bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abelson-induced phosphorylation of TACC3 modulates its interaction with microtubules and affects its impact on axon outgrowth and guidance
Authors: Erdogan Burcu , St. Clair Riley M. , Cammarata Garrett M. , Zaccaro Timothy , Ballif Bryan A. , Lowery Laura Anne 
Published: February 2020

AbstractAxon guidance is a critical process in forming the connections between a neuron and its target. The growth cone steers the growing axon towards the appropriate direction by integrating extracellular guidance cues and initiating intracellular signal transduction pathways downstream of these cues. The growth cone generates these responses by remodeling its cytoskeletal components. Regulation of microtubule dynamics within the growth cone is important for making guidance decisions. TACC3, as a microtubule plus-end binding protein, modulates microtubule dynamics during axon outgrowth and guidance. We have previously shown that embryos depleted of TACC3 displayed spinal cord axon guidance defects, while TACC3-overexpressing spinal neurons showed increased resistance to Slit2-induced growth cone collapse. Here, in order to investigate the mechanism behind TACC3-mediated axon guidance, we studied the importance of tyrosine phosphorylation induced by Abelson tyrosine kinase. We find that the phosphorylatable tyrosines within the TACC domain are important for the microtubule plus-end tracking behavior of TACC3. Moreover, TACC domain phosphorylation impacts axon outgrowth and guidance, and it also regulates microtubule extension into the growth cone periphery. Together, our results suggest that phosphorylation of TACC3 is a key regulatory mechanism by which TACC3 controls axon outgrowth and pathfinding decisions of neurons during embryonic development.
Calcium homeostasis plays important roles in the internalisation and activities of the small synthetic antifungal peptide PAF26
Authors: Alexander Akira JT , Munoz Alberto , Marcos Jose F. , Read Nick D. 
Published: February 2020

ABSTRACTFungal diseases are responsible for the deaths of over 1.5 million people worldwide annually. Antifungal peptides represent a useful source of antifungals with novel mechanisms-of-action, and potentially provide new methods of overcoming resistance. Here we investigate the mode-of-action of the small, rationally designed synthetic antifungal peptide PAF26 using the model fungusNeurospora crassa. Here we show that the cell killing activity of PAF26 is dependent on extracellular Ca2+and the presence of fully functioning fungal Ca2+homeostatic/signalling machinery. In a screen of mutants with deletions in Ca2+-signalling machinery, we identified three mutants more tolerant to PAF26. The Ca2+ATPase NCA-2 was found to be involved in the initial interaction of PAF26 with the cell envelope. The vacuolar Ca2+channel YVC-1 was shown to be essential for its accumulation and concentration within the vacuolar system. The Ca2+channel CCH-1 was found to be required to prevent the translocation of PAF26 across the plasma membrane. In the wild type, Ca2+removal from the medium resulted in the peptide remaining trapped in small vesicles as in theΔyvc-1mutant. It is therefore apparent that cell killing by PAF26 is complex and unusually dependent on extracellular Ca2+and components of the Ca2+-regulatory machinery.AUTHOR SUMMARYLife threatening diseases can be caused when fungi invade human tissues. These invasions often occur when a person’s immune defences are down, often due to treatments for cancer or transplantation. These infections are commonly buried deep within the body and as such are difficult to access and treat. Current medications are often highly toxic to the patient. There is also a worrying rise in drug resistance seen in fungi sampled from patients, with infections effectively untreatable – a death sentence. Antifungal peptides such as PAF26 provide a possible solution by offering a cheap and rapidly produced alternative to conventional drugs. However, unlike antibacterial peptides, little is known about how these small molecules mostly exert their effects and cause death. Using live-cell imaging and deletion mutants, this study provides an analysis of the important roles that Ca2+-homeostasis and Ca2+-signalling, and possible accompanying vacuolar fusion, play during the dynamic internalization and interaction with and within the fungal cell following PAF26 treatment.
Motor training strengthens corticospinal suppression during movement preparation
Authors: Vassiliadis Pierre , Derosiere Gerard , Grandjean Julien , Duque Julie 
Published: February 2020

