Sensorimotor prediction is used to direct gaze toward task-relevant locations in a goal-directed throwing task.

Previous research has shown that action effects of self-generated movements are internally predicted before outcome feedback becomes available. To test whether these sensorimotor predictions are used to facilitate visual information uptake for feedback processing, we measured eye movements during the execution of a goal-directed throwing task. Participants could fully observe the effects of their throwing actions (ball trajectory, and either hitting or missing a target) in most of the trials. In a portion of the trials, the ball trajectory was not visible, and participants only received static information about the outcome. We observed a large proportion of predictive saccades, shifting gaze toward the goal region before the ball arrived and outcome feedback became available. Fixation locations after predictive saccades systematically covaried with future ball positions in trials with continuous ball flight information, but notably also in trials with static outcome feedback and only efferent and proprioceptive information about the movement that could be used for predictions. Fixation durations at the chosen positions after feedback onset were modulated by action outcome (longer durations for misses than for hits) and outcome uncertainty (longer durations for narrow vs. clear outcomes). Combining both effects, durations were longest for narrow errors and shortest for clear hits, indicating that the chosen locations offer informational value for feedback processing. Thus, humans are able to use sensorimotor predictions to direct their gaze toward task-relevant feedback locations. Outcome-dependent saccade latency differences (miss vs. hit) indicate that also predictive valuation processes are involved in planning predictive saccades.

A Novel RNA Aptamer as Synthetic Inducer of DasR Controlled Transcription.

Progress in the synthetic biology field is driven by the development of new tools for synthetic circuit engineering. Traditionally, the focus has relied on protein-based designs. In recent years, the use of RNA-based tools has tremendously increased, due to their versatile functionality and applicability. A promising class of molecules is RNA aptamers, small, single-stranded RNA molecules that bind to a target molecule with high affinity and specificity. When targeting bacterial repressors, RNA aptamers allow one to add a new layer to an established protein-based regulation. In the present study, we selected an RNA aptamer binding the bacterial repressor DasR, preventing its binding to its operator sequence and activating DasR-controlled transcription in vivo. This was made possible only by the combination of an in vitro selection and subsequent in vivo screening. Next-generation sequencing of the selection process proved the importance of the in vivo screening for the discovery of aptamers functioning in the cell. Mutational and biochemical studies led to the identification of the minimal necessary binding motif. Taken together, the resulting combination of bacterial repressor and RNA aptamer enlarges the synthetic biology toolbox by adding a new level of regulation.

Development of a novel tobramycin dependent riboswitch.

We herein report the selection and characterization of a new riboswitch dependent on the aminoglycoside tobramycin. Its dynamic range rivals even the tetracycline dependent riboswitch to be the current best performing, synthetic riboswitch that controls translation initiation. The riboswitch was selected with RNA Capture-SELEX, a method that not only selects for binding but also for structural changes in aptamers on binding. This study demonstrates how this method can fundamentally reduce the labour required for the de novo identification of synthetic riboswitches. The initially selected riboswitch candidate harbours two distinct tobramycin binding sites with KDs of 1.1 nM and 2.4 µM, respectively, and can distinguish between tobramycin and the closely related compounds kanamycin A and B. Using detailed genetic and biochemical analyses and 1H NMR spectroscopy, the proposed secondary structure of the riboswitch was verified and the tobramycin binding sites were characterized. The two binding sites were found to be essentially non-overlapping, allowing for a separate investigation of their contribution to the activity of the riboswitch. We thereby found that only the high-affinity binding site was responsible for regulatory activity, which allowed us to engineer a riboswitch from only this site with a minimal sequence size of 33 nt and outstanding performance.

Motor outcomes congruent with intentions may sharpen metacognitive representations.

