Visual influence on bimanual haptic slant adaptation.

Adapting to particular features of a haptic shape, for example, the slant of a surface, affects how a subsequently touched shape is perceived (aftereffect). Previous studies showed that this adaptation is largely based on our proprioceptive sense of hand posture, yet the influence of vision on haptic shape adaptation has been relatively unexplored. Here, using a slant-adaptation paradigm, we investigated whether visual information affects haptic adaptation and, if so, how. To this end, we varied the available visual cues during the adaptation period. This process ranged from providing visual information only about the slant of the surface, or the reference frame in which it is presented, to only providing visual information about the location of the fingertips. Additionally, we tested several combinations of these visual cues. We show that, as soon as the visual information can be used as a spatial reference to link the own fingertip position to the surface slant, haptic adaptation is very much reduced. This result means that, under these viewing conditions, vision dominates touch and is one reason why we do not easily adapt to haptic shape in our daily life, because we usually have visual information about both hand and object available simultaneously.

Body structural representation in schizotypy.

A deficient sense of self, typically observed in schizophrenia spectrum disorders, is often accompanied by abnormalities in bodily perception and awareness. These abnormalities are seemingly among the most powerful predictive factors for the onset of schizophrenic illnesses. According to the hypothesis of the psychosis continuum, high schizotypal traits in the general population may be characterized by a progressive sense of detachment from one's lived body. Building upon previous research that found an abnormal Body Structural Representation (BSR) in individuals with schizophrenia, this study aims to extend these findings to schizotypy. To investigate this, we utilized the Finger Localization Task (FLT), in which participants must identify the finger touched by the experimenter, and the In Between Task (IBT), in which two fingers are touched and participants must specify the number of fingers in between the two stimulated fingers. We found that individuals with high schizotypy were significantly less accurate than individuals with low schizotypy in determining the spatial configuration of their own fingers relative to each other. Most significantly, performances on both tasks were negatively correlated with the score on the Dissociative Experiences Scale (DES). These findings support the hypothesis that the progressive loss of one's sense of self is associated with abnormal bodily experiences and dissociative symptomatology which may represent a potential marker for schizophrenia proneness.

The temporal sensitivity to the tactile-induced double flash illusion mediates the impact of beta oscillations on schizotypal personality traits.

The coherent experience of the self and the world depends on the ability to integrate vs. segregate sensory information. Optimal temporal integration between the senses is mediated by oscillatory properties of neural activity. Previous research showed reduced temporal sensitivity to multisensory events in schizotypy, a personality trait linked to schizophrenia. Here we used the tactile-induced Double-Flash-Illusion (tDFI) to investigate the tactile-to-visual temporal sensitivity in schizotypy, as indexed by the temporal window of illusion (TWI) and its neural underpinnings. We measured EEG oscillations within the beta band, recently shown to correlate with the tDFI. We found individuals with higher schizotypal traits to have wider TWI and slower beta waves accounting for the temporal window within which they perceive the illusion. Our results indicate reduced tactile-to-visual temporal sensitivity to mediate the effect of slowed oscillatory beta activity on schizotypal personality traits. We conclude that slowed oscillatory patterns might constitute an early marker for psychosis proneness.

The Human 2-Cys Peroxiredoxins form Widespread, Cysteine-Dependent- and Isoform-Specific Protein-Protein Interactions.

Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by H2O2 acting as a second messenger. However, H2O2 actually reacts poorly with most cysteine thiols and it is not clear how H2O2 discriminates between cysteines to trigger appropriate signaling cascades in the presence of dedicated H2O2 scavengers like peroxiredoxins (PRDXs). It was recently suggested that peroxiredoxins act as peroxidases and facilitate H2O2-dependent oxidation of redox-regulated proteins via disulfide exchange reactions. It is unknown how the peroxiredoxin-based relay model achieves the selective substrate targeting required for adequate cellular signaling. Using a systematic mass-spectrometry-based approach to identify cysteine-dependent interactors of the five human 2-Cys peroxiredoxins, we show that all five human 2-Cys peroxiredoxins can form disulfide-dependent heterodimers with a large set of proteins. Each isoform displays a preference for a subset of disulfide-dependent binding partners, and we explore isoform-specific properties that might underlie this preference. We provide evidence that peroxiredoxin-based redox relays can proceed via two distinct molecular mechanisms. Altogether, our results support the theory that peroxiredoxins could play a role in providing not only reactivity but also selectivity in the transduction of peroxide signals to generate complex cellular signaling responses.

