An interactive motion perception tool for kindergarteners (and vision scientists).

We implement Adelson and Bergen's spatiotemporal energy model with extension to three-dimensional (x-y-t) in an interactive tool. It helps gain an easy understanding of early (first-order) visual motion perception. We demonstrate its usefulness in explaining an assortment of phenomena, including some that are typically not associated with the spatiotemporal energy model.

Protein structure prediction with in-cell photo-crosslinking mass spectrometry and deep learning.

While AlphaFold2 can predict accurate protein structures from the primary sequence, challenges remain for proteins that undergo conformational changes or for which few homologous sequences are known. Here we introduce AlphaLink, a modified version of the AlphaFold2 algorithm that incorporates experimental distance restraint information into its network architecture. By employing sparse experimental contacts as anchor points, AlphaLink improves on the performance of AlphaFold2 in predicting challenging targets. We confirm this experimentally by using the noncanonical amino acid photo-leucine to obtain information on residue-residue contacts inside cells by crosslinking mass spectrometry. The program can predict distinct conformations of proteins on the basis of the distance restraints provided, demonstrating the value of experimental data in driving protein structure prediction. The noise-tolerant framework for integrating data in protein structure prediction presented here opens a path to accurate characterization of protein structures from in-cell data.

[Metabolic acidosis in neobladder patients : Risk factors and treatment options]. / Metabolische Azidose bei Neoblasepatienten : Risikofaktoren und Therapiemöglichkeiten.

BACKGROUND: In cystectomy patients who underwent neobladder creation, the intestinal mucosa of the neobladder is in constant contact with urine, which may result in chronic metabolic acidosis (CMA) due to specific absorption capabilities of the intestinal mucosa. Despite being a prevalent comorbidity, the risk factors for CMA and its diagnostic parameters are poorly understood. OBJECTIVES: This review examines the risk factors associated with the development of CMA and their prevalence in patients with a neobladder. MATERIALS AND METHODS: We conducted a systematic literature search using the PubMed database to detect studies about the topics CMA and neobladder that were published between 2000 and 2020. The prevalence and risk factors for CMA in neobladder patients were assessed by reviewing 23 studies. RESULTS: Acidosis is most prevalent during the first year after surgery (25-70%). Risk factors are renal failure, high continence, old age and diabetes mellitus. CONCLUSIONS: The prevalence of CMA is at its highest during the early postoperative period for neobladder patients, so for this time period, weekly diagnostic investigations are recommended according to the German S3-guidelines for the "Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinomsent für Neoblasepatienten". Blood gas tests should not only be used to analyze the pH value but also to detect and counteract acid-base imbalance issues in time. The recommended normalization of serum bicarbonate levels with oral bicarbonate follows patient-specific therapy strategies.

Association between Development of Metabolic Acidosis and Improvement of Urinary Continence after Ileal Neobladder Creation.

PURPOSE: Ileal neobladder construction is a common choice for orthotopic urinary diversion following radical cystectomy. We investigated risk factors for metabolic acidosis during the early recovery period. MATERIALS AND METHODS: This study relied on retrospectively collected data on 345 patients who underwent inpatient rehabilitation after radical cystectomy and ileal neobladder construction for bladder cancer between January 2014 and March 2017. Acid-base status, use of sodium bicarbonate to correct metabolic acidosis and continence status were evaluated at the beginning and end of 3 weeks of inpatient rehabilitation. Multivariate logistic regression analysis was performed to identify risk factors associated with the development of metabolic acidosis. RESULTS: At the start of rehabilitation a median of 29 days after surgery (IQR 23-37) 200 patients (58.0%) had metabolic acidosis. During the inpatient rehabilitation period the need for oral sodium bicarbonate replacement due to acidosis increased significantly from 45.2% to 86.7% of patients (p <0.001) while urine loss measured by a 24-hour pad test decreased significantly from a median of 387 (IQR 98-918) to 88 gm (IQR 5-388, p <0.001). The median base excess was within the normal range (-1.2 mmol/l, IQR -2.4 - 0.0) at the end of inpatient rehabilitation. Decreased urinary leakage was identified as an independent risk factor for metabolic acidosis.Conclusions:The risk of metabolic acidosis after neobladder construction correlated with continuously improved continence in the early recovery period. Therefore, during this period the acid-base status should be assessed more frequently to identify metabolic acidosis.

