bluuebunny/crossref_metadata_2025_split huggingface dataset:
The macrocyclizing protease butelase 1 remains auto-catalytic and reveals the structural basis for ligase activity
Authors: James Amy M. , Haywood Joel , Leroux Julie , Ignasiak Katarzyna , Elliott Alysha G. , Schmidberger Jason W. , Fisher Mark F. , Nonis Samuel G. , Fenske Ricarda , Bond Charles S. , Mylne Joshua S. 
Published: July 2018

AbstractPlant asparaginyl endopeptidases (AEPs) are expressed as inactive zymogens that perform seed storage protein maturation upon cleavage dependent auto-activation in the low pH environment of storage vacuoles. AEPs have attracted attention for their macrocyclization reactions and have been classified as cleavage or ligation specialists. However, we have recently shown that the ability of AEPs to produce either cyclic or acyclic products can be altered by mutations to the active site region, and that several AEPs are capable of macrocyclization given favorable pH conditions. One AEP extracted from Clitoria ternatea seeds (butelase 1) is classified as a ligase rather than a protease, presenting an opportunity to test for loss of cleavage activity. Here, making recombinant butelase 1 and rescuing an Arabidopsis thaliana mutant lacking AEP, we show butelase 1 retains cleavage functions in vitro and in vivo. The in vivo rescue was incomplete, consistent with some trade-off for butelase 1 specialization toward macrocyclization. Its crystal structure showed an active site with only subtle differences from cleaving AEPs, suggesting the many differences in its peptide binding region are the source of its efficient macrocyclization. All considered, it seems either butelase 1 has not fully specialized or a requirement for auto-catalytic cleavage is an evolutionary constraint upon macrocyclizing AEPs.
Brain dynamics and temporal trajectories during task and naturalistic processing
Authors: Venkatesh Manasij , Jaja Joseph , Pessoa Luiz 
Published: July 2018

AbstractHuman functional Magnetic Resonance Imaging (fMRI) data are acquired while participants engage in diverse perceptual, motor, cognitive, and emotional tasks. Although data are acquired temporally, they are most often treated in a quasi-static manner. Yet, a fuller understanding of the mechanisms that support mental functions necessitates the characterization of dynamic properties. Here, we describe an approach employing a class of recurrent neural networks called reservoir computing, and show the feasibility and potential of using it for the analysis of temporal properties of brain data. We show that reservoirs can be used effectively both for condition classification and for characterizing lower-dimensional “trajectories” of temporal data. Classification accuracy was approximately 90% for short clips of “social interactions” and around 70% for clips extracted from movie segments. Data representations with 12 or fewer dimensions (from an original space with over 300) attained classification accuracy within 5% of the full data. We hypothesize that such low-dimensional trajectories may provide “signatures” that can be associated with tasks and/or mental states. The approach was applied across participants (that is, training in one set of participants, and testing in a separate group), showing that representations generalized well to unseen participants. Taken together, we believe the present approach provides a promising framework to characterize dynamic fMRI information during both tasks and naturalistic conditions.
Connectivity dynamics from wakefulness to sleep
Authors: Damaraju Eswar , Tagliazucchi Enzo , Laufs Helmut , Calhoun Vince D 
Published: July 2018

AbstractInterest in time-resolved connectivity in fMRI has grown rapidly in recent years. The most widely used technique for studying connectivity changes over time utilizes a sliding windows approach. There has been some debate about the utility of shorter versus longer windows, the use of fixed versus adaptive windows, as well as whether observed resting state dynamics during wakefulness may be predominantly due to changes in sleep state and subject head motion. In this work we use an independent component analysis (ICA)-based pipeline applied to concurrent EEG/fMRI data collected during wakefulness and various sleep stages and show: 1) connectivity states obtained from clustering sliding windowed correlations of resting state functional network time courses well classify the sleep states obtained from EEG data, 2) using shorter sliding windows instead of longer non-overlapping windows improves the ability to capture transition dynamics even at windows as short as 30 seconds, 3) motion appears to be mostly associated with one of the states rather than spread across all of them 4) a fixed tapered sliding window approach outperforms an adaptive dynamic conditional correlation approach, and 5) consistent with prior EEG/fMRI work, we identify evidence of multiple states within the wakeful condition which are able to be classified with high accuracy. Classification of wakeful only states suggest the presence of time-varying changes in connectivity in fMRI data beyond sleep state or motion. Results also inform about advantageous technical choices, and the identification of different clusters within wakefulness that are separable suggest further studies in this direction.
Predicting Negative Control Drugs to Support Research in Drug Safety
Authors: Hao Yun , Tatonetti Nicholas P. 
Published: July 2018

