bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrical Propagation of Condensed and Diffuse Ions Along Actin Filaments
Authors: Hunley Christian , Marucho Marcelo 
Published: April 2021

AbstractIn this article, we elucidate the role of divalent ion condensation and high polarization of immobile water molecules in the condensed layer on the propagation of ionic calcium waves along actin filaments. We introduced a novel electrical triple layer model and used a non-linear Debye-Huckel theory with a non-linear, dissipative, electrical transmission line model to characterize the physicochemical properties of each monomer in the filament. This characterization is carried out in terms of an electric circuit model containing monomeric flow resistances and ionic capacitances in both the condensed and diffuse layers. In our studies, we characterized the biocylindrical actin filament model using a high resolution molecular structure. We considered resting and excited states of a neuron using representative mono and divalent electrolyte mixtures. Additionally, we used 0.05Vand 0.15Vvoltage inputs to study ionic waves in voltage clamp experiments on actin filaments. Our results reveal that the physicochemical properties characterizing the condensed and diffuse layers lead to different electrical conduction mediums depending on the ionic species and the neuron state. This region specific propagation mechanism provides a more realistic avenue of delivery by way of cytoskeleton filaments for larger charged cationic species. This new direct path for transporting divalent ions might be crucial for many electrical processes that connect different compartments of the neuron to the soma.
Artificial mosaic brain evolution of relative telencephalon size improves cognitive performance in the guppy (Poecilia reticulata)
Authors: Triki Zegni , Fong Stephanie , Amcoff Mirjam , Kolm Niclas 
Published: April 2021

AbstractThe telencephalon is a brain region believed to have played an essential role during cognitive evolution in vertebrates. However, till now, all the evidence on the evolutionary association between telencephalon size and cognition stem from comparative studies. To experimentally investigate the potential evolutionary association between cognitive abilities and telencephalon size, we used male guppies artificially selected for large and small telencephalon relative to the rest of the brain. In a detour task, we tested a functionally important aspect of executive cognitive ability; inhibitory control abilities. We found that males with larger telencephalon outperformed males with smaller telencephalon. They showed faster improvement in performance during detour training and were more successful in reaching the food reward without touching the transparent barrier. Together, our findings provide the first experimental evidence showing that evolutionary enlargements of relative telencephalon size confer cognitive benefits, supporting an important role for mosaic brain evolution during cognitive evolution.
Unveiling the neural correlates of habit in the dorsal striatum
Authors: Vandaele Y. , Janak P.H. 
Published: April 2021

AbstractWe have recently reported sustained inhibition in the dorsomedial striatum (DMS) and sustained excitation in the dorsolateral striatum (DLS) during execution of a lever press sequence in a discrete-trials task promoting habit. This sustained dorsostriatal activity was present early on, and did not clearly change in step with improved performance over ten training sessions. Early onset of sequence-related neural activity could have resulted from rapid habitual learning promoted by presentation of lever cues, predicting reward availability and delivery. To test this hypothesis, we compared DLS and DMS spiking activity in the discrete trials habit-promoting task with two task variants that promote goal-directed behavior. Comparison of the three tasks revealed that mean neuronal spiking activity was generally sustained across the lever press sequence in the task promoting habit and characterized by overall excitation in DLS and inhibition in DMS relative to baseline. In contrast, mean activity differences in DLS and DMS were much less prominent, and most changes occurred transiently around individual lever presses, in the tasks promoting goal-directed behavior. These results indicate that sequence delineation cues, such as the lever cues in these studies, promote habitual behavior and that this habitual behavior is encoded in the striatum by cue-triggered sustained DLS excitation and DMS inhibition that likely reflects cue-elicited behavioral chunking.
Perfluorooctanoic Acid Induces Liver and Serum Dyslipidemia in Humanized PPARα Mice fed an American Diet
Authors: Schlezinger JJ , Hyötyläinen T , Sinioja T , Boston C , Puckett H , Oliver J , Heiger-Bernays W , Webster TF 
Published: April 2021

AbstractPer- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPARα)-expressing mice fed an American diet. Mice were exposed to PFOA (3.3 mg/l) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 μg/ml. In male and female hPPARα mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of hPPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Across studies, a non-monotonic effect of PFOA on serum TG is evident, with the serum PFOA concentration in this study falling near the “null point” between increasing and decreasing serum TG. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.
Cobolt: Joint analysis of multimodal single-cell sequencing data
Authors: Gong Boying , Zhou Yun , Purdom Elizabeth 
Published: April 2021

