how temporal processing is altered in myopia and during myopic progression. Methods. In backward visual masking, a target's visibility is reduced by a mask presented quickly after the target. Thirty emmetropes, 40 low myopes, and 22 high myopes aged 18 to 26 years completed location and resolution masking tasks. The location task examined the ability to detect letters with low contrast and large stimulus size. The resolution task involved identifying a small letter and tested resolution and color discrimination. Target and mask stimuli were presented at nine short interstimulus intervals (12 to 259 ms) and at 1000 ms (long interstimulus interval condition). Results. In comparison with emmetropes, myopes had reduced ability in both locating and identifying briefly presented stimuli but were more affected by backward masking for a low contrast location task than for a resolution task. Performances of low and high myopes, as well as stable and progressing myopes, were similar for both masking tasks. Task performance was not correlated with myopia magnitude. Conclusions. Myopes were more affected than emmetropes by masking stimuli for the location task. This was not affected by magnitude or progression rate of myopia, suggesting that myopes have the propensity for poor performance in locating briefly presented low contrast objects at an early stage of myopia development.

Transcriptome Profiling of Sexual Maturation and Mating in the Mediterranean Fruit Fly, Ceratitis capitata

Sexual maturation and mating in insects are generally accompanied by major physiological and behavioural changes. Many of these changes are related to the need to locate a mate and subsequently, in the case of females, to switch from mate searching to oviposition behaviour. The prodigious reproductive capacity of the Mediterranean fruit fly, Ceratitis capitata, is one of the factors that has led to its success as an invasive pest species. To identify the molecular changes related to maturation and mating status in male and female medfly, a microarray-based gene expression approach was used to compare the head transcriptomes of sexually immature, mature virgin, and mated individuals. Attention was focused on the changes in abundance of transcripts related to reproduction, behaviour, sensory perception of chemical stimulus, and immune system processes. Broad transcriptional changes were recorded during female maturation, while post-mating transcriptional changes in females were, by contrast, modest. In male medfly, transcriptional changes were consistent both during maturation and as a consequence of mating. Of particular note was the lack of the mating-induced immune responses that have been recorded for Drosophila melanogaster, that may be due to the different reproductive strategies of these species. This study, in addition to increasing our understanding of the molecular machinery behind maturation and mating in the medfly, has identified important gene targets that might be useful in the future management of this pest.

Time-varying bispectral analysis of auditory evoked multi-channel scalp EEG

Time-varying bispectra, computed using a classical sliding window short-time Fourier approach, are analyzed for scalp EEG potentials evoked by an auditory stimulus and new observations are presented. A single, short duration tone is presented from the left or the right, direction unknown to the test subject. The subject responds by moving the eyes to the direction of the sound. EEG epochs sampled at 200 Hz for repeated trials are processed between -70 ms and +1200 ms with reference to the stimulus. It is observed that for an ensemble of correctly recognized cases, the best matching timevarying bispectra at (8 Hz, 8Hz) are for PZ-FZ channels and this is also largely the case for grand averages but not for power spectra at 8 Hz. Out of 11 subjects, the only exception for time-varying bispectral match was a subject with family history of Alzheimer’s disease and the difference was in bicoherence, not biphase.