bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of conformation-sensitive anti-amyloid protofibril monoclonal antibodies using an engineered chaperone-like amyloid-binding protein
Authors: Vallen Graham W , Bonito-Oliva Alessandra , Agostinelli Rita , Karim Riyaz , Deguzman Jeremy , Kelleher Kerry , Petro Marianne , Lindström Anna-Karin , Graff Caroline , Wood Kathleen M. , Tchistiakova Lioudmila , Marquette Kimberly , Wes Paul D. , Sakmar Thomas P. 
Published: February 2019

AbstractThe hypothesis that amyloid beta peptides (Aβ) are central to the pathogenesis of sporadic Alzheimer’s disease (AD) is still hotly debated. Although several monoclonal antibodies (mAbs) against Aβ have failed in therapeutic clinical trials, two conformation-selective, anti-Aβ mAbs continue to show promise. A significant challenge has been to discover mAbs that preferentially target Aβ protofibrils over natively-folded monomeric peptides or amyloid plaques. We have engineered a novel chaperone-like amyloid-binding protein (CLABP), Nucleobindin 1 (NUCB1), which enables the stabilization of protofibrils, allowing them to be used as immunogens in mice to facilitate the generation of mAbs that recognize Aβ protofibrils. An immunization campaign and subsequent screening funnel identified a panel of mAbs with high-affinity to Aβ. Two mAbs in particular, 1A8 and 7C8, displayed significant conformation sensitivity and preferentially bound Aβ protofibrils over monomers. Furthermore, 1A8 delayed Aβ aggregation, but did not prevent eventual fibril formation, while 7C8 significantly and dose-dependently reduced fibril formation by inhibiting both primary and secondary nucleation. Both mAbs protected against protofibril-induced cytotoxicityin vitro,and showed distinctive staining patterns by immunohistochemistry in PS1/APP mice and in post-mortem AD brain tissue. In summary, we describe a novel method to stabilize soluble Aβ protofibrils for use in immunization campaigns. We hypothesize that the stabilized protofibrils retain the neoepitopes of the Aβ protofibril and the aggregates found in mouse models of disease and post-mortem AD brain tissue.
Repertoire-wide phylogenetic models of B cell molecular evolution reveal evolutionary signatures of aging and vaccination
Authors: Hoehn Kenneth B , Vander Heiden Jason A. , Zhou Julian Q. , Lunter Gerton , Pybus Oliver G. , Kleinstein Steven H. 
Published: February 2019

AbstractIn order to produce effective antibodies, B cells undergo rapid somatic hypermutation (SHM) and selection for binding affinity to antigen via a process called affinity maturation. The similarities between this process and evolution by natural selection have led many groups to use evolutionary and phylogenetic methods to characterize the development of immunological memory, vaccination, and other processes that depend on affinity maturation. However, these applications are limited by several features of affinity maturation that violate assumptions in standard phylogenetic models. Further, most phylogenetic models are designed to be applied to individual lineages comprising genetically diverse sequences, while B cell repertoires often consist of hundreds to thousands of separate low-diversity lineages. Here, we introduce a hierarchical phylogenetic framework that incorporates the unique features of SHM, and integrates information from all lineages in a repertoire to more precisely estimate model parameters. We demonstrate the power of this approach by characterizing previously un-described phenomena in affinity maturation. First, we find evidence consistent with age related changes in SHM hot-and cold-spot motifs. Second, we identify a consistent relationship between increased tree length and signs of increased negative selection, apparent in the repertoires of both healthy subjects and those undergoing active immune responses. This suggests that B cell lineages shift towards negative selection over time as a general feature of affinity maturation. Our study provides a framework for undertaking repertoire-wide phylogenetic testing of SHM hypotheses, and provides a new means of charactering the process of mutation and selection during affinity maturation.
Sensorimotor system engagement during ASL sign perception: an EEG study in deaf signers and hearing non-signers
Authors: Kubicek Emily , Quandt Lorna 
Published: February 2019