AbstractA growing number of single-cell sequencing platforms enable joint profiling of multiple omics from the same cells. We present Cobolt, a novel method that not only allows for analyzing the data from joint-modality platforms, but provides a coherent framework for the integration of multiple datasets measured on different modalities. We demonstrate its performance on multi-modality data of gene expression and chromatin accessibility and illustrate the integration abilities of Cobolt by jointly analyzing this multi-modality data with single-cell RNA-seq and ATAC-seq datasets.
Halfway to self-sustainability: Reintroduced migratory European Northern Bald Ibises (Geronticus eremita) still need management interventions for population viability
Authors: Drenske Sinah , Radchuk Viktoriia , Scherer Cédric , Esterer Corinna , Kowarik Ingo , Fritz Johannes , Kramer-Schadt Stephanie 
Published: April 2021

AbstractNorthern Bald Ibis (NBI) have disappeared from Europe already in Middle Age. Since 2003 a migratory population is reintroduced in Central Europe. We conducted demographic analyses of survival and reproduction of 384 NBI over a period of 12 years (2008-2019). These data also formed the basis for a population viability analysis (PVA) simulating the possible future development of the NBI population in different scenarios. We tested life-stage specific survival rates for differences between these stages, raising types and colonies as well as the influence of stochastic events and NBI supplements on the population growth.Stage specific survival rates ranged from 0.64 to 0.78. 61% of the mature females reproduce with a mean fecundity of 2.15 fledglings per nest. The complementary PVA indicated that the release population is close to self-sustainability with a given lambda 0.95 and 24% extinction probability within 50 years. Of the 326 future scenarios tested, 94 % reached the criteria of <5% extinction probability and population growth rates >1. In case of positive population growth, stochastic events had a limited effect. Of 820 sub-scenarios with different stochastic event frequencies and severities 87 % show population growth despite the occurrence of stochastic events.Predictions can be made based on the results of the individual-based model as to whether and under what circumstances the reintroduced NBI population can survive. This study shows that a PVA can support reintroduction success that should work closely together with the project in the field for mutual benefit, to optimize future management decisions.
Optogenetic control of receptors reveals distinct roles for actin- and Cdc42-dependent negative signals in chemotactic signal processing
Authors: Bell George R. R. , Rincón Esther , Akdoğan Emel , Collins Sean R. 
Published: April 2021

AbstractDuring chemotaxis, neutrophils use cell surface G-Protein Coupled Receptors (GPCRs) to detect chemoattractant gradients1–4. The downstream signaling system is wired with multiple feedback loops that amplify weak inputs and promote spatial separation of cell front and rear activities1, 5–8. Positive feedback could promote rapid signal spreading9, yet information from the receptors is transmitted with high spatial fidelity, enabling detection of small differences in chemoattractant concentration across the cell1. How the signal transduction network achieves signal amplification while preserving spatial information remains unclear. The GTPase Cdc42 is a cell-front polarity coordinator that is predictive of cell turning, suggesting an important role in spatial processing10. To directly measure information flow from receptors to Cdc42, we paired zebrafish parapinopsina, an optogenetic GPCR that allows reversible ON/OFF receptor control with a spectrally compatible red/far red Cdc42 FRET biosensor. Using this new toolkit, we show that positive and negative signals downstream of G-proteins shape a rapid, dose-dependent Cdc42 response. Furthermore, F-actin and Cdc42 itself provide two distinct negative signals that limit the duration and spatial spread of Cdc42 activation, maintaining output signals local to the originating receptors.
Calculating the divergence time by direct comparison between individuals and the out-group
Authors: Sun Tingting , Liu Qing , Shang Meiqi , Wang Kejian 
Published: April 2021

AbstractInvestigating the divergence time between different populations has been of fundamental interest in evolution biology. In this study, we reanalysed the mitochondrial and Y chromosome DNA of the 1000 Genomes Project, and revealed that most single nucleotide polymorphisms (SNPs) are specific to minority and would be classified as low-frequency mutations. Using these polymorphisms, we recalculated the divergence time of different populations by direct comparison between individuals and the out-group.
Fungal jasmonate as a novel morphogenetic signal for pathogenesis
Authors: Liu Yingyao , Pagac Martin , Yang Fan , Patkar Rajesh N. , Naqvi Naweed I. 
Published: April 2021