No free lunch in ball catching: A comparison of Cartesian and angular representations for control.

How to run most effectively to catch a projectile, such as a baseball, that is flying in the air for a long period of time? The question about the best solution to the ball catching problem has been subject to intense scientific debate for almost 50 years. It turns out that this scientific debate is not focused on the ball catching problem alone, but revolves around the research question what constitutes the ingredients of intelligent decision making. Over time, two opposing views have emerged: the generalist view regarding intelligence as the ability to solve any task without knowing goal and environment in advance, based on optimal decision making using predictive models; and the specialist view which argues that intelligent decision making does not have to be based on predictive models and not even optimal, advocating simple and efficient rules of thumb (heuristics) as superior to enable accurate decisions. We study two types of approaches to the ball catching problem, one for each view, and investigate their properties using both a theoretical analysis and a broad set of simulation experiments. Our study shows that neither of the two types of approaches can be regarded as superior in solving all relevant variants of the ball catching problem: each approach is optimal under a different realistic environmental condition. Therefore, predictive models neither guarantee nor prevent success a priori, and we further show that the key difference between the generalist and the specialist approach to ball catching is the type of input representation used to control the agent. From this finding, we conclude that the right solution to a decision making or control problem is orthogonal to the generalist and specialist approach, and thus requires a reconciliation of the two views in favor of a representation-centric view.

Elastic network model of learned maintained contacts to predict protein motion.

We present a novel elastic network model, lmcENM, to determine protein motion even for localized functional motions that involve substantial changes in the protein's contact topology. Existing elastic network models assume that the contact topology remains unchanged throughout the motion and are thus most appropriate to simulate highly collective function-related movements. lmcENM uses machine learning to differentiate breaking from maintained contacts. We show that lmcENM accurately captures functional transitions unexplained by the classical ENM and three reference ENM variants, while preserving the simplicity of classical ENM. We demonstrate the effectiveness of our approach on a large set of proteins covering different motion types. Our results suggest that accurately predicting a "deformation-invariant" contact topology offers a promising route to increase the general applicability of ENMs. We also find that to correctly predict this contact topology a combination of several features seems to be relevant which may vary slightly depending on the protein. Additionally, we present case studies of two biologically interesting systems, Ferric Citrate membrane transporter FecA and Arachidonate 15-Lipoxygenase.

EPSILON-CP: using deep learning to combine information from multiple sources for protein contact prediction.

BACKGROUND: Accurately predicted contacts allow to compute the 3D structure of a protein. Since the solution space of native residue-residue contact pairs is very large, it is necessary to leverage information to identify relevant regions of the solution space, i.e. correct contacts. Every additional source of information can contribute to narrowing down candidate regions. Therefore, recent methods combined evolutionary and sequence-based information as well as evolutionary and physicochemical information. We develop a new contact predictor (EPSILON-CP) that goes beyond current methods by combining evolutionary, physicochemical, and sequence-based information. The problems resulting from the increased dimensionality and complexity of the learning problem are combated with a careful feature analysis, which results in a drastically reduced feature set. The different information sources are combined using deep neural networks. RESULTS: On 21 hard CASP11 FM targets, EPSILON-CP achieves a mean precision of 35.7% for top- L/10 predicted long-range contacts, which is 11% better than the CASP11 winning version of MetaPSICOV. The improvement on 1.5L is 17%. Furthermore, in this study we find that the amino acid composition, a commonly used feature, is rendered ineffective in the context of meta approaches. The size of the refined feature set decreased by 75%, enabling a significant increase in training data for machine learning, contributing significantly to the observed improvements. CONCLUSIONS: Exploiting as much and diverse information as possible is key to accurate contact prediction. Simply merging the information introduces new challenges. Our study suggests that critical feature analysis can improve the performance of contact prediction methods that combine multiple information sources. EPSILON-CP is available as a webservice: http://compbio.robotics.tu-berlin.de/epsilon/.