AbstractTraining can improve motor skills and modify neural activity at rest and during movement execution. Learning-related modulations may also concern motor preparation but the neural correlates and the potential behavioral relevance of such adjustments remain unclear. In humans, preparatory processes have been largely investigated using transcranial magnetic stimulation (TMS) with several studies reporting decreased corticospinal excitability (CSE) relative to a baseline measure; a phenomenon called preparatory suppression. Here, we investigated the effect of motor training on preparatory suppression of CSE in humans, as compared to modulatory changes at rest. We trained participants to initiate quick movements in an instructed-delay reaction time (RT) task and used TMS to investigate changes in CSE over the practice blocks. Training on the task speeded up RTs, with no repercussion on error rates. Training also increased baseline CSE at rest. Most interestingly, we found that motor activity during action preparation did not mirror the training-related rise in resting CSE. Rather, the degree of preparatory suppression from the rising baseline strengthened with practice. This training-related change in preparatory suppression predicted RT gains (but not the changes in baseline CSE): subjects showing a stronger expansion of preparatory suppression were also those exhibiting larger gains in RTs. Finally, such relationship between RTs and preparatory suppression was also evident at the single-trial level: RTs were generally faster in trials where preparatory suppression was deeper. These findings suggest that training induces changes in motor preparatory processes that are linked to an enhanced ability to initiate fast movements.New and NoteworthyAny movement is preceded by a period of preparation, which involves a broad suppression of the corticospinal pathway, a phenomenon called preparatory suppression. Here, we show that motor training strengthens preparatory suppression and that this strengthening is associated with an acceleration of movement initiation. Our findings yield an extension of former work, highlighting a key role of preparatory suppression in training-driven behavioral improvements.
The prospective sense of agency is rooted in local and global properties of intrinsic functional brain networks
Authors: Di Plinio Simone , Gianni Perrucci Mauro , Ebisch Sjoerd J.H. 
Published: February 2020

ABSTRACTThe sense of agency (SoA) refers to a constitutional aspect of the self describing the extent to which individuals feel in control over their actions and consequences thereof. Although the SoA has been associated with mental health and well-being, it is still unknown how interindividual variability in the SoA is embedded in the intrinsic brain organization. We hypothesized that the prospective component of an implicit SoA is associated with brain networks related to SoA and sensorimotor predictions on multiple spatial scales. We replicated previous findings by showing a significant prospective SoA as indicated by intentional binding effects. Then, using task-free functional magnetic resonance imaging (fMRI) and graph analysis, we analyzed associations between intentional binding effects and the intrinsic brain organization at regional, modular, and whole-brain scales. The results showed that inter-modular connections of a fronto-parietal module including the premotor cortex, supramarginal gyrus, and dorsal precuneus are associated with individual differences in prospective intentional binding. Notably, prospective intentional binding effects were also related to global brain modularity within a specific structural resolution range. These findings suggest that an implicit SoA generated through sensorimotor predictions relies on the intrinsic organization of the brain connectome on both local and global scales.
Opposite effects of choice history and stimulus history resolve a paradox of sequential choice bias
Authors: Bosch Ella , Fritsche Matthias , Ehinger Benedikt V. , de Lange Floris P 
Published: February 2020

ABSTRACTPerceptual decisions are biased towards previous decisions. Previous research suggests that this choice repetition bias is increased after previous decisions of high confidence, as inferred from response time measures (Urai et al., 2017), but also when previous decisions were based on weak sensory evidence (Akaishi et al., 2014). As weak sensory evidence is typically associated with low confidence, these previous findings appear conflicting. To resolve this conflict, we set out to investigate the effect of decision confidence on choice repetition more directly by measuring explicit confidence ratings in a motion coherence discrimination task. Moreover, we explored how choice and stimulus history jointly affect subsequent perceptual choices. We found that participants were more likely to repeat previous choices of high subjective confidence, as well as previous fast choices, confirming the boost of choice repetition with decision confidence. Furthermore, we discovered that current choices were biased away from the previous evidence direction, not previous choice, and that this effect grew with previous evidence strength. These findings point towards simultaneous biases of choice repetition, modulated by decision confidence, and adaptation, modulated by the strength of evidence, which bias current perceptual decisions in opposite directions.
Toward a comprehensive understanding of EEG and its analyses
Authors: Rocha A. F. 
Published: February 2020