AbstractA key question that has remained unanswered is how pathogenic fungi switch from vegetative growth to infection-related morphogenesis during a disease cycle. Here, we identify a fungal oxylipin analogous to the well-known phytohormone jasmonic acid, as the principal morphogenesis signal responsible for such a developmental switch to pathogenicity in the rice-blast fungusMagnaporthe oryzae. We explored the molecular function(s) of such intrinsic jasmonic acid during pathogenic differentiation inM. oryzaeviaOPR1, which encodes a 12-Oxo-phytodienoic Acid Reductase essential for its biosynthesis. Loss ofOPR1led to prolonged vegetative growth, and a delayed initiation and improper development of infection structures inM. oryzae, reminiscent of phenotypes observed in mutants (e.g.pth11Δ andcpkaΔ) that are compromised for cyclic AMP signaling. Genetic- or chemical-complementation completely restored proper germ tube growth and appressorium formation inopr1Δ. Liquid chromatography mass spectrometry-based quantification revealed increased OPDA accumulation and a significant decrease in JA levels in theopr1Δ. Most interestingly, exogenous jasmonic acid also restored appressorium formation in thepth11Δ mutant that lacks G protein/cyclic AMP signaling. Epistasis analysis placed fungal jasmonate upstream of the cyclic AMP signaling in rice blast. Lastly, we show that intrinsic jasmonate orchestrates the cessation of vegetative phase and initiates pathogenic development via a regulatory interaction with the cyclic AMP cascade and redox signaling in rice blast.
Heterogeneous but not random: Cargo degradation in phagosomes is kinetically coupled to their intracellular mobility
Authors: Yu Yanqi , Zhang Zihan , Walpole Glenn F. W. , Yu Yan 
Published: April 2021

AbstractImmune cells degrade internalized pathogens in phagosomes through sequential biochemical changes. The degradation must be fast enough for effective infection control. The presumption is that each phagosome degrades cargos autonomously with a distinct but stochastic kinetic rate. Here we report that the degradation kinetics of individual phagosomes is not stochastic but coupled to their intracellular motility. By engineering RotSensors that are optically anisotropic, magnetic responsive, and fluorogenic in response to degradation activities in phagosomes, we monitored cargo degradation kinetics in single phagosomes simultaneously with their translational and rotational dynamics. We show that phagosomes that move faster centripetally are more likely to encounter and fuse with lysosomes, thereby acidifying faster and degrading cargos more efficiently. The degradation rates increase nearly linearly with the translational and rotational velocities of phagosomes. Our results indicate that the centripetal motion of phagosomes functions as a clock for controlling the progression of cargo degradation.
Profiling of transcribedcis-regulatory elements in single cells
Authors: Moody Jonathan , Kouno Tsukasa , Suzuki Akari , Shibayama Youtaro , Terao Chikashi , Chang Jen-Chien , López-Redondo Fernando , Yip Chi Wai , Severin Jessica , Suetsugu Hiroyuki , Ando Yoshinari , Yamamoto Kazuhiko , Carninci Piero , Shin Jay W. , Hon Chung-Chau 
Published: April 2021

AbstractProfiling ofcis-regulatory elements (CREs, mostly promoters and enhancers) in single cells allows the interrogation of the cell-type and cell-state-specific contexts of gene regulation and genetic predisposition to diseases. Here we demonstrate single-cell RNA-5′end-sequencing (sc-end5-seq) methods can detect transcribed CREs (tCREs), enabling simultaneous quantification of gene expression and enhancer activities in a single assay at no extra cost. We showed enhancer RNAs can be detected using sc-end5-seq methods with either random or oligo(dT) priming. To analyze tCREs in single cells, we developedSCAFE(Single Cell Analysis of Five-prime Ends) to identify genuine tCREs and analyze their activities (https://github.com/chung-lab/scafe). As compared to accessible CRE (aCRE, based on chromatin accessibility), tCREs are more accurate in predicting CRE interactions by co-activity, more sensitive in detecting shifts in alternative promoter usage and more enriched in diseases heritability. Our results highlight additional dimensions within sc-end5-seq data which can be used for interrogating gene regulation and disease heritability.
DeepDDS: deep graph neural network with attention mechanism to predict synergistic drug combinations
Authors: Wang Jinxian , Liu Xuejun , Shen Siyuan , Deng Lei , Liu Hui 
Published: April 2021