Blind Evaluation of Hybrid Protein Structure Analysis Methods based on Cross-Linking.

Hybrid methods combine experimental data and computational modeling to analyze protein structures that are elusive to structure determination. To spur the development of hybrid methods, we propose to test them in the context of the CASP experiment and would like to invite experimental groups to participate in this initiative.

Blind testing of cross-linking/mass spectrometry hybrid methods in CASP11.

Hybrid approaches combine computational methods with experimental data. The information contained in the experimental data can be leveraged to probe the structure of proteins otherwise elusive to computational methods. Compared with computational methods, the structures produced by hybrid methods exhibit some degree of experimental validation. In spite of these advantages, most hybrid methods have not yet been validated in blind tests, hampering their development. Here, we describe the first blind test of a specific cross-link based hybrid method in CASP. This blind test was coordinated by the CASP organizers and utilized a novel, high-density cross-linking/mass-spectrometry (CLMS) approach that is able to collect high-density CLMS data in a matter of days. This experimental protocol was developed in the Rappsilber laboratory. This approach exploits the chemistry of a highly reactive, photoactivatable cross-linker to produce an order of magnitude more cross-links than homobifunctional cross-linkers. The Rappsilber laboratory generated experimental CLMS data based on this protocol, submitted the data to the CASP organizers which then released this data to the CASP11 prediction groups in a separate, CLMS assisted modeling experiment. We did not observe a clear improvement of assisted models, presumably because the properties of the CLMS data-uncertainty in cross-link identification and residue-residue assignment, and uneven distribution over the protein-were largely unknown to the prediction groups and their approaches were not yet tailored to this kind of data. We also suggest modifications to the CLMS-CASP experiment and discuss the importance of rigorous blind testing in the development of hybrid methods. Proteins 2016; 84(Suppl 1):152-163. © 2016 The Authors Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

Blind testing cross-linking/mass spectrometry under the auspices of the 11th critical assessment of methods of protein structure prediction (CASP11).

Determining the structure of a protein by any method requires various contributions from experimental and computational sides. In a recent study, high-density cross-linking/mass spectrometry (HD-CLMS) data in combination with ab initio structure prediction determined the structure of human serum albumin (HSA) domains, with an RMSD to X-ray structure of up to 2.5 Å, or 3.4 Å in the context of blood serum. This paper reports the blind test on the readiness of this technology through the help of Critical Assessment of protein Structure Prediction (CASP). We identified between 201-381 unique residue pairs at an estimated 5% FDR (at link level albeit with missing site assignment precision evaluation), for four target proteins. HD-CLMS proved reliable once crystal structures were released. However, improvements in structure prediction using cross-link data were slight. We identified two reasons for this. Spread of cross-links along the protein sequence and the tightness of the spatial constraints must be improved. However, for the selected targets even ideal contact data derived from crystal structures did not allow modellers to arrive at the observed structure. Consequently, the progress of HD-CLMS in conjunction with computational modeling methods as a structure determination method, depends on advances on both arms of this hybrid approach.

Serum Albumin Domain Structures in Human Blood Serum by Mass Spectrometry and Computational Biology.