We can monitor our intentional movements and form explicit representations about our movements, allowing us to describe how we move our bodies. But it is unclear which information this metacognitive monitoring relies on. For example, when throwing a ball to hit a target, we might use the visual information about how the ball flew to metacognitively assess our performance. Alternatively, we might disregard the ball trajectory - given that it is not directly relevant to our goal - and metacognitively assess our performance based solely on whether we reached the goal of hitting the target. In two experiments we aimed to distinguish between these two alternatives and asked whether the distal outcome of a goal-directed action (hitting or missing a target) informs the metacognitive representations of our own movements. Participants performed a semi-virtual task where they moved their arm to throw a virtual ball at a target. After each throw, participants discriminated which of two ball trajectories displayed on the screen corresponded to the flight path of their throw and then rated their confidence in this decision. The task included two conditions that differed on whether the distal outcome of the two trajectories shown matched (congruent) or differed (incongruent). Participants were significantly more accurate in discriminating between the two trajectories, and responded faster in the incongruent condition and, accordingly, were significantly more confident on these trials. Crucially, we found significant differences in metacognitive performance (measured as meta-d'/d') between the two conditions only on successful trials, where the virtual ball had hit the target. These results indicate that participants successfully incorporated information about the outcome of the movement into both their discrimination and confidence responses. However, information about the outcome selectively sharpened the precision of confidence ratings only when the outcome of their throw matched their intention. We argue that these findings underline the separation between the different levels of information that may contribute to body monitoring, and we provide evidence that intentions might play a central role in metacognitive motor representations.

Metacognitive Domains Are Not Aligned along a Dimension of Internal-External Information Source.

It is still debated whether metacognition, or the ability to monitor our own mental states, relies on processes that are "domain-general" (a single set of processes can account for the monitoring of any mental process) or "domain-specific" (metacognition is accomplished by a collection of multiple monitoring modules, one for each cognitive domain). It has been speculated that two broad categories of metacognitive processes may exist: those that monitor primarily externally generated versus those that monitor primarily internally generated information. To test this proposed division, we measured metacognitive performance (using m-ratio, a signal detection theoretical measure) in four tasks that could be ranked along an internal-external axis of the source of information, namely memory, motor, visuomotor, and visual tasks. We found correlations between m-ratios in visuomotor and motor tasks, but no correlations between m-ratios in visual and visuomotor tasks, or between motor and memory tasks. While we found no correlation in metacognitive ability between visual and memory tasks, and a positive correlation between visuomotor and motor tasks, we found no evidence for a correlation between motor and memory tasks. This pattern of correlations does not support the grouping of domains based on whether the source of information is primarily internal or external. We suggest that other groupings could be more reflective of the nature of metacognition and discuss the need to consider other non-domain task-features when using correlations as a way to test the underlying shared processes between domains.

BRCA1-associated RING domain-1 (BARD1) loss and GBP1 expression enhance sensitivity to DNA damage in Ewing sarcoma.

Ewing sarcoma is a fusion oncoprotein-driven primary bone tumor. A subset of patients (~10%) with Ewing sarcoma are known to harbor germline variants in a growing number of genes involved in DNA damage repair. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. We thus questioned the impact of BARD1 loss on Ewing cell sensitivity to DNA damage and the Ewing sarcoma transcriptome. We demonstrate that PSaRC318 cells, a novel patient-derived cell line harboring a pathogenic BARD1 variant, are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that BARD1 loss enhances cell sensitivity to PARP inhibition plus radiation. Additionally, RNA-seq analysis revealed that loss of BARD1 results in the upregulation of GBP1 (guanylate-binding protein 1), a protein whose expression is associated with variable response to therapy depending on the adult carcinoma subtype examined. Here, we demonstrate that GBP1 contributes to the enhanced sensitivity of BARD1 deficient Ewing cells to DNA damage. Together, our findings demonstrate the impact of loss-of function mutations in DNA damage repair genes, such as BARD1, on Ewing sarcoma treatment response.

Predictability shapes movement kinematics and grip force regulation in human object handovers.

In contrast to a self-generated action, a human-to-human object handover represents a semi-predictable task, due to a lack of exact knowledge about the partner's future movement behavior. Thus far, it has not been determined which behavioral characteristics result from dealing with this prevailing uncertainty, although this distinction would enhance the understanding of underlying motor control strategies in such semi-predictable situations. Behavioral effects of mutual interaction during object handovers were therefore investigated in the current study, by comparing grip force profiles and kinematic data from predictable solo-handovers (between the two hands of one person) with data from semi-predictable partner-handovers. There were significant decreases in passers' mean release rates as well as corresponding increases in handover durations in partner-handovers compared to solo-handovers. Likewise, receivers in partner-handovers employed lower mean grip force rates to take the object, which speaks for feedback reliance of both partners in the load transfer process of partner-handovers. Increased vertical object displacement in this phase might represent timing deficits due to the prediction uncertainties in partner-handovers. The data also provided first evidence that left-handed people serving as receivers in partner-handovers exhibit an altered take-over strategy compared to right-handed receivers.