SummaryBackgroundEEG is the oldest tool for studying human cognitive function, but it is blamed to be useless because its poor spatial resolution despite it excellent temporal discrimination. Such comments arise from a reductionist point of view about the cerebral function. However, if the brain is assumed to be a distributed processing system recruiting different types of cells widely distribute over the cortex, then EEG temporal resolution and the many different tools available for its analysis, turn it the tool of choice to investigate human cognition.ProposalTo better understand the different types of information encoded in the recorded cortical electrical activity, a clear model of the cortical structure and function of the different cortical column layers is presented and discussed. Taking this model into consideration, different available techniques for EEG analysis are discussed, under the assumption that tool combination is a necessity to provide a full comprehension of dynamics of the cortical activity supporting human cognition.MethodologyThe present approach combines many of the existing methods of analysis to extract better and richer information from the EEG, and proposes additional analysis to better characterize many of the EEG components identified by these different methods.AnalysisData on language understanding published elsewhere are used to illustrate how to use this combined and complex EEG analysis to disclose important details of cognitive cerebral dynamics, which reveal that cognitive neural circuits are scale free networks supporting entrainment of a large number of cortical column assemblies distributed all over the cortex.ConclusionsReasoning is then assumed to result from a well orchestrated large scale entrainment
Visual Attention Through Uncertainty Minimization in Recurrent Generative Models
Authors: Standvoss Kai , Quax Silvan C. , van Gerven Marcel A.J. 
Published: February 2020

AbstractAllocating visual attention through saccadic eye movements is a key ability of intelligent agents. Attention is both influenced through bottom-up stimulus properties as well as top-down task demands. The interaction of these two attention mechanisms is not yet fully understood. A parsimonious reconciliation posits that both processes serve the minimization of predictive uncertainty. We propose a recurrent generative neural network model that predicts a visual scene based on foveated glimpses. The model shifts its attention in order to minimize the uncertainty in its predictions. We show that the proposed model produces naturalistic eye movements focusing on informative stimulus regions. Introducing additional tasks modulates the saccade patterns towards task-relevant stimulus regions. The model’s saccade characteristics correspond well with previous experimental data in humans, providing evidence that uncertainty minimization could be a fundamental mechanisms for the allocation of visual attention.
Bifurcation analysis of an impulsive system describing Partial Nitritation and Anammox in a hybrid reactor
Authors: Wade Matthew J. , Wolkowicz Gail S. K. 
Published: February 2020

AbstractLow-energy deammonification under mainstream conditions is a technology that has received significant attention in recent years as the water industry drives towards long-term sustainability goals. Simultaneous partial nitritation-Anammox (PN/A) is one process that can provide substantial energy reduction and lower sludge yields. Mathematical modelling of such a process offers engineers insights into the conditions for maximising the potential of PN/A. Laureniet al., Water Res. (2019) have recently published a reduced mechanistic model of the process in a sequencing batch reactor, which indicates the effect of three key operating parameters (Anammox biofilm activity, dissolved oxygen concentration and fraction of solids wasted) on performance. The analysis of the model is limited, however, to simulation with relatively few discrete parameter sets. Here, we demonstrate through the use of bifurcation theory applied to an impulsive system, that a phase space can be generated describing the continuous separation of system equilibria. Mapping process performance data onto these spaces allows engineers to target suitable operating regimes for specific objectives. Here, for example, we note that the nitrogen removal efficiency is maximised close to the trans-critical bifurcation curve denoting nitrite oxidising bacteria washout, but control of solids washout and Anammox biofilm activity can also reduce oxygen requirements whilst maintaining an appropriate Hydraulic Retention Time. The approach taken is significant given the possibility for using such a methodology for models of increasing complexity, which will enable engineers to probe the entire parameter space of systems of higher dimensionality and realism in a consistent manner.
Refinement of protein structure via contact based potentials in replica exchange simulations
Authors: Voronin Arthur , Weiel Marie , Schug Alexander 
Published: February 2020