No need to touch this: Bimanual haptic slant adaptation does not require touch.

In our daily life, we often interact with objects using both hands raising the question the question to what extent information between the hands is shared. It has, for instance, been shown that curvature adaptation aftereffects can transfer from the adapted hand to the non-adapted hand. However, this transfer only occurred for dynamic exploration, e.g. by moving a single finger over a surface, but not for static exploration when keeping static contact with the surface and combining the information from different parts of the hand. This raises the question to what extent adaptation to object shape is shared between the hands when both hands are used in static fashion simultaneously and the object shape estimates require information from both hands. Here we addressed this question in three experiments using a slant adaptation paradigm. In Experiment 1 we investigated whether an aftereffect of static bimanual adaptation occurs at all and whether it transfers to conditions in which one hand was moving. In Experiment 2 participants adapted either to a felt slanted surface or simply be holding their hands in mid-air at similar positions, to investigate to what extent the effects of static bimanual adaptation are posture-based rather than object based. Experiment 3 further explored the idea that bimanual adaptation is largely posture based. We found that bimanual adaptation using static touch did lead to aftereffects when using the same static exploration mode for testing. However, the aftereffect did not transfer to any exploration mode that included a dynamic component. Moreover, we found similar aftereffects both with and without a haptic surface. Thus, we conclude that static bimanual adaptation is of proprioceptive nature and does not occur at the level at which the object is represented.

Cross-talk between redox signalling and protein aggregation.

It is well established that both an increase in reactive oxygen species (ROS: i.e. O2•-, H2O2 and OH•), as well as protein aggregation, accompany ageing and proteinopathies such as Parkinson's and Alzheimer's disease. However, it is far from clear whether there is a causal relation between the two. This review describes how protein aggregation can be affected both by redox signalling (downstream of H2O2), as well as by ROS-induced damage, and aims to give an overview of the current knowledge of how redox signalling affects protein aggregation and vice versa. Redox signalling has been shown to play roles in almost every step of protein aggregation and amyloid formation, from aggregation initiation to the rapid oligomerization of large amyloids, which tend to be less toxic than oligomeric prefibrillar aggregates. We explore the hypothesis that age-associated elevated ROS production could be part of a redox signalling-dependent-stress response in an attempt to curb protein aggregation and minimize toxicity.

Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A.

The tumor suppressor p16INK4A induces cell cycle arrest and senescence in response to oncogenic transformation and is therefore frequently lost in cancer. p16INK4A is also known to accumulate under conditions of oxidative stress. Thus, we hypothesized it could potentially be regulated by reversible oxidation of cysteines (redox signaling). Here we report that oxidation of the single cysteine in p16INK4A in human cells occurs under relatively mild oxidizing conditions and leads to disulfide-dependent dimerization. p16INK4A is an all α-helical protein, but we find that upon cysteine-dependent dimerization, p16INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-ß sheet structure, and typical dimensions found in electron microscopy. p16INK4A amyloid formation abolishes its function as a Cyclin Dependent Kinase 4/6 inhibitor. Collectively, these observations mechanistically link the cellular redox state to the inactivation of p16INK4A through the formation of amyloid fibrils.

Effects of prolonged exposure to feedback delay on the qualitative subjective experience of virtual reality.