Can Stephen Curry really know?-Conscious access to outcome prediction of motor actions.

The NBA player Stephen Curry has a habit of turning away from the basket right after taking three-point shots even before the ball reaches the basket, suggesting that he can reliably predict whether the just released shot will hit or not. In order to use this "knowledge" to deliberately decide which action to take next, Stephen Curry needs conscious access to the results of internal processes of outcome prediction and valuation. In general, computational simulations and empirical data suggest that the quality of such internal predictions is related to motor skill level. Whether the results of internal predictions can reliably be consciously accessed, however, is less clear. In the current study, 30 participants each practiced a virtual goal-oriented throwing task for 1000 trials. Every second trial, they were required to verbally predict the success of the current throw. Results showed that on average, verbal prediction accuracy was above an individually computed chance level, taking into account individual success rates and response strategies. Furthermore, prediction accuracy was related to task skill level. Participants with better performances predicted the success of their throws more accurately than participants with poorer performances. For the poorer performing individuals, movement execution was negatively affected when the verbalized predictions were required. They also showed no noticeable modulation of speech characteristics (response latency) for correct and incorrect predictions as observed in the high performers.

Relevance of Predictive and Postdictive Error Information in the Course of Motor Learning.

The prediction of the sensory consequences of physical movements is a fundamental feature of the human brain. This function is attributed to a forward model, which generates predictions based on sensory and efferent information. The neural processes underlying such predictions have been studied using the error-related negativity (ERN) as a fronto-central event-related potential in electroencephalogram (EEG) tracings. In this experiment, 16 participants practiced a novel motor task for 4000 trials over ten sessions. Neural correlates of error processing were recorded in sessions one, five, and ten. Along with significant improvements in task performance, the ERN amplitude increased over the sessions. Simultaneously, the feedback-related negativity (FRN), a neural marker corresponding to the processing of movement-outcome feedback, attenuated with learning. The findings suggest that early in learning, the motor control system relies more on information from external feedback about terminal outcome. With increasing task performance, the forward model is able to generate more accurate outcome predictions, which, as a result, increasingly contributes to error processing. The data also suggests a complementary relationship between the ERN and the FRN over motor learning.

Measuring metacognition of direct and indirect parameters of voluntary movement.

We can make exquisitely precise movements without the apparent need for conscious monitoring. But can we monitor the low-level movement parameters when prompted? And what are the mechanisms that allow us to monitor our movements? To answer these questions, we designed a semivirtual ball throwing task. On each trial, participants first threw a virtual ball by moving their arm (with or without visual feedback, or replayed from a previous trial) and then made a two-alternative forced choice on the resulting ball trajectory. They then rated their confidence in their decision. We measured metacognitive efficiency using meta-d'/d' and compared it between different informational domains of the first-order task (motor, visuomotor or visual information alone), as well as between two different versions of the task based on different parameters of the movement: proximal (position of the arm) or distal (resulting trajectory of the ball thrown). We found that participants were able to monitor their performance based on distal motor information as well as when proximal information was available. Their metacognitive efficiency was also equally high in conditions with different sources of information available. The analysis of correlations across participants revealed an unexpected result: While metacognitive efficiency correlated between informational domains (which would indicate domain-generality of metacognition), it did not correlate across the different parameters of movement. We discuss possible sources of this discrepancy and argue that specific first-order task demands may play a crucial role in our metacognitive ability and should be considered when making inferences about domain-generality based on correlations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Focused Review on Neural Correlates of Different Types of Motor Errors and Related Terminological Issues.

