bluuebunny/crossref_metadata_2025_split huggingface dataset:
Less Is More: A Mutation in the Chemical Defense Pathway ofErysimum cheiranthoides(Brassicaceae) Reduces Total Cardenolide Abundance but Increases Resistance to Insect Herbivores
Authors: Mirzaei Mahdieh , Züst Tobias , Hastings Amy P. , Agrawal Anurag A. , Jander Georg 
Published: May 2020

AbstractMany plants produce structurally related defensive metabolites with the same target sites in insect herbivores. Two possible drivers of this chemical diversity are: (i) interacting effects of structurally related compounds increase resistance against individual herbivores, and (ii) variants of the same chemical structures differentially affect diverse herbivore species or feeding guilds.Erysimum cheiranthoidesL (Brassicaceae; wormseed wallflower) produces abundant and diverse cardenolide toxins, which are derived from digitoxigenin, cannogenol, and strophanthidin, all of which inhibit Na+/K+-ATPases in animal cells. Here we describe anE. cheiranthoidesmutant with 66% lower cardenolide content, resulting from greatly decreased cannogenol- and strophanthidin-derived cardenolides, partially compensated for by increases in digitoxigenin-derived cardenolides. This compositional change created a more even cardenolide distribution, decreased the average cardenolide polarity, but did not impact glucosinolates, a different class of chemical defenses. Growth of generalist herbivores from two feeding guilds,Myzus persicaeSulzer (Hemiptera: Aphididae; green peach aphid) andTrichoplusia niHübner (Lepidoptera: Noctuidae; cabbage looper), was decreased on the mutant line compared to wildtype. Both herbivores accumulated cardenolides in proportion to plant content, withT. niaccumulating higher total concentrations thanM. persicae.Helveticoside, an abundant cardenolide inE. cheiranthoides, was absent inM. persicae, suggesting that this compound is not present in the phloem. Our results support the hypothesis that cardenolide diversity protects plants against different herbivores, with digitoxigenin-derived compounds providing better protection against insects likeM. persicaeandT. ni, whereas cannogenol and strophanthidin provide better protection against other herbivores ofE. cheiranthoides.FundingThis research was funded by US National Science Foundation awards 1907491 to AAA and 1645256 to GJ and AAA, Swiss National Science Foundation grant PZ00P3-161472 to TZ, and a Triad Foundation grant to GJ.
Robust Sequence Determinants of α-Synuclein Toxicity in Yeast Implicate Membrane Binding
Authors: Newberry Robert W. , Arhar Taylor , Costello Jean , Hartoularos George C. , Maxwell Alison M. , Naing Zun Zar Chi , Pittman Maureen , Reddy Nishith R. , Schwarz Daniel M. C. , Wassarman Douglas R. , Wu Taia S. , Barrero Daniel , Caggiano Christa , Catching Adam , Cavazos Taylor B. , Estes Laurel S. , Faust Bryan , Fink Elissa A. , Goldman Miriam A. , Gomez Yessica K. , Gordon M. Grace , Gunsalus Laura M. , Hoppe Nick , Jaime-Garza Maru , Johnson Matthew C. , Jones Matthew G. , Kung Andrew F. , Lopez Kyle E. , Lumpe Jared , Martyn Calla , McCarthy Elizabeth E. , Miller-Vedam Lakshmi E. , Navarro Erik J. , Palar Aji , Pellegrino Jenna , Saylor Wren , Stephens Christina A. , Strickland Jack , Torosyan Hayarpi , Wankowicz Stephanie A. , Wong Daniel R. , Wong Garrett , Redding Sy , Chow Eric D. , DeGrado William F. , Kampmann Martin 
Published: May 2020

ABSTRACTProtein conformations are shaped by cellular environments, but how environmental changes alter the conformational landscapes of specific proteinsin vivoremains largely uncharacterized, in part due to the challenge of probing protein structures in living cells. Here, we use deep mutational scanning to investigate how a toxic conformation of α-synuclein, a dynamic protein linked to Parkinson’s disease, responds to perturbations of cellular proteostasis. In the context of a course for graduate students in the UCSF Integrative Program in Quantitative Biology, we screened a comprehensive library of α-synuclein missense mutants in yeast cells treated with a variety of small molecules that perturb cellular processes linked to α-synuclein biology and pathobiology. We found that the conformation of α-synuclein previously shown to drive yeast toxicity—an extended, membrane-bound helix—is largely unaffected by these chemical perturbations, underscoring the importance of this conformational state as a driver of cellular toxicity. On the other hand, the chemical perturbations have a significant effect on the ability of mutations to suppress α-synuclein toxicity. Moreover, we find that sequence determinants of α-synuclein toxicity are well described by a simple structural model of the membrane-bound helix. This model predicts that α-synuclein penetrates the membrane to constant depth across its length but that membrane affinity decreases toward the C terminus, which is consistent with orthogonal biophysical measurements. Finally, we discuss how parallelized chemical genetics experiments can provide a robust framework for inquiry-based graduate coursework.
Artistoo: build, share, and explore simulations of cells and tissues in the web browser
Authors: Wortel Inge M. N. , Textor Johannes 
Published: May 2020