When interacting with virtual environments, feedback delays between making a movement and seeing the visual consequences of that movement are detrimental for the subjective quality of the VR experience. Here we used standard measures of subjective experiences such as ownership, agency and presence to investigate whether prolonged exposure to the delay, and thus the possibility to adapt to it, leads to the recovery of the qualitative experience of VR. Participants performed a target-tracking task in a Virtual Reality environment. We measured the participants' tracking performance in terms of spatial and temporal errors with respect to the target in both No-Delay and Delay conditions. Additionally, participants rated their sense of "ownership" of holding a virtual tool, agency and presence on each trial using sliding scales. These single trial ratings were compared to the results of the more traditional questionnaires for ownership and agency and presence for both No-Delay and Delay conditions. We found that the participants' sliding scales ratings corresponded very well to the scores obtained from the traditional questionnaires. Moreover, not only did participants behaviourally adapt to the delay, their ratings of ownership and agency significantly improved with prolonged exposure to the delay. Together the results suggest a tight link between the ability to perform a behavioural task and the subjective ratings of ownership and agency in virtual reality.

Haptic adaptation to slant: No transfer between exploration modes.

Human touch is an inherently active sense: to estimate an object's shape humans often move their hand across its surface. This way the object is sampled both in a serial (sampling different parts of the object across time) and parallel fashion (sampling using different parts of the hand simultaneously). Both the serial (moving a single finger) and parallel (static contact with the entire hand) exploration modes provide reliable and similar global shape information, suggesting the possibility that this information is shared early in the sensory cortex. In contrast, we here show the opposite. Using an adaptation-and-transfer paradigm, a change in haptic perception was induced by slant-adaptation using either the serial or parallel exploration mode. A unified shape-based coding would predict that this would equally affect perception using other exploration modes. However, we found that adaptation-induced perceptual changes did not transfer between exploration modes. Instead, serial and parallel exploration components adapted simultaneously, but to different kinaesthetic aspects of exploration behaviour rather than object-shape per se. These results indicate that a potential combination of information from different exploration modes can only occur at down-stream cortical processing stages, at which adaptation is no longer effective.

Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma.

To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed. Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance.

Statistically Optimal Multisensory Cue Integration: A Practical Tutorial.

Humans combine redundant multisensory estimates into a coherent multimodal percept. Experiments in cue integration have shown for many modality pairs and perceptual tasks that multisensory information is fused in a statistically optimal manner: observers take the unimodal sensory reliability into consideration when performing perceptual judgments. They combine the senses according to the rules of Maximum Likelihood Estimation to maximize overall perceptual precision. This tutorial explains in an accessible manner how to design optimal cue integration experiments and how to analyse the results from these experiments to test whether humans follow the predictions of the optimal cue integration model. The tutorial is meant for novices in multisensory integration and requires very little training in formal models and psychophysical methods. For each step in the experimental design and analysis, rules of thumb and practical examples are provided. We also publish Matlab code for an example experiment on cue integration and a Matlab toolbox for data analysis that accompanies the tutorial online. This way, readers can learn about the techniques by trying them out themselves. We hope to provide readers with the tools necessary to design their own experiments on optimal cue integration and enable them to take part in explaining when, why and how humans combine multisensory information optimally.

Relative errors can cue absolute visuomotor mappings.

When repeatedly switching between two visuomotor mappings, e.g. in a reaching or pointing task, adaptation tends to speed up over time. That is, when the error in the feedback corresponds to a mapping switch, fast adaptation occurs. Yet, what is learned, the relative error or the absolute mappings? When switching between mappings, errors with a size corresponding to the relative difference between the mappings will occur more often than other large errors. Thus, we could learn to correct more for errors with this familiar size (Error Learning). On the other hand, it has been shown that the human visuomotor system can store several absolute visuomotor mappings (Mapping Learning) and can use associated contextual cues to retrieve them. Thus, when contextual information is present, no error feedback is needed to switch between mappings. Using a rapid pointing task, we investigated how these two types of learning may each contribute when repeatedly switching between mappings in the absence of task-irrelevant contextual cues. After training, we examined how participants changed their behaviour when a single error probe indicated either the often-experienced error (Error Learning) or one of the previously experienced absolute mappings (Mapping Learning). Results were consistent with Mapping Learning despite the relative nature of the error information in the feedback. This shows that errors in the feedback can have a double role in visuomotor behaviour: they drive the general adaptation process by making corrections possible on subsequent movements, as well as serve as contextual cues that can signal a learned absolute mapping.