Chemical cross-linking combined with mass spectrometry has proven useful for studying protein-protein interactions and protein structure, however the low density of cross-link data has so far precluded its use in determining structures de novo. Cross-linking density has been typically limited by the chemical selectivity of the standard cross-linking reagents that are commonly used for protein cross-linking. We have implemented the use of a heterobifunctional cross-linking reagent, sulfosuccinimidyl 4,4'-azipentanoate (sulfo-SDA), combining a traditional sulfo-N-hydroxysuccinimide (sulfo-NHS) ester and a UV photoactivatable diazirine group. This diazirine yields a highly reactive and promiscuous carbene species, the net result being a greatly increased number of cross-links compared with homobifunctional, NHS-based cross-linkers. We present a novel methodology that combines the use of this high density photo-cross-linking data with conformational space search to investigate the structure of human serum albumin domains, from purified samples, and in its native environment, human blood serum. Our approach is able to determine human serum albumin domain structures with good accuracy: root-mean-square deviation to crystal structure are 2.8/5.6/2.9 Å (purified samples) and 4.5/5.9/4.8Å (serum samples) for domains A/B/C for the first selected structure; 2.5/4.9/2.9 Å (purified samples) and 3.5/5.2/3.8 Å (serum samples) for the best out of top five selected structures. Our proof-of-concept study on human serum albumin demonstrates initial potential of our approach for determining the structures of more proteins in the complex biological contexts in which they function and which they may require for correct folding. Data are available via ProteomeXchange with identifier PXD001692.

Analysis of free modeling predictions by RBO aleph in CASP11.

The CASP experiment is a biannual benchmark for assessing protein structure prediction methods. In CASP11, RBO Aleph ranked as one of the top-performing automated servers in the free modeling category. This category consists of targets for which structural templates are not easily retrievable. We analyze the performance of RBO Aleph and show that its success in CASP was a result of its ab initio structure prediction protocol. A detailed analysis of this protocol demonstrates that two components unique to our method greatly contributed to prediction quality: residue-residue contact prediction by EPC-map and contact-guided conformational space search by model-based search (MBS). Interestingly, our analysis also points to a possible fundamental problem in evaluating the performance of protein structure prediction methods: Improvements in components of the method do not necessarily lead to improvements of the entire method. This points to the fact that these components interact in ways that are poorly understood. This problem, if indeed true, represents a significant obstacle to community-wide progress. Proteins 2016; 84(Suppl 1):87-104. © 2015 Wiley Periodicals, Inc.

RBO Aleph: leveraging novel information sources for protein structure prediction.

RBO Aleph is a novel protein structure prediction web server for template-based modeling, protein contact prediction and ab initio structure prediction. The server has a strong emphasis on modeling difficult protein targets for which templates cannot be detected. RBO Aleph's unique features are (i) the use of combined evolutionary and physicochemical information to perform residue-residue contact prediction and (ii) leveraging this contact information effectively in conformational space search. RBO Aleph emerged as one of the leading approaches to ab initio protein structure prediction and contact prediction during the most recent Critical Assessment of Protein Structure Prediction experiment (CASP11, 2014). In addition to RBO Aleph's main focus on ab initio modeling, the server also provides state-of-the-art template-based modeling services. Based on template availability, RBO Aleph switches automatically between template-based modeling and ab initio prediction based on the target protein sequence, facilitating use especially for non-expert users. The RBO Aleph web server offers a range of tools for visualization and data analysis, such as the visualization of predicted models, predicted contacts and the estimated prediction error along the model's backbone. The server is accessible at http://compbio.robotics.tu-berlin.de/rbo_aleph/.

Learning to explore the structure of kinematic objects in a virtual environment.

The current study tested the quantity and quality of human exploration learning in a virtual environment. Given the everyday experience of humans with physical object exploration, we document substantial practice gains in the time, force, and number of actions needed to classify the structure of virtual chains, marking the joints as revolute, prismatic, or rigid. In line with current work on skill acquisition, participants could generalize the new and efficient psychomotor patterns of object exploration to novel objects. On the one hand, practice gains in exploration performance could be captured by a negative exponential practice function. On the other hand, they could be linked to strategies and strategy change. After quantifying how much was learned in object exploration and identifying the time course of practice-related gains in exploration efficiency (speed), we identified what was learned. First, we identified strategy components that were associated with efficient (fast) exploration performance: sequential processing, simultaneous use of both hands, low use of pulling rather than pushing, and low use of force. Only the latter was beneficial irrespective of the characteristics of the other strategy components. Second, we therefore characterized efficient exploration behavior by strategies that simultaneously take into account the abovementioned strategy components. We observed that participants maintained a high level of flexibility, sampling from a pool of exploration strategies trading the level of psycho-motoric challenges with exploration speed. We discuss the findings pursuing the aim of advancing intelligent object exploration by combining analytic (object exploration in humans) and synthetic work (object exploration in robots) in the same virtual environment.