ABSTRACTWhen a person observes someone else performing an action, the observer’s sensorimotor cortex activates as if the observer is the one performing the action, a phenomenon known as action simulation. While this process has been well-established for basic (e.g. grasping) and complex (e.g. dancing) actions, it remains unknown if the framework of action simulation is applicable to visual languages such as American Sign Language (ASL). We conducted an EEG experiment with deaf signers and hearing non-signers to compare overall sensorimotor EEG between groups, and to test whether sensorimotor systems are differentially sensitive to signs that are produced with one hand (“1H”) or two hands (“2H”). We predicted greater alpha and beta event-related desynchronization (previously correlated with action simulation) during the perception of 2H ASL signs compared to 1H ASL signs, due to greater demands on sensorimotor processing systems required for producing two-handed actions. We recorded EEG from both groups as they observed videos of ASL signs, half 1H and half 2H. Event-related spectral perturbations (ERSPs) in the alpha and beta ranges were computed for the two conditions at central electrode sites overlying the sensorimotor cortex. Sensorimotor EEG responses in both Hearing and Deaf groups were sensitive to the observed gross motor characteristics of the observed signs. We show for the first time that despite hearing non-signers showing overall more sensorimotor cortex involvement during sign observation, mirroring-related processes are in fact involved when deaf signers observe signs.
Tuned normalization in perceptual decision-making circuits can explain seemingly suboptimal confidence behavior
Authors: Maniscalco Brian , Odegaard Brian , Grimaldi Piercesare , Cho Seong Hah , Basso Michele A. , Lau Hakwan , Peters Megan A. K. 
Published: February 2019

AbstractCurrent dominant views hold that perceptual confidence reflects the probability that a decision is correct. Although these views have enjoyed some empirical support, recent behavioral results indicate that confidence and the probability of being correct can be dissociated. An alternative hypothesis suggests that confidence instead reflects the magnitude of evidence in favor of a decision while being relatively insensitive to the evidence opposing the decision. We considered how this alternative hypothesis might be biologically instantiated by developing a simple leaky competing accumulator neural network model incorporating a known property of sensory neurons: tuned normalization. The key idea of the model is that each accumulator neuron’s normalization ‘tuning’ dictates its contribution to perceptual decisions versus confidence judgments. We demonstrate that this biologically plausible model can account for several counterintuitive findings reported in the literature, where confidence and decision accuracy were shown to dissociate -- and that the differential contribution a neuron makes to decisions versus confidence judgments based on its normalization tuning is vital to capturing some of these effects. One critical prediction of the model is that systematic variability in normalization tuning exists not only in sensory cortices but also in the decision-making circuitry. We tested and validated this prediction in macaque superior colliculus (SC; a region implicated in decision-making). The confirmation of this novel prediction provides direct support for our model. These findings suggest that the brain has developed and implements this alternative, heuristic theory of perceptual confidence computation by capitalizing on the diversity of neural resources available.SignificanceThe dominant view of perceptual confidence proposes that confidence optimally reflects the probability that a decision is correct. But recent empirical evidence suggests that perceptual confidence exhibits a suboptimal ‘confirmation bias’, just as in human decision-making in general. We tested how this ‘bias’ might be neurally implemented by building a biologically plausible neural network model, and showed that the ‘bias’ emerges when each neuron’s degree of divisive normalization dictates how it drives decisions versus confidence judgments. We confirmed the model’s biological substrate using electrophysiological recordings in monkeys. These results challenge the dominant model, suggesting that the brain instead capitalizes on the diversity of available machinery (i.e., neuronal resources) to implementheuristic-- not optimal -- strategies to compute subjective confidence.
Accurate inference of tree topologies from multiple sequence alignments using deep learning
Authors: Suvorov Anton , Hochuli Joshua , Schrider Daniel R. 
Published: February 2019

AbstractReconstructing the phylogenetic relationships between species is one of the most formidable tasks in evolutionary biology. Multiple methods exist to reconstruct phylogenetic trees, each with their own strengths and weaknesses. Both simulation and empirical studies have identified several “zones” of parameter space where accuracy of some methods can plummet, even for four-taxon trees. Further, some methods can have undesirable statistical properties such as statistical inconsistency and/or the tendency to be positively misleading (i.e. assert strong support for the incorrect tree topology). Recently, deep learning techniques have made inroads on a number of both new and longstanding problems in biological research. Here we designed a deep convolutional neural network (CNN) to infer quartet topologies from multiple sequence alignments. This CNN can readily be trained to make inferences using both gapped and ungapped data. We show that our approach is highly accurate, often outperforming traditional methods, and is remarkably robust to bias-inducing regions of parameter space such as the Felsenstein zone and the Farris zone. We also demonstrate that the confidence scores produced by our CNN can more accurately assess support for the chosen topology than bootstrap and posterior probability scores from traditional methods. While numerous practical challenges remain, these findings suggest that deep learning approaches such as ours have the potential to produce more accurate phylogenetic inferences.
Tsr4 is a cytoplasmic chaperone for the ribosomal protein Rps2 inSaccharomyces cerevisiae
Authors: Black Joshua J. , Musalgaonkar Sharmishtha , Johnson Arlen W. 
Published: February 2019