Two-way communication between the metabolic and cell cycle machineries: the molecular basis.

The relationship between cellular metabolism and the cell cycle machinery is by no means unidirectional. The ability of a cell to enter the cell cycle critically depends on the availability of metabolites. Conversely, the cell cycle machinery commits to regulating metabolic networks in order to support cell survival and proliferation. In this review, we will give an account of how the cell cycle machinery and metabolism are interconnected. Acquiring information on how communication takes place among metabolic signaling networks and the cell cycle controllers is crucial to increase our understanding of the deregulation thereof in disease, including cancer.

Mapping shape to visuomotor mapping: learning and generalisation of sensorimotor behaviour based on contextual information.

Humans can learn and store multiple visuomotor mappings (dual-adaptation) when feedback for each is provided alternately. Moreover, learned context cues associated with each mapping can be used to switch between the stored mappings. However, little is known about the associative learning between cue and required visuomotor mapping, and how learning generalises to novel but similar conditions. To investigate these questions, participants performed a rapid target-pointing task while we manipulated the offset between visual feedback and movement end-points. The visual feedback was presented with horizontal offsets of different amounts, dependent on the targets shape. Participants thus needed to use different visuomotor mappings between target location and required motor response depending on the target shape in order to "hit" it. The target shapes were taken from a continuous set of shapes, morphed between spiky and circular shapes. After training we tested participants performance, without feedback, on different target shapes that had not been learned previously. We compared two hypotheses. First, we hypothesised that participants could (explicitly) extract the linear relationship between target shape and visuomotor mapping and generalise accordingly. Second, using previous findings of visuomotor learning, we developed a (implicit) Bayesian learning model that predicts generalisation that is more consistent with categorisation (i.e. use one mapping or the other). The experimental results show that, although learning the associations requires explicit awareness of the cues' role, participants apply the mapping corresponding to the trained shape that is most similar to the current one, consistent with the Bayesian learning model. Furthermore, the Bayesian learning model predicts that learning should slow down with increased numbers of training pairs, which was confirmed by the present results. In short, we found a good correspondence between the Bayesian learning model and the empirical results indicating that this model poses a possible mechanism for simultaneously learning multiple visuomotor mappings.

Exploration mode affects visuohaptic integration of surface orientation.

We experience the world mostly in a multisensory fashion using a combination of all of our senses. Depending on the modality we can select different exploration strategies for extracting perceptual information. For instance, using touch we can enclose an object in our hand to explore parts of the object in parallel. Alternatively, we can trace the object with a single finger to explore its parts in a serial fashion. In this study we investigated whether the exploration mode (parallel vs. serial) affects the way sensory signals are combined. To this end, participants visually and haptically explored surfaces that varied in roll angle and indicated which side of the surface was perceived as higher. In Experiment 1, the exploration mode was the same for both modalities (i.e., both parallel or both serial). In Experiment 2, we introduced a difference in exploration mode between the two modalities (visual exploration was parallel while haptic exploration was serial or vice versa). The results showed that visual and haptic signals were combined in a statistically optimal fashion only when the exploration modes were the same. In case of an asymmetry in the exploration modes across modalities, integration was suboptimal. This indicates that spatial-temporal discrepancies in the acquisition of information in the two senses (i.e., haptic and visual) can lead to the breakdown of sensory integration.

Predictability is necessary for closed-loop visual feedback delay adaptation.