AbstractMotivationDrug combination therapy has become a increasingly promising method in the treatment of cancer. However, the number of possible drug combinations is so huge that it is hard to screen synergistic drug combinations through wet-lab experiments. Therefore, computational screening has become an important way to prioritize drug combinations. Graph neural network have recently shown remarkable performance in the prediction of compound-protein interactions, but it has not been applied to the screening of drug combinations.ResultsIn this paper, we proposed a deep learning model based on graph neural networks and attention mechanism to identify drug combinations that can effectively inhibit the viability of specific cancer cells. The feature embeddings of drug molecule structure and gene expression profiles were taken as input to multi-layer feedforward neural network to identify the synergistic drug combinations. We compared DeepDDS with classical machine learning methods and other deep learning-based methods on benchmark data set, and the leave-one-out experimental results showed that DeepDDS achieved better performance than competitive methods. Also, on an independent test set released by well-known pharmaceutical enterprise AstraZeneca, DeepDDS was superior to competitive methods by more than 16% predictive precision. Furthermore, we explored the interpretability of the graph attention network, and found the correlation matrix of atomic features revealed important chemical substructures of drugs. We believed that DeepDDS is an effective tool that prioritized synergistic drug combinations for further wet-lab experiment validation.Availability and implementationSource code and data are available athttps://github.com/Sinwang404/DeepDDS/tree/master
Offline knowledge assimilations ensue online obscurity to inspire implicit learning
Authors: Aly Mohamed H. , Abdou Kareem , Okubo-Suzuki Reiko , Nomoto Masanori , Inokuchi Kaoru 
Published: April 2021

AbstractPassive priming of prior knowledge to assimilate ongoing experiences underlies advanced cognitive processing. However, the necessary neural dynamics of memory assimilation remains elusive. Uninstructed brain could also show boosted creativity, particularly after idling states, yet it remains unclear whether the idling brain can spontaneously spark relevant knowledge assimilations. We established a paradigm that links/separates context-dependent memories according to geometrical similarities. Mice exploring one of four contexts one day before undergoing contextual fear conditioning in a square context showed a gradual fear transfer to pre-exposed geometrically relevant contexts next day, but not after 15 min. Anterior cingulate cortex neurons representing relevant, rather than distinct, memories were significantly co-reactivated during post-conditioning sleep only, before their selective integration next day during testing. Disrupting sleep co-reactivations prevented assimilation while preserving recent memory consolidation. Thus, assimilating pertinent memories during sleep through co-reactivation of their respective engrams represents the neural underpinnings of sleep-triggered implicit cortical learning.
Improved methods and optimized design for CRISPR Cas9 and Cas12a homology-directed repair
Authors: Schubert Mollie S. , Thommandru Bernice , Woodley Jessica , Turk Rolf , Yan Shuqi , Kurgan Gavin , McNeill Matthew S. , Rettig Garrett R. 
Published: April 2021

ABSTRACTCRISPR-Cas proteins are used to introduce double-stranded breaks (DSBs) at targeted genomic loci. DSBs are repaired by endogenous cellular pathways such as non-homologous end joining (NHEJ) and homology-directed repair (HDR). Providing a DNA template during repair allows for precise introduction of a desired mutation via the HDR pathway. However, rates of repair by HDR are often slow compared to the more rapid but less accurate NHEJ-mediated repair. Here, we describe comprehensive design considerations and optimized methods for highly efficient HDR using single-stranded oligodeoxynucleotide (ssODN) donor templates for several CRISPR-Cas systems includingS.p.Cas9,S.p.Cas9 D10A nickase, andA.s.Cas12a delivered as ribonucleoprotein complexes with synthetic guide RNAs. Features relating to guide RNA selection, donor strand preference, and incorporation of blocking mutations in the donor template to prevent re-cleavage were investigated and were implemented in a novel online tool for HDR donor template design. Additionally, we employ chemically modified HDR donor templates in combination with a small molecule to boost HDR efficiency up to 10-fold. These findings allow for high frequencies of precise repair utilizing HDR in multiple mammalian cell lines. Tool availability:www.idtdna.com/HDR
Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic and Chemogenic Manipulations
Authors: Alhassen Wedad , Kobayashi Yuki , Su Jessica , Robbins Brianna , Ngyuen Henry , Myint Thant , Yu Micah , Nauli Surya M. , Saito Yumiko , Alachkar Amal 
Published: April 2021

AbstractThe melanin concentrating hormone (MCH) system is involved in numerous functions including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. MCH acts on a G protein-coupled receptor MCHR1, which expresses ubiquitously in the brain and localizes to neuronal primary cilia. Cilia act as cells’ antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in-vivo. In the current work, we examined the effects of the activation and inactivation of MCH system on cilia lengths by using different methodologies, including pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation, or indirectly through optogenetic and chemogenetic- mediated excitation of MCH neurons, causes cilia shortening. Contrarily, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induces cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions, and implicate cilia MCHR1 as a potential therapeutic target for the treatment of pathological conditions characterized by impaired cilia function.