AbstractEukaryotic ribosome biogenesis requires the action of approximately 200trans-acting factors and the incorporation of 79 ribosomal proteins (RPs). The delivery of RPs to pre-ribosomes is a major challenge for the cell because RPs are often highly basic and contain intrinsically disordered regions prone to nonspecific interactions and aggregation. To counteract this, eukaryotes developed dedicated chaperones for certain RPs that promote their solubility and expression, often by binding eukaryotic-specific extensions of the RPs. Rps2 (uS5) is a universally conserved RP that assembles into nuclear pre-40S subunits. However, a chaperone for Rps2 had not been identified. Our lab previously characterized Tsr4 as a 40S biogenesis factor of unknown function. Here, we report that Tsr4 co-translationally associates with Rps2. Rps2 harbors a eukaryotic-specific N-terminal extension that was critical for its interaction with Tsr4. Moreover, Tsr4 perturbation resulted in decreased Rps2 levels and phenocopied Rps2 depletion. Despite Rps2 joining nuclear pre-40S particles, Tsr4 appeared to be restricted to the cytoplasmic. Thus, we conclude that Tsr4 is a cytoplasmic chaperone dedicated to Rps2.
RASSF1A is required for the maintenance of nuclear actin levels
Authors: Chatzifrangkeskou Maria , Pefani Dafni-Eleftheria , Eyres Michael , Vendrell Iolanda , Fischer Roman , Pankova Daniela , O’Neill Eric 
Published: February 2019

SummaryNuclear actin participates in many essential cellular processes including gene transcription, chromatic remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin-9 and exportin-6, but how this transport is regulated remains unclear. Here we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin-6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleo-cytoplasmic actin transport and the concomitant regulation of Myocardin-related transcription factor A (MRTF-A), a coactivator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MTRF/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MTRF/SRF in tumour suppression.
In vitro characterization of the colibactin-activating peptidase ClbP enables development of a fluorogenic activity probe
Authors: Volpe Matthew R. , Wilson Matthew R. , Brotherton Carolyn A. , Winter Ethan S. , Johnson Sheila E. , Balskus Emily P. 
Published: February 2019

ABSTRACTThe gut bacterial genotoxin colibactin has been linked to the development of colorectal cancer. In the final stages of colibactin’s biosynthesis, an inactive precursor (pre-colibactin) undergoes proteolytic cleavage by ClbP, an unusual inner-membrane-bound periplasmic peptidase, to generate the active genotoxin. This enzyme presents an opportunity to monitor and modulate colibactin biosynthesis, but its active form has not been studied in vitro and limited tools exist to measure its activity. Here, we describe the in vitro biochemical characterization of catalytically active, full-length ClbP. We elucidate its substrate preferences and use this information to develop a fluorogenic activity probe. This tool will enable the discovery of ClbP inhibitors and streamline identification of colibactin-producing bacteria.
The Linked Selection Signature of Rapid Adaptation in Temporal Genomic Data
Authors: Buffalo Vince , Coop Graham 
Published: February 2019

AbstractPopulations can adapt over short, ecological timescales via standing genetic variation. Genomic data collected over tens of generations in both natural and lab populations is increasingly used to find selected loci underpinning such rapid adaptation. Although selection on large effect loci may be detectable in such data, often the fitness differences between individuals have a polygenic architecture, such that selection at any one locus leads to allele frequency changes that are too subtle to distinguish from genetic drift. However, one promising signal comes from the fact that selection on polygenic traits leads to heritable fitness backgrounds that neutral alleles can become stochastically associated with. These associations perturb neutral allele frequency trajectories, creating autocovariance across generations that can be directly measured from temporal genomic data. We develop theory that predicts the magnitude of these temporal autocovariances, showing that it is determined by the level of additive genetic variation, recombination, and linkage disequilibria in a region. Furthermore, by using analytic expressions for the temporal variances and autocovariances in allele frequency, we demonstrate one can estimate the additive genetic variation for fitness and the drift-effective population size from temporal genomic data. Finally, we also show how the proportion of total variation in allele frequency change due to linked selection can be estimated from temporal data. Temporal genomic data offers strong opportunities to identify the role linked selection has on genome-wide diversity over short timescales, and can help bridge population genetic and quantitative genetic studies of adaptation.
A Bayesian framework for unifying data cleaning, source separation and imaging of electroencephalographic signals
Authors: Ojeda Alejandro , Klug Marius , Kreutz-Delgado Kenneth , Gramann Klaus , Mishra Jyoti 
Published: February 2019