The Error-related negativity (Ne/ERN) and the feedback-related negativity (FRN), two event-related potentials in electroencephalogram tracings, have been used to examine error processing in conscious actions. In the classical terminology the Ne/ERN and the FRN are differentiated with respect to whether internal (Ne/ERN) or external (FRN) error information is processed. In motor tasks, however, errors of different types can be made: A wrong action can be selected that is not adequate to achieve the task goal (or action effect), or the correctly selected action can be mis-performed such that the task goal might be missed (movement error). Depending on the motor task and the temporal sequences of these events, internal and external error information can coincide. Hence, a clear distinction of the information source is difficult, and the classical terminology that differentiates the Ne/ERN and the FRN with respect to internal and external error information becomes ambiguous. But, a stronger focus on the characteristics of the definition of "task" and the cause of "errors", as well as on temporal characteristics of event-related potentials with respect to the task action allows separate examination of the processing of movement errors, the processing of the prediction of action effect errors, or the processing of the detection of action effect errors. The present article gives an overview of example studies investigating the Ne/ERN and the FRN in motor tasks, classifies them with respect to action effect errors or movement errors, and proposes updated terminology.

Critical protein-protein interactions within the CARMA1-BCL10-MALT1 complex: Take-home points for the cell biologist.

The CBM complex, which is composed of the proteins CARMA1, BCL10, and MALT1, serves multiple pivotal roles as a mediator of T-cell receptor and B-cell receptor-dependent NF-κB induction and lymphocyte activation. CARMA1, BCL10, and MALT1 are each proto-oncoproteins and dysregulation of CBM signaling, as a result of somatic gain-of-function mutation or chromosomal translocation, is a hallmark of multiple lymphoid malignancies including Activated B-cell Diffuse Large B-cell Lymphoma. Moreover, loss-of-function as well as gain-of-function germline mutations in CBM complex proteins have been associated with a range of immune dysregulation syndromes. A wealth of detailed structural information has become available over the past decade through meticulous interrogation of the interactions between CBM components. Here, we review key findings regarding the biochemical nature of these protein-protein interactions which have ultimately led the field to a sophisticated understanding of how these proteins assemble into high-order filamentous CBM complexes. To date, approaches to therapeutic inhibition of the CBM complex for the treatment of lymphoid malignancy and/or auto-immunity have focused on blocking MALT1 protease function. We also review key studies relating to the structural impact of MALT1 protease inhibitors on key protein-protein interactions.

GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.

Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.

Valence-dependent brain potentials of processing augmented feedback in learning a complex arm movement sequence.

ERPs in the EEG were scrutinized in learning a complex arm movement sequence with the aim to examine valence effects on processing augmented feedback during practice. Twenty-four healthy subjects practiced one session with 192 feedback trials according to an adaptive bandwidth feedback approach with a high informational level of feedback information (i.e., amplitude and direction of errors). The bandwidth for successful performance (increase of a score for a monetary competition) was manipulated to yield a success rate (positive feedback frequency) of approximately 50% adaptive to the current performance level. This allowed a variation of feedback valence unconfounded by success rate. In line with our hypotheses, the EEG data showed a valence-dependent feedback-related negativity (FRN) and a later fronto-central component at the FCz electrode as well as a P300 component at the Pz electrode. Moreover, the P300 and amplitudes in the FRN time window reduced in the second half of practice but were still dependent on feedback valence. Behavioral adjustments were larger after feedback with negative valence and were predicted by the late fronto-central component. The data support the assumption of feedback valence-dependent modulation of attentional cognitive involvement in motor control and learning.

Predictive error processing distinguishes between relevant and irrelevant errors after visuomotor learning.

Error processing is an important aspect of learning. The detection and online correction of an error as well as error-based adaptation of subsequent movements enables humans to improve behavior. For this improvement, it is necessary to differentiate between relevant and irrelevant errors. Behavioral adaptations are only reasonable when an error is attributed to one's own behavior and therefore regarded as relevant for subsequent adjustments, whereas irrelevant errors caused by unsystematic external influences should be disregarded. Here, we ask whether error predictions as indexed by the error-related negativity (Ne/ERN) can be used to differentiate relevant and irrelevant errors in movements with a complex visuomotor mapping. Using event-related potentials, we compared the neural activation between relevant (self-induced/internal) errors and irrelevant (externally manipulated) errors in a virtual goal-oriented throwing task. Results show that the Ne/ERN responds more strongly to self-induced errors, while the feedback-related negativity (FRN) more strongly correlates with externally manipulated errors. Moreover, subsequent behavioral adjustments were larger in the relevant compared to the irrelevant error trials. We conclude that predictive processes, marked by the Ne/ERN, can subserve error attribution in naturalistic, complex visuomotor tasks like throwing.