In case of delayed visual feedback during visuomotor tasks, like in some sluggish computer games, humans can modulate their behavior to compensate for the delay. However, opinions on the nature of this compensation diverge. Some studies suggest that humans adapt to feedback delays with lasting changes in motor behavior (aftereffects) and a recalibration of time perception. Other studies have shown little or no evidence for such semipermanent recalibration in the temporal domain. We hypothesize that predictability of the reference signal (target to be tracked) is necessary for semipermanent delay adaptation. To test this hypothesis, we trained participants with a 200 ms visual feedback delay in a visually guided manual tracking task, varying the predictability of the reference signal between conditions, but keeping reference motion and feedback delay constant. In Experiment 1, we focused on motor behavior. Only training in the predictable condition brings about all of the adaptive changes and aftereffects expected from delay adaptation. In Experiment 2, we used a synchronization task to investigate perceived simultaneity (perceptuomotor learning). Supporting the hypothesis, participants recalibrated subjective visuomotor simultaneity only when trained in the predictable condition. Such a shift in perceived simultaneity was also observed in Experiment 3, using an interval estimation task. These results show that delay adaptation in motor control can modulate the perceived temporal alignment of vision and kinesthetically sensed movement. The coadaptation of motor prediction and target prediction (reference extrapolation) seems necessary for such genuine delay adaptation. This offers an explanation for divergent results in the literature.

The eyes grasp, the hands see: metric category knowledge transfers between vision and touch.

Categorization of seen objects is often determined by the shapes of objects. However, shape is not exclusive to the visual modality: The haptic system also is expert at identifying shapes. Hence, an important question for understanding shape processing is whether humans store separate modality-dependent shape representations, or whether information is integrated into one multisensory representation. To answer this question, we created a metric space of computer-generated novel objects varying in shape. These objects were then printed using a 3-D printer, to generate tangible stimuli. In a categorization experiment, participants first explored the objects visually and haptically. We found that both modalities led to highly similar categorization behavior. Next, participants were trained either visually or haptically on shape categories within the metric space. As expected, visual training increased visual performance, and haptic training increased haptic performance. Importantly, however, we found that visual training also improved haptic performance, and vice versa. Two additional experiments showed that the location of the categorical boundary in the metric space also transferred across modalities, as did heightened discriminability of objects adjacent to the boundary. This observed transfer of metric category knowledge across modalities indicates that visual and haptic forms of shape information are integrated into a shared multisensory representation.

Knowing each random error of our ways, but hardly correcting for it: an instance of optimal performance.

Random errors are omnipresent in sensorimotor tasks due to perceptual and motor noise. The question is, are humans aware of their random errors on an instance-by-instance basis? The appealing answer would be 'no' because it seems intuitive that humans would otherwise immediately correct for the errors online, thereby increasing sensorimotor precision. However, here we show the opposite. Participants pointed to visual targets with varying degree of feedback. After movement completion participants indicated whether they believed they landed left or right of target. Surprisingly, participants' left/right-discriminability was well above chance, even without visual feedback. Only when forced to correct for the error after movement completion did participants loose knowledge about the remaining error, indicating that random errors can only be accessed offline. When correcting, participants applied the optimal correction gain, a weighting factor between perceptual and motor noise, minimizing end-point variance. Together these results show that humans optimally combine direct information about sensorimotor noise in the system (the current random error), with indirect knowledge about the variance of the perceptual and motor noise distributions. Yet, they only appear to do so offline after movement completion, not while the movement is still in progress, suggesting that during movement proprioceptive information is less precise.

Switching between visuomotor mappings: learning absolute mappings or relative shifts.

Adaptation to specific visuomotor mappings becomes faster when switching back and forth between them. What is learned when repeatedly switching between the visuomotor mappings: the absolute mappings or the relative shift between the mappings? To test this, we trained participants in a rapid pointing task using a unique color cue as context for each mapping between pointing location and visual feedback. After extensive training, participants adapted to a new mapping using a neutral contextual cue. For catch trials (a change in cue and no visual feedback) different adaptation performances are predicted depending on how the mappings are encoded. When encoding an absolute mapping for each cue, participants would fall back to the mapping associated with the cue irrespective of the state they are currently in. In contrast, when a shift in mapping is encoded for the cue, pointing performance will shift relative to the current mapping by an amount equal to the difference between the previously learned mappings. Results indicate that the contextual cues signal absolute visuomotor mappings rather than relative shifts between mappings.