AbstractElectroencephalographic (EEG) source imaging depends upon sophisticated signal processing algorithms for data cleaning, source separation, and localization. Typically, these problems are addressed separately using a variety of heuristics, making it difficult to systematize a methodology for extracting robust EEG source estimates on a wide range of experimental paradigms. In this paper, we propose a unifying Bayesian framework in which these apparently dissimilar problems can be understood and solved in a principled manner using a single algorithm. We explicitly model the effect of non-brain sources by augmenting the lead field matrix with a dictionary of stereotypical artifact scalp projections. We propose to populate the artifact dictionary with non-brain scalp projections obtained by running Independent Component Analysis (ICA) on an EEG database. Within a parametric empirical Bayes (PEB) framework, we use an anatomical brain atlas to parameterize a source prior distribution that encourages sparsity in the number of cortical regions. We show that, in our inversion algorithm, PEB+ (PEB with the addition of artifact modeling), the sparsity prior has the property of inducing the segregation of the cortical activity into a few maximally independent components with known anatomical support. Artifacts produced by electrooculographic and electromyographic activity as well as single-channel spikes are also segregated into their respective components. Of theoretical relevance, we use our framework to point out the connections between Infomax ICA and distributed source imaging. We use real data to demonstrate that PEB+ outperforms Infomax for source separation on short segments of data and, unlike the popular Artifact Subspace Removal algorithm, it can reduce artifacts without significantly distorting clean epochs. Finally, we analyze mobile brain/body imaging data to characterize the brain dynamics supporting heading computation during full-body rotations. In this example, we run PEB+ followed by the spectral analysis of the activity in the retrosplenial cortex, largely replicating the findings of previous experimental literature.
Super-resolution displacement mapping of unbound single molecules reveals nanoscale heterogeneities in intracellular diffusivity
Authors: Xiang Limin , Chen Kun , Yan Rui , Li Wan , Xu Ke 
Published: February 2019

AbstractIntracellular diffusion underlies vital processes of the cell. However, it remains difficult to elucidate how an average-sized protein diffuses in the cell with good spatial resolution and sensitivity. Here we report single-molecule displacement/diffusivity mapping (SMdM), a super-resolution strategy that enables the nanoscale mapping of intracellular diffusivity through the local statistics of instantaneous displacements of freely diffusing single molecules. We thus show that diffusion in the cytoplasm and in the nucleus to both be spatially heterogeneous at the nanoscale, and such variations in local diffusivity correlate strongly with the ultrastructure of the actin cytoskeleton and the chromosome, respectively. Moreover, we identify the net charge of the diffuser as a key determinant of diffusion rate: intriguingly, the possession of positive, but not negative, net charges significantly impedes diffusion, and the exact degree of slowdown is determined by the specific subcellular environments.
Communication between distinct subunit interfaces of the cohesin complex promotes its topological entrapment of DNA
Authors: Guacci Vincent , Chatterjee Fiona , Robison Brett , Koshland Douglas 
Published: February 2019

ABSTRACTCohesin mediates higher-order chromosome structure. Its biological activities require topological entrapment of DNA within a lumen(s) formed by cohesin subunits. The reversible dissociation of cohesin’s Smc3p and Mcd1p subunits are postulated to form a regulated gate that allows DNA entry and exit into the lumen. We assessed gate-independent functions of this interface in yeast using a fusion protein that joins Smc3p to Mcd1p. We show that in vivo all the regulators of cohesin promote DNA binding of cohesion by mechanisms independent of opening this gate. Furthermore, we show that this interface has a gate-independent activity essential for cohesin to bind chromosomes. We propose this interface regulates DNA entrapment by controlling the opening and closing of one or more distal interfaces formed by cohesin subunits, likely by inducing a conformation change in cohesin. Furthermore, cohesin regulators modulate the interface to control both DNA entrapment and cohesin functions after DNA binding.
The Role of Proactive and Reactive Cognitive Control for Target Selection in Multiple-Target Search
Authors: Ort Eduard , Fahrenfort Johannes J. , Reeder Reshanne , Pollmann Stefan , Olivers Christian N. L. 
Published: February 2019

AbstractCognitive control can involve proactive (preparatory) and reactive (corrective) mechanisms. Using a gaze-contingent eye tracking paradigm combined with fMRI, we investigated the involvement of these different modes of control and their underlying neural networks, when switching between different targets in multiple-target search. Participants simultaneously searched for two possible targets presented among distractors, and selected one of them. In one condition, only one of the targets was available in each display, so that the choice was imposed, and reactive control would be required. In the other condition, both targets were present, giving observers free choice over target selection, and allowing for proactive control. Switch costs emerged only when targets were imposed and not when target selection was free. We found differential levels of activity in the frontoparietal control network depending on whether target switches were free or imposed. Furthermore, we observed core regions of the default mode network to be active during target repetitions, indicating reduced control on these trials. Free and imposed switches jointly activated parietal and posterior frontal cortices, while free switches additionally activated anterior frontal cortices. These findings highlight unique contributions of proactive and reactive control during visual search.