Combining physicochemical and evolutionary information for protein contact prediction.

We introduce a novel contact prediction method that achieves high prediction accuracy by combining evolutionary and physicochemical information about native contacts. We obtain evolutionary information from multiple-sequence alignments and physicochemical information from predicted ab initio protein structures. These structures represent low-energy states in an energy landscape and thus capture the physicochemical information encoded in the energy function. Such low-energy structures are likely to contain native contacts, even if their overall fold is not native. To differentiate native from non-native contacts in those structures, we develop a graph-based representation of the structural context of contacts. We then use this representation to train an support vector machine classifier to identify most likely native contacts in otherwise non-native structures. The resulting contact predictions are highly accurate. As a result of combining two sources of information--evolutionary and physicochemical--we maintain prediction accuracy even when only few sequence homologs are present. We show that the predicted contacts help to improve ab initio structure prediction. A web service is available at http://compbio.robotics.tu-berlin.de/epc-map/.

Guiding conformation space search with an all-atom energy potential.

The most significant impediment for protein structure prediction is the inadequacy of conformation space search. Conformation space is too large and the energy landscape too rugged for existing search methods to consistently find near-optimal minima. To alleviate this problem, we present model-based search, a novel conformation space search method. Model-based search uses highly accurate information obtained during search to build an approximate, partial model of the energy landscape. Model-based search aggregates information in the model as it progresses, and in turn uses this information to guide exploration toward regions most likely to contain a near-optimal minimum. We validate our method by predicting the structure of 32 proteins, ranging in length from 49 to 213 amino acids. Our results demonstrate that model-based search is more effective at finding low-energy conformations in high-dimensional conformation spaces than existing search methods. The reduction in energy translates into structure predictions of increased accuracy.

A methodology for efficiently sampling the conformation space of molecular structures.

Motivated by recently developed computational techniques for studying protein flexibility, and their potential applications in docking, we propose an efficient method for sampling the conformational space of complex molecular structures. We focus on the loop closure problem, identified in the work of Thorpe and Lei (2004 Phil. Mag. 84 1323-31) as a primary bottleneck in the fast simulation of molecular motions. By modeling a molecular structure as a branching robot, we use an intuitive method in which the robot holds onto itself for maintaining loop constraints. New conformations are generated by applying random external forces, while internal, attractive forces pull the loops closed. Our implementation, tested on several model molecules with low number of degrees of freedom but many interconnected loops, gives promising results that show an almost four times speed-up on the benchmark cube-molecule of Thorpe and Lei.

Improving protein structure prediction with model-based search.

MOTIVATION: De novo protein structure prediction can be formulated as search in a high-dimensional space. One of the most frequently used computational tools to solve such search problems is the Monte Carlo method. We present a novel search technique, called model-based search. This method samples the high-dimensional search space to build an approximate model of the underlying function. This model is incrementally refined in areas of interest, whereas areas that are not of interest are excluded from further exploration. Model-based search derives its efficiency from the fact that the information obtained during the exploration of the search space is used to guide further exploration. In contrast, Monte Carlo-based techniques lack memory and exploration is performed based on random walks, ignoring the information obtained in previous steps. RESULTS: Model-based search is applied to protein structure prediction, where search is employed to find the global minimum of the protein's energy landscape. We show that model-based search uses computational resources more efficiently to find lower-energy conformations of proteins than one of the leading protein structure prediction methods, which relies on a tailored Monte Carlo method to perform a search. The performance improvements become more pronounced as the dimensionality of the search problem increases. We argue that model-based search will enable more accurate protein structure prediction than was previously possible. Furthermore, we believe that similar performance improvements can be expected in other problems that are currently solved using Monte Carlo-based search methods. AVAILABILITY: An implementation of model-based search can be obtained by contacting the authors.