ABSTRACTThe lack of high-quality reference data is a major limitation in drug safety and drug discovery science. Unreliable standards prohibit the use of supervised learning methods and make evaluation of algorithms difficult. While some data is available for positive examples (e.g. which drugs are associated with a side effect), there are no systematic resources of negative controls. To solve this issue, we introduced SIDERctrl, a computational method that ranks drugs based on the likelihood of not causing a side effect. We applied SIDERctrl to predict negative controls from unreported drugs of 890 side effects in SIDER. Our predictions decreased the false negative rate by one-third according to a validation study using AEOLUS data. Three sets of predicted negative controls by different thresholds of precision were provided, and can be accessed at http://tatonettilab.org/resources/negative-drugs.html. This new reference standard will be important in chemical biology, drug development, and pharmacoepidemiology.KEY POINTSThe lack of systematic resources providing negative control drugs limits the performance of existing research in drug safety.We developed a novel method that integrated chemical and biological properties a drug and the target proteins to calculate the likelihood of the drug being negative control.We applied our method to 890 side effects, and showed that our method significantly decreased the false negative rate of predictions.
Analysis of microbial community structure of pit mud for Chinese strong-flavor liquor fermentation using next generation DNA sequencing of full-length 16S rRNA
Authors: Liu Zuolin , Han Ying , Li Junwei , Cao Runjie , He Hongkui , Li Anjun , Zhang Zhizhou 
Published: July 2018

AbstractThe pit is the necessary bioreactor for brewing process of Chinese strong-flavor liquor. Pit mud in pits contains a large number of microorganisms and is a complex ecosystem. The analysis of bacterial flora in pit mud is of great significance to understand liquor fermentation mechanisms. To overcome taxonomic limitations of short reads in 16S rRNA variable region sequencing, we used high-throughput DNA sequencing of near full-length 16S rRNA gene to analyze microbial compositions of different types of pit mud that produce different qualities of strong-flavor liquor. The results showed that the main species in pit mud were Pseudomonas extremaustralis 14-3, Pseudomonas veronii, Serratia marcescens WW4, and Clostridium leptum in Ruminiclostridium. The microbial diversity of pit mud with different quality was significantly different. From poor to good quality of pit mud (thus the quality of liquor), the relative abundances of Ruminiclostridium and Syntrophomonas in Firmicutes was increased, and the relative abundance of Olsenella in Actinobacteria also increased, but the relative abundances of Pseudomonas and Serratia in Proteobacteria were decreased. The surprising findings of this study include that the diversity of intermediate level quality of N pit mud was the lowest, and the diversity levels of high quality pit mud G and poor quality pit mud B were similar. Correlation analysis showed that there were high positive correlations (r > 0.8) among different microbial groups in the flora. Based on the analysis of the microbial structures of pit mud in different quality, the good quality pit mud has a higher microbial diversity, but how this higher diversity and differential microbial compositions contribute to better quality of liquor fermentation remains obscure.
Measuring cis-regulatory energetics in living cells using allelic manifolds
Authors: Forcier Talitha , Ayaz Andalus , Gill Manraj S. , Jones Daniel , Phillips Rob , Kinney Justin B. 
Published: July 2018

AbstractGene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of “allelic manifolds”, a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by twoEscherichia coliTFs, CRP and σ70RNA polymerase. Doing so, we consistently obtained energetic measurements precise to ~ 0.1 kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.
Ramping and phasic dopamine activity accounts for efficient cognitive resource allocation during reinforcement learning
Authors: Song Minryung R. , Lee Sang Wan 
Published: July 2018

AbstractDopamine activity may transition between two patterns: phasic responses to reward-predicting cues and ramping activity arising when an agent approaches the reward. However, when and why dopamine activity transitions between these modes is not understood. We hypothesize that the transition between ramping and phasic patterns reflects resource allocation which addresses the task dimensionality problem during reinforcement learning (RL). By parsimoniously modifying a standard temporal difference (TD) learning model to accommodate a mixed presentation of both experimental and environmental stimuli, we simulated dopamine transitions and compared it with experimental data from four different studies. The results suggested that dopamine transitions from ramping to phasic patterns as the agent narrows down candidate stimuli for the task; the opposite occurs when the agent needs to re-learn candidate stimuli due to a value change. These results lend insight into how dopamine deals with the tradeoff between cognitive resource and task dimensionality during RL.
Effects of depression on prefrontal-striatal goal-directed and habitual control
Authors: Heo Suyeon , Lee Sang Wan 
Published: July 2018