AbstractProteins are complex biomolecules which perform critical tasks in living organisms. Knowledge of a protein’s structure is essential for understanding its physiological function in detail. Despite the incredible progress in experimental techniques, protein structure determination is still expensive, time-consuming, and arduous. That is why computer simulations are often used to complement or interpret experimental data. Here, we explore howin silicoprotein structure determination based on replica exchange molecular dynamics can benefit from including contact information derived from theoretical and experimental sources, such as direct coupling analysis or NMR spectroscopy. To reflect the influence from erroneous and noisy data we probe how false-positive contacts influence the simulated ensemble. Specifically, we integrate varying numbers of randomly selected native and non-native contacts and explore how such a bias can guide simulations towards the native state. We investigate the number of contacts needed for a significant enrichment of native-like conformations and show the capabilities and limitations of this method. Adhering to a threshold of approximately 75% true-positive contacts within a simulation, we obtain an ensemble with native-like conformations of high quality. We find that contact-guided REX MD is capable of delivering physically reasonable models of a protein’s structure.Author summaryProtein structure prediction, that is obtaining a protein structure starting from a sequence using any computational method, is a great challenge. Over the past years a broad variety of methods evolved, ranging from algorithms for “blind” orde novopredictions using Monte-Carlo or physics-based biomolecular simulation methods to algorithms transferring structure information obtained from known homologous proteins. Recently, purely data-driven approaches using neural networks have shown to be capable of predicting high-quality structures. However, some local structural motifs are only poorly resolved and need further refinement. Here, we explore to what extent contact information helps guiding replica exchange molecular dynamics towards the native fold. By adding a contact pair bias potential to the energy function, we effectively guide the search towards the target structure by narrowing the conformational space to be sampled. We find that such an energetic bias, even if containing false-positive contacts to a certain extent, greatly enhances the refinement process and improves the chance of finding the native state in a single run.
Buffering and total calcium levels determine the presence of oscillatory regimes in cardiac cells
Authors: Marchena M. , Echebarria Blas , Shiferaw Yohannes , Alvarez-Lacalle Enrique 
Published: February 2020

AbstractCalcium oscillations and waves are often behind instances of extra depolarization in cardiac cells, eventually giving rise to life-threatening arrhythmias. In this work, we study the conditions for the appearance of calcium oscillations in both a detailed subcellular model of calcium dynamics and a minimal model that takes into account just the minimal ingredients of the calcium toolkit. To avoid the effects of homeostatic changes and the interaction with the action potential we consider the somewhat artificial condition of a cell without pacing and with no calcium exchange with the extracellular medium. This permits us to isolate the main reasons responsible for the oscillations by controlling externally the total calcium content of the cell. We find that as the calcium content is increased, the system transitions between two stationary states, corresponding to one with closed ryanodine receptors (RyR) and most calcium in the cell stored in the sarcoplasmic reticulum (SR), and another, with open RyRs and a depleted SR. In between these states, calcium oscillations may appear. This transition depends very sensitively in the amount of buffering in the cell. We find, for instance, that at high values of calsequestrin (CSQ) oscillations disappear, while they are present for a broad range of parameters at low values of CSQ. Using the minimal model, we can relate the stability of the oscillating state to the nullcline structure of the system, and find that its range of existence is bounded by a homoclinic and a Hopf bifurcation.Author summaryIn cardiac cells, calcium plays a very important role. An increase in calcium levels is the trigger used by the cell to initiate contraction. Besides, calcium modulates several transmembrane currents, affecting the cell transmembrane potential. Thus, dysregulations in calcium handling have been associated with the appearance of arrhythmias. Often, this dysregulation results in the appearance of periodic calcium waves or global oscillations, providing a pro-arrhythmic substrate. In this paper, we study the onset of calcium oscillations in cardiac cells using both a detailed subcellular model of calcium dynamics and a minimal model that takes into account just the minimal ingredients of the calcium toolkit. Both reproduce the main experimental results and link this behavior with the presence of different steady-state solutions and bifurcations that depend on the total amount of calcium in the cell and in the level of buffering present. We expect that this work will help to clarify the conditions under which calcium oscillations appear in cardiac myocytes and, therefore, will represent a step further in the understanding of the origin of cardiac arrhythmias.
Unstructured mRNAs form multivalent RNA-RNA interactions to generate TIS granule networks
Authors: Ma Weirui , Zhen Gang , Xie Wei , Mayr Christine 
Published: February 2020

SummaryThe TIS granule network is a constitutively expressed membraneless organelle that concentrates mRNAs with AU-rich elements and interacts with the major site of protein synthesis, the rough endoplasmic reticulum. Most known biomolecular condensates are sphere-like, but TIS granules have a mesh-like morphology. Throughin vivoandin vitroreconstitution experiments we discovered that this shape is generated by extensive intermolecular RNA-RNA interactions. They are mostly accomplished by mRNAs with large unstructured regions in their 3′UTRs that we call intrinsically disordered regions (IDRs). As AU-rich RNA is a potent chaperone that suppresses protein aggregation and is overrepresented in mRNAs with IDRs, our data suggests that TIS granules concentrate mRNAs that assist protein folding. In addition, the proximity of translating mRNAs in TIS granule networks may enable co-translational protein complex formation.