Inference statistical analysis of continuous data based on confidence bands-Traditional and new approaches.

In the analysis of continuous data, researchers are often faced with the problem that statistical methods developed for single-point data (e.g., t test, analysis of variance) are not always appropriate for their purposes. Either methodological adaptations of single-point methods will need to be made, or confidence bands are the method of choice. In this article, we compare three prominent techniques to analyze continuous data (single-point methods, Gaussian confidence bands, and function-based resampling methods to construct confidence bands) with regard to their testing principles, prerequisites, and outputs in the analysis of continuous data. In addition, we introduce a new technique that combines the advantages of the existing methods and can be applied to a wide range of data. Furthermore, we introduce a method enabling a priori and a posteriori power analyses for experiments with continuous data.

'Medical Clearance' of Patients With Acute Mental Health Needs in the Emergency Department: A Literature Review and Practice Recommendations.

INTRODUCTION: Emergency departments have seen increasing numbers of patients presenting with acute mental illness. Currently, there is not a standard for assessing the medical stability of these patients prior to transfer to inpatient psychiatric services, which causes unnecessary delays in patient care. OBJECTIVE: Provide a literature review and multidisciplinary expert consensus recommendations to simplify and expedite the medical evaluation of patients requiring admission to inpatient psychiatric facilities. METHODS: A task force with representation from emergency physicians (Wisconsin Chapter of the American College of Emergency Physicians) and psychiatrists (Wisconsin Psychiatric Association) met to create this position statement. The members reviewed clinical practice guidelines and primary literature sources to develop evidence-based recommendations. RESULTS: Five categories of recommendations were developed: (1) A detailed history and physical exam should constitute the minimum necessary information required for most medical assessments. (2) Clinical information should guide further diagnostic testing; therefore, receiving facility blanket requirements for routine testing should be abandoned. (3) Emergency physicians should understand the limited medical capabilities of institutes of mental disease. Obtaining reasonable diagnostic testing that is not available at these facilities may be appropriate, though this should not delay patient transfer. (4) Structured medical evaluation algorithms should be used to enhance the uniformity of medical assessments for these patients. This task force recommends the Wisconsin SMART Form. (5) Emergency physicians and psychiatrists should communicate more regularly without intermediaries, both at the clinical encounter and beyond. CONCLUSION: The recommendations in this paper are endorsed by the Wisconsin Chapter of the American College of Emergency Physicians and the Wisconsin Psychiatric Association, which strongly urge affected medical providers to adopt them into routine practice.

Accuracy of Motor Error Predictions for Different Sensory Signals.

Detecting and evaluating errors in action execution is essential for learning. Through complex interactions of the inverse and the forward model, the human motor system can predict and subsequently adjust ongoing or subsequent actions. Inputs to such a prediction are efferent and afferent signals from various sources. The aim of the current study was to examine the impact of visual as well as a combination of efferent and proprioceptive input signals to error prediction in a complex motor task. Predicting motor errors has been shown to be correlated with a neural signal known as the error-related negativity (Ne/ERN). Here, we tested how the Ne/ERN amplitude was modulated by the availability of different sensory signals in a semi-virtual throwing task where the action outcome (hit or miss of the target) was temporally delayed relative to movement execution allowing participants to form predictions about the outcome prior to the availability of knowledge of results. 19 participants practiced the task and electroencephalogram was recorded in two test conditions. In the Visual condition, participants received only visual input by passively observing the throwing movement. In the EffProp condition, participants actively executed the task while visual information about the real and the virtual effector was occluded. Hence, only efferent and proprioceptive signals were available. Results show a significant modulation of the Ne/ERN in the Visual condition while no effect could be observed in the EffProp condition. In addition, amplitudes of the feedback-related negativity in response to the actual outcome feedback were found to be inversely related to the Ne/ERN amplitudes. Our findings indicate that error prediction is modulated by the availability of input signals to the forward model. The observed amplitudes were found to be attenuated in comparison to previous studies, in which all efferent and sensory inputs were present. Furthermore, we assume that visual signals are weighted higher than proprioceptive signals, at least in goal-oriented tasks with visual targets.