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Designing of implant surfaces using a suitable ligand for cell adhesion to stimulate specific biological responses of stem cells will boost the application of regenerative implants. For example, materials that facilitate rapid and guided migration of stem cells would promote tissue regeneration. When seeded on fibronectin (FN) that was homogeneously immmobilized to NCO-sP(EO-stat-PO), which otherwise prevents protein binding and cell adhesion, human mesenchymal stem cells (MSC) revealed a faster migration, increased spreading and a more rapid organization of different cellular components for cell adhesion on fibronectin than on a glass surface. To further explore, how a structural organization of FN controls the behavior of MSC, adhesive lines of FN with varying width between 10 µm and 80 µm and spacings between 5 µm and 20 µm that did not allow cell adhesion were generated. In dependance on both line width and gaps, cells formed adjacent cell contacts, were individually organized in lines, or bridged the lines. With decreasing sizes of FN lines, speed and directionality of cell migration increased, which correlated with organization of the actin cytoskeleton, size and shape of the nuclei as well as of focal adhesions. Together, defined FN lines and gaps enabled a fine tuning of the structural organization of cellular components and migration. Microstructured adhesive substrates can mimic the extracellular matrix in vivo and stimulate cellular mechanisms which play a role in tissue regeneration.

The aim of the present study was to test the biocompatibility and functionality of orthopaedic bone implants with immobilized oligonucleotides serving as anchor stands for rhBMP-2 and rhVEGF-A conjugated with complementary oligonucleotides in an osteoporotic rat model. Al2O3-blasted acid etched Ti6Al4V implants, carrying oligonucleotide anchor strands and hybridized with rhBMP-2 or rhVEGF-A through complementary 31-mer oligonucleotide stands were inserted into the proximal tibia of ovariectomized rats. At the time of surgery (15 weeks after ovariectomy) microCT analysis showed significantly lower bone mineral density compared to non-ovariectomized animals. Bone-implant contact (BIC) and pullout-force were not negatively affected by non-hybridized anchor strands. Twelve weeks after surgery, a significantly higher pullout force was found for BMP-2 hybridized to the anchor strands compared to non-hybridized anchor strands or native samples, and on histomorphometric analysis BIC was highest in the BMP group. Thus, we could show the biocompatibility and in vivo functionality of this modular, self-organizing system for immobilization and subsequent release of BMP-2 in vivo.

Over the past decade there has been increasing enthusiasm in the cognitive neurosciences around using network science to understand the system-level changes associated with brain disorders. A growing literature has used whole-brain fMRI analysis to examine changes in the brain's subnetworks following traumatic brain injury (TBI). Much of network modeling in this literature has focused on static network mapping, which provides a window into gross inter-nodal relationships, but is insensitive to more subtle fluctuations in network dynamics, which may be an important predictor of neural network plasticity. In this study, we examine the dynamic connectivity with focus on state-level connectivity (state) and evaluate the reliability of dynamic network states over the course of two runs of intermittent task and resting data. The goal was to examine the dynamic properties of neural networks engaged periodically with task stimulation in order to determine: 1) the reliability of inter-nodal and network-level characteristics over time and 2) the transitions between distinct network states after traumatic brain injury. To do so, we enrolled 23 individuals with moderate and severe TBI at least 1-year post injury and 19 age- and education-matched healthy adults using functional MRI methods, dynamic connectivity modeling, and graph theory. The results reveal several distinct network "states" that were reliably evident when comparing runs; the overall frequency of dynamic network states are highly reproducible (r-values>0.8) for both samples. Analysis of movement between states resulted in fewer state transitions in the TBI sample and, in a few cases, brain injury resulted in the appearance of states not exhibited by the healthy control (HC) sample. Overall, the findings presented here demonstrate the reliability of observable dynamic mental states during periods of on-task performance and support emerging evidence that brain injury may result in diminished network dynamics., Competing Interests: SMR’s affiliation with Quantitative Science Solutions (QS2) does not alter our adherence to PLOS ONE policies on sharing data and materials.

Visuo-haptic biases are observed when bringing your unseen hand to a visual target. The biases are different between, but consistent within participants. We investigated the usefulness of adjusting haptic guidance to these user-specific biases in aligning haptic and visual perception. By adjusting haptic guidance according to the biases, we aimed to reduce the conflict between the modalities. We first measured the biases using an adaptive procedure. Next, we measured performance in a pointing task using three conditions: 1) visual images that were adjusted to user-specific biases, without haptic guidance, 2) veridical visual images combined with haptic guidance, and 3) shifted visual images combined with haptic guidance. Adding haptic guidance increased precision. Combining haptic guidance with user-specific visual information yielded the highest accuracy and the lowest level of conflict with the guidance at the end point. These results show the potential of correcting for user-specific perceptual biases when designing haptic guidance.