ABSTRACTDepression is characterized by deficits in the reinforcement learning (RL) process. Although many computational and neural studies have extended our knowledge of the impact of depression on RL, most focus on habitual control (model-free RL), yielding a relatively poor understanding of goal-directed control (model-based RL) and arbitration control to find a balance between the two. We investigate the effects of depression on goal-directed and habitual control in the prefrontal–striatal circuitry. We find that depression is associated with attenuated state and reward prediction error representation in the insula and caudate, a disruption of arbitration control in the predominantly inferior lateral prefrontal cortex and frontopolar cortex, and suboptimal value–action conversion. These findings fully characterize how depression influences different levels of RL, challenging previous conflicting views that depression simply influences either habitual or goal-directed control. Our study creates possibilities for various clinical applications, such as early diagnosis and behavioral therapy design.
Lewis rat NLRP1 inflammasome activation is mediated by threeToxoplasma gondiidense granule proteins
Authors: Wang Yifan , Cirelli Kimberly M. , Barros Patricio D.C. , Sangaré Lamba Omar , Butty Vincent , Hassan Musa A. , Pesavento Patricia , Mete Asli , Saeij Jeroen P.J. 
Published: July 2018

AbstractThe Lewis rat is the only known warm-blooded animal that has sterile immunity toToxoplasma. Upon invasion of Lewis rat macrophagesToxoplasmarapidly activates the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 1 (NLRP1) inflammasome resulting in interleukin (IL)-1β secretion and a form of cell death known as pyroptosis, which preventsToxoplasmareplication. Using a chemical mutagenesis screen we identifiedToxoplasmamutants that no longer induced pyroptosis. Whole genome sequencing led to the identification of threeToxoplasmaparasitophorous vacuole-localized dense granule proteins, GRA35, GRA42 and GRA43 that are individually required for inflammasome activation in Lewis rat macrophages. Macrophage infection with Δgra35, Δgra42, and Δgra43parasites leads to greatly reduced cell death and reduced IL-1β secretion. Lewis rat macrophage infected with parasites containing single, double or triple deletion of these GRAs showed similar levels of cell viability suggesting the three GRAs function in the same pathway that activates the inflammasome. Deletion ofGRA42andGRA43resulted in GRA35, and other GRAs, being retained inside the parasitophorous vacuole instead of being localized to the parasitophorous vacuole membrane.Toxoplasmadeficient in GRA35, GRA42 or GRA43 do not establish chronic infection in Lewis rats, but have reduced cyst number in parasite-susceptible F344 rats, in whichToxoplasmadoes not activate the NLRP1 inflammasome, revealing these GRAs determine parasitein vivofitness independent of their role in inflammasome activation. Overall, our data suggest thatToxoplasmadense granule proteins that localize to the parasitophorous vacuole membrane are novel mediators of host NLRP1 inflammasome activation.ImportanceInflammasomes are a major component of the innate immune system and responsible for detecting various microbial and environmental danger signals. The Lewis rat has sterile immunity toToxoplasmabecause upon invasion of Lewis rat macrophages the parasite rapidly activates the NLRP1 inflammasome resulting in cell death and parasite elimination. The work reported here identified thatToxoplasmaGRA35, GRA42 and GRA43 are required for activation of the Lewis rat NLRP1 inflammasome. GRA42 and GRA43 mediate the correct localization of other GRAs, including GRA35, to the parasitophorous vacuole membrane. In addition to their role in inflammasome activation, these three GRAs are also important for parasitein vivofitness in aToxoplasma-susceptible rat strain. Thus, these results give new insight into NLRP1 inflammasome activation byToxoplasmaeffectors and identified three GRAs that are required for pathogenesis of the parasite.
Mnemonic introspection in macaques is dependent on dorsolateral prefrontal cortex but not orbitofrontal cortex
Authors: Kwok Sze Chai , Cai Yudian , Buckley Mark J. 
Published: July 2018