Humans make both random and systematic errors when reproducing learned movements. Intuitive haptic guidance that assists one to make the movements reduces such errors. Our study examined whether any additional haptic information about the location of the target reduces errors in a position reproduction task, or whether the haptic guidance needs to be assistive to do so. Holding a haptic device, subjects made reaches to visible targets without time constraints. They did so in a no-guidance condition, and in guidance conditions in which the direction of the force with respect to the target differed, but the force scaled with the distance to the target in the same way. We examined whether guidance forces directed towards the target would reduce subjects' errors in reproducing a prior position to the same extent as do forces rotated by 90 degrees or 180 degrees, as it might because the forces provide the same information in all three cases. Without vision of the arm, both the accuracy and precision were significantly better with guidance directed towards the target than in all other conditions. The errors with rotated guidance did not differ from those without guidance. Not surprisingly, the movements tended to be faster when guidance forces directed the reaches to the target. This study shows that haptic guidance significantly improved motor performance when using it was intuitive, while non-intuitively presented information did not lead to any improvements and seemed to be ignored even in our simple paradigm with static targets and no time constraints.

We use visual information to guide our grasping movements. When grasping an object with a precision grip, the two digits need to reach two different positions more or less simultaneously, but the eyes can only be directed to one position at a time. Several studies that have examined eye movements in grasping have found that people tend to direct their gaze near where their index finger will contact the object. Here we aimed at better understanding why people do so by asking participants to lift an object off a horizontal surface. They were to grasp the object with a precision grip while movements of their hand, eye and head were recorded. We confirmed that people tend to look closer to positions that a digit needs to reach more accurately. Moreover, we show that where they look as they reach for the object depends on where they were looking before, presumably because they try to minimize the time during which the eyes are moving so fast that no new visual information is acquired. Most importantly, we confirmed that people have a bias to direct gaze towards the index finger's contact point rather than towards that of the thumb. In our study, this cannot be explained by the index finger contacting the object before the thumb. Instead, it appears to be because the index finger moves to a position that is hidden behind the object that is grasped, probably making this the place at which one is most likely to encounter unexpected problems that would benefit from visual guidance. However, this cannot explain the bias that was found in previous studies, where neither contact point was hidden, so it cannot be the only explanation for the bias.

In dynamic environments, it is crucial to accurately consider the timing of information. For instance, during saccades the eyes rotate so fast that even small temporal errors in relating retinal stimulation by flashed stimuli to extra-retinal information about the eyes' orientations will give rise to substantial errors in where the stimuli are judged to be. If spatial localization involves judging the eyes' orientations at the estimated time of the flash, we should be able to manipulate the pattern of mislocalization by altering the estimated time of the flash. We reasoned that if we presented a relevant flash within a short rapid sequence of irrelevant flashes, participants' estimates of when the relevant flash was presented might be shifted towards the centre of the sequence. In a first experiment, we presented five bars at different positions around the time of a saccade. Four of the bars were black. Either the second or the fourth bar in the sequence was red. The task was to localize the red bar. We found that when the red bar was presented second in the sequence, it was judged to be further in the direction of the saccade than when it was presented fourth in the sequence. Could this be because the red bar was processed faster when more black bars preceded it? In a second experiment, a red bar was either presented alone or followed by two black bars. When two black bars followed it, it was judged to be further in the direction of the saccade. We conclude that the spatial localization of flashed stimuli involves judging the eye orientation at the estimated time of the flash.

Reaching movements towards an object are continuously guided by visual information about the target and the arm. Such guidance increases precision and allows one to adjust the movement if the target unexpectedly moves. On-going arm movements are also influenced by motion in the surrounding. Fast responses to motion in the surrounding could help cope with moving obstacles and with the consequences of changes in one's eye orientation and vantage point. To further evaluate how motion in the surrounding influences interceptive movements we asked subjects to tap a moving target when it reached a second, static target. We varied the direction and location of motion in the surrounding, as well as details of the stimuli that are known to influence eye movements. Subjects were most sensitive to motion in the background when such motion was near the targets. Whether or not the eyes were moving, and the direction of the background motion in relation to the direction in which the eyes were moving, had very little influence on the response to the background motion. We conclude that the responses to background motion are driven by motion near the target rather than by a global analysis of the optic flow and its relation with other information about self-motion.

Even when provided with feedback after every movement, adaptation levels off before biases are completely removed. Incomplete adaptation has recently been attributed to forgetting: the adaptation is already partially forgotten by the time the next movement is made. Here we test whether this idea is correct. If so, the final level of adaptation is determined by a balance between learning and forgetting. Because we learn from perceived errors, scaling these errors by a magnification factor has the same effect as subjects increasing the amount by which they learn from each error. In contrast, there is no reason to expect scaling the errors to affect forgetting. The magnification factor should therefore influence the balance between learning and forgetting, and thereby the final level of adaptation. We found that adaptation was indeed more complete for larger magnification factors. This supports the idea that incomplete adaptation is caused by part of what has been learnt quickly being forgotten.