ABSTRACTThe human prefrontal cortex (PFC) has been associated more with meta-perceptual as opposed to meta-memory decisions from correlational neuroimaging investigations. Recently, metacognitive abilities have also been shown to be causally dependent upon anterior and dorsal PFC in non-human primate lesion studies. Two studies, utilizing post-decision wagering paradigms and reversible inactivation, challenged this meta-perceptual versus meta-memory notion and showed that dorsal and anterior prefrontal areas are associated with metamemory for experienced objects and awareness of ignorance respectively. Causal investigations are important but scarce; nothing is known, for example, about the causal contributions of prefrontal sub-regions to spatial metamemory. Here, we investigated the effects of dorsal versus ventral PFC lesions on two-alternative forced choice spatial discrimination tasks in male macaque monkeys. Importantly, we were rigorous in approach and applied three independent but complementary indices used to quantify individual animals’ metacognitive ability (“type II sensitivity”) namelymeta-d′, d′ measures, and Phi coefficient (Φ). Our results were consistent across indices: while neither lesions to superior dorsolateral PFC (sdlPFC) nor orbitofrontal cortex (OFC) impaired spatial recognition performance, only monkeys with sdlPFC lesions were impaired in meta-accuracy. Together with the observation that the same OFC lesioned monkeys were impaired in updating rule-value in a Wisconsin Card Sorting Test analog, we therefore document a functional double-dissociation between these two PFC regions. Out study presents important causal evidence that other dimensions, namely domain-specific processing (e.g., spatial versus non-spatial metamemory), also need considerations in understanding the functional specialization in the neural underpinnings of introspection.Significance StatementThis study demonstrates macaque monkeys’ meta-cognitive capability of introspecting its own memory success is causally dependent on intact superior dorsolateral prefrontal cortices (PFC) but not the orbitofrontal cortices. Combining neurosurgical techniques on monkeys and state-of-the-art measures of metacognition, we affirm a critical role of the PFC in supporting spatial meta-recognition memory and delineate functional specificity within PFC for distinct elements of metacognition.
Coherent-hybrid STED: a tunable photo-physical pinhole for super-resolution imaging at high contrast
Authors: Pereira António J. , Sousa Mafalda , Almeida Ana C. , Ferreira Luísa T. , Costa Ana Rita , Novais-Cruz Marco , Ferrás Cristina , Sousa Mónica Mendes , Sampaio Paula , Belsley Michael , Maiato Helder 
Published: July 2018

AbstractResolution in microscopy is not limited by diffraction as long as a nonlinear sample response is exploited. In a paradigmatic example, stimulated-emission depletion (STED) fluorescence microscopy fundamentally ‘breaks’ the diffraction limit by using a structured optical pattern to saturate depletion on a previously excited sample area. Two-dimensional (2D) STED, the canonical low-noise STED mode, structures the STED beam by using a vortex phase mask, achieving a significant lateral resolution improvement over confocal fluorescence microscopy. However, axial resolution and optical sectioning remain bound to diffraction. Here we use a tunable coherent-hybrid (CH) beam to improve optical sectioning, markedly reducing background fluorescence. CH-STED, which inherits the 2D-STED immunity to spherical aberration, diversifies the depletion strategy, allowing an optimal balance between two key metrics (lateral resolution and background suppression) to be found. CH-STED is used to perform high-contrast imaging of complex biological structures, such as the mitotic spindle and the neuron cell body.
Quantitative Interactome Proteomics Reveals a Molecular Basis for ATF6-Dependent Regulation of a Destabilized Amyloidogenic Protein
Authors: Plate Lars , Rius Bibiana , Nguyen Bianca , Genereux Joseph C. , Kelly Jeffery W. , Wiseman R. Luke 
Published: July 2018

ABSTRACTActivation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to selectively reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in diverse systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. Here, we establish a quantitative interactomics platform with improved throughput and sensitivity to define how ATF6 activation selectively reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with Light Chain Amyloidosis (AL). We show that ATF6 activation increases the targeting of this destabilized LC to a select subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion to downstream secretory environments. Our results define a molecular basis for the selective, ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this endogenous UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.
Single-cell copy number variant detection reveals the dynamics and diversity of adaptation
Authors: Lauer Stephanie , Avecilla Grace , Spealman Pieter , Sethia Gunjan , Brandt Nathan , Levy Sasha , Gresham David 
Published: July 2018

AbstractCopy number variants (CNVs) are a pervasive, but understudied source of genetic variation and evolutionary potential. Long-term evolution experiments in chemostats provide an ideal system for studying the molecular processes underlying CNV formation and the temporal dynamics ofde novoCNVs. Here, we developed a fluorescent reporter to monitor gene amplifications and deletions at a specific locus with single-cell resolution. Using a CNV reporter in nitrogen-limited chemostats, we find thatGAP1CNVs are repeatedly generated and selected during the early stages of adaptive evolution resulting in predictable dynamics of CNV selection. However, subsequent diversification of populations defines a second phase of evolutionary dynamics that cannot be predicted. Using whole genome sequencing, we identified a variety ofGAP1CNVs that vary in size and copy number. DespiteGAP1’s proximity to tandem repeats that facilitate intrachromosomal recombination, we find that non-allelic homologous recombination (NAHR) between flanking tandem repeats occurs infrequently. Rather, breakpoint characterization revealed that for at least 50% ofGAP1CNVs, origin-dependent inverted-repeat amplification (ODIRA), a DNA replication mediated process, is the likely mechanism. We also find evidence that ODIRA generatesDUR3CNVs, indicating that it may be a common mechanism of gene amplification. We combined the CNV reporter with barcode lineage tracking and found that 103-104independent CNV-containing lineages initially compete within populations, which results in extreme clonal interference. Our study introduces a novel means of studying CNVs in heterogeneous cell populations and provides insight into the underlying dynamics of CNVs in evolution.