Novel data showing an important role of microRNAs in mediating tumour progression opened a new field of possible molecular targets for cytotoxic ribonucleases. Recently, antitumour and antimetastatic activities of pancreatic ribonuclease A were demonstrated and here genome-wide profiles of microRNAs in the tumour and blood of mice bearing Lewis lung carcinoma after treatment with RNase A were analysed by high-throughput Sequencing by Oligonucleotide Ligation and Detection (SOLiD™) sequencing technology. Sequencing data showed that RNase A therapy resulted in the boost of 116 microRNAs in tumour tissue and a significant drop of 137 microRNAs in the bloodstream that were confirmed by qPCR. The microRNA boost in the tumour was accompanied by the overexpression of microRNA processing genes: RNASEN (Drosha), xpo5, dicer1, and eif2c2 (Ago2). Ribonuclease activity of RNase A was shown to be crucial for the activation of both microRNA synthesis and expression of the microRNA processing genes. In the tumour tissue, RNase A caused the upregulation of both oncomirs and tumour-suppressor microRNAs, including microRNAs of the let-7 family, known to negatively regulate tumour progression. Our results suggest that the alteration of microRNA signature caused by RNase A treatment leads to the attenuation of tumour malignancy.

Information from cutaneous, muscle and joint receptors is combined with efferent information to create a reliable percept of the configuration of our body (proprioception). We exposed the hand to several horizontal force fields to examine whether external forces influence this percept. In an end-point task subjects reached visually presented positions with their unseen hand. In a vector reproduction task, subjects had to judge a distance and direction visually and reproduce the corresponding vector by moving the unseen hand. We found systematic individual errors in the reproduction of the end-points and vectors, but these errors did not vary systematically with the force fields. This suggests that human proprioception accounts for external forces applied to the hand when sensing the position of the hand in the horizontal plane.

Recent work has shown that humans can learn or detect complex dependencies among variables. Even learning a simple dependency involves the identification of an underlying model and the learning of its parameters. This process represents learning a structured problem. We are interested in an empirical assessment of some of the factors that enable humans to learn such a dependency over time. More specifically, we look at how the statistics of the presentation of samples from a given structure influence learning. Participants engage in an experimental task where they are required to predict the timing of a target. At the outset, they are oblivious to the existence of a relationship between the position of a stimulus and the required temporal response to intercept it. Different groups of participants are either presented with a Random Walk where consecutive stimuli were correlated or with stimuli that were uncorrelated over time. We find that the structural relationship implicit in the task is only learned in the conditions where the stimuli are independently drawn. This leads us to believe that humans require rich and independent sampling to learn hidden structures among variables.

A stimulus that is flashed around the time of a saccade tends to be mislocalized in the direction of the saccade target. Our question is whether the mislocalization is related to the position of the saccade target within the image or to the gaze position at the end of the saccade. We separated the two with a visual illusion that influences the perceived distance to the target of the saccade and thus saccade endpoint without affecting the perceived position of the saccade target within the image. We asked participants to make horizontal saccades from the left to the right end of the shaft of a Müller-Lyer figure. Around the time of the saccade, we flashed a bar at one of five possible positions and asked participants to indicate its location by touching the screen. As expected, participants made shorter saccades along the fins-in (<->) configuration than along the fins-out (>-<) configuration of the figure. The illusion also influenced the mislocalization pattern during saccades, with flashes presented with the fins-out configuration being perceived beyond flashes presented with the fins-in configuration. The difference between the patterns of mislocalization for bars flashed during the saccade for the two configurations corresponded quantitatively with a prediction based on compression towards the saccade endpoint considering the magnitude of the effect of the illusion on saccade amplitude. We conclude that mislocalization is related to the eye position at the end of the saccade, rather than to the position of the saccade target within the image.

Grasping is a prototype of human motor coordination. Nevertheless, it is not known what determines the typical movement patterns of grasping. One way to approach this issue is by building models. We developed a model based on the movements of the individual digits. In our model the following objectives were taken into account for each digit: move smoothly to the preselected goal position on the object without hitting other surfaces, arrive at about the same time as the other digit and never move too far from the other digit. These objectives were implemented by regarding the tips of the digits as point masses with a spring between them, each attracted to its goal position and repelled from objects' surfaces. Their movements were damped. Using a single set of parameters, our model can reproduce a wider variety of experimental findings than any previous model of grasping. Apart from reproducing known effects (even the angles under which digits approach trapezoidal objects' surfaces, which no other model can explain), our model predicted that the increase in maximum grip aperture with object size should be greater for blocks than for cylinders. A survey of the literature shows that this is indeed how humans behave. The model can also adequately predict how single digit pointing movements are made. This supports the idea that grasping kinematics follow from the movements of the individual digits.

Background: It has been reported that participants judge an object to be closer after a stick has been used to touch it than after touching it with the hand. In this study we try to find out why this is so., Methodology: We showed six participants a cylindrical object on a table. On separate trials (randomly intermixed) participants either estimated verbally how far the object is from their body or they touched a remembered location. Touching was done either with the hand or with a stick (in separate blocks). In three different sessions, participants touched either the object location or the location halfway to the object location. Verbal judgments were given either in centimeters or in terms of whether the object would be reachable with the hand. No differences in verbal distance judgments or touching responses were found between the blocks in which the stick or the hand was used., Conclusion: Instead of finding out why the judged distance changes when using a tool, we found that using a stick does not necessarily alter judged distances or judgments about the reachability of objects.