AbstractSummaryThe Cellular Potts Model (CPM) is a powerfulin silicomethod for simulating diverse biological processes at tissue scale. Because of its inherently graphical nature, this model should in theory be accessible to a large audience of biologists – without requiring extensive mathematical expertise. But in practice, CPMs are mostly implemented in specialized frameworks that users need to master before they can run and modify the simulation. We here present Artistoo (Artificial Tissue Toolbox), a JavaScript library for building “explorable” CPM simulations where users can change model parameters and see their effects in real time. Artistoo simulations run directly in the web browser and do not require any third-party software, plugins, or back-end servers. Although implemented in JavaScript, Artistoo does not suffer from a major performance loss compared to frameworks written in C++; it remains sufficiently fast to let users interact with simulations in real time. Artistoo provides an opportunity to unlock CPM models for a broader audience: interactive simulations can be shared through a simple URL in azero-installsetting. We discuss how such model sharing may benefit modelling research, science dissemination, open science, and education.Availability and ImplementationArtistoo is an open-source library released under the MIT license, and is freely available on GitHub athttps://github.com/ingewortel/artistoo.ContactJohannes.Textor@radboudumc.nl
Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance
Authors: Berry Brandon J. , Baldzizhar Aksana , Wojtovich Andrew P. 
Published: May 2020

ABSTRACTOrganisms adapt to their environment through coordinated changes in mitochondrial function and metabolism. The mitochondrial protonmotive force (PMF) is an electrochemical gradient that powers ATP synthesis and adjusts metabolism to energetic demands via cellular signaling. It is unknown how or where transient PMF changes are sensed and signaled due to lack of precise spatiotemporal controlin vivo.We addressed this by expressing a light-activated proton pump in mitochondria to spatiotemporally “turn off” mitochondrial function through PMF dissipation in tissues with light. We applied our construct – mitochondria-OFF (mtOFF) – to understand how metabolic status impacts hypoxia resistance, a response that relies on mitochondrial function. mtOFF activation induced starvation-like behavior mediated by AMP-activated protein kinase (AMPK). We found prophylactic mtOFF activation increased survival following hypoxia, and that protection relied on neuronal AMPK. Our study links spatiotemporal control of mitochondrial PMF to cellular metabolic changes that mediate behavior and stress resistance.
Preterm birth impedes structural and functional development of cerebellar Purkinje cells in the developing baboon cerebellum
Authors: Barron Tara , Kim Jun Hee 
Published: May 2020

AbstractHuman cerebellar development occurs late in gestation and is hindered by preterm birth. The fetal development of Purkinje cells, the primary output cells of the cerebellar cortex, is crucial for the structure and function of the cerebellum. However, morphological and electrophysiological features in Purkinje cells at different gestational ages, and the effects of neonatal intensive care unit (NICU) experience on cerebellar development are unexplored. Utilizing non-human primate baboon cerebellum, we investigated Purkinje cell development during the last trimester of pregnancy and the effect of NICU experience following premature birth on developmental features of Purkinje cells. Immunostaining and whole-cell patch clamp recordings of Purkinje cells in the baboon cerebellum at different gestational ages revealed that molecular layer width, driven by Purkinje dendrite extension, drastically increased and refinement of action potential waveform properties occurred throughout the last trimester of pregnancy. Preterm birth followed by NICU experience for 2 weeks impeded development of Purkinje cells, including action potential waveform properties, synaptic input, and dendrite extension compared with age-matched controls. In addition, these alterations impact Purkinje cell output, reducing the spontaneous firing frequency in deep cerebellar nucleus (DCN) neurons. Taken together, primate cerebellum undergoes developmental refinements during late gestation, and NICU experience following preterm birth alters morphological and physiological features in the cerebellum that can lead to functional deficits.Summary StatementBaboon cerebellum undergoes developmental refinements during late gestation, and NICU experience following preterm birth impacts cellular development in the cerebellum that can lead to functional deficits.
Higher-order thalamic implication in the processing of bilateral sensory events
Authors: Castejon Carlos , Nuñez Angel 
Published: May 2020

AbstractIn the rodent whisker system, it is well assumed that VPM and POm encode stimulations of the contralateral whisker pad. However, during tactile exploration whiskers are usually stimulated bilaterally. Accordingly, the integration of tactile information from the two sides of the body seems to be fundamental in the processing of these events. Here, to investigate whether POm could be able to codify these bilateral dynamics, whisker-evoked responses in this thalamic nucleus were examined byin vivoextracellular recordings in anesthetized rats using contralateral and ipsilateral stimuli. Strikingly, we found that POm is also able to respond to tactile stimulation of ipsilateral whiskers. Our findings reveal the implication of POm in the representation of bilateral tactile events by integrating simultaneous signals arising from both whisker pads and demonstrate the implication of the higher-order sensory thalamus in the encoding of bilateral sensory events. This can have important implications in bilateral perceptual function.
Fast and accurate approximation of the joint site frequency spectrum of multiple populations
Authors: Jewett Ethan M. 
Published: May 2020

AbstractThe site frequency spectrum (SFS) is a statistic that summarizes the distribution of derived allele frequencies in a sample of DNA sequences. The SFS provides useful information about genetic variation within and among populations and it can used to make population genetic inferences. Methods for computing the SFS based on the diffusion approximation are computationally efficient when computing all terms of the SFS simultaneously and they can handle complicated demographic scenarios. However, in practice it is sometimes only necessary to compute a subset of terms of the SFS, in which case coalescent-based methods can achieve greater computational efficiency. Here, we present simple and accurate approximate formulas for the expected joint SFS for multiple populations connected by migration. Compared with existing exact approaches, our approximate formulas greatly reduce the complexity of computing each entry of the SFS and have simple forms. The computational complexity of our method depends on the index of the entry to be computed, rather than on the sample size, and the accuracy of our approximation improves as the sample size increases.
SARS-CoV-2 is well adapted for humans. What does this mean for re-emergence?
Authors: Zhan Shing Hei , Deverman Benjamin E. , Chan Yujia Alina 
Published: May 2020

AbstractIn a side-by-side comparison of evolutionary dynamics between the 2019/2020 SARS-CoV-2 and the 2003 SARS-CoV, we were surprised to find that SARS-CoV-2 resembles SARS-CoV in the late phase of the 2003 epidemic after SARS-CoV had developed several advantageous adaptations for human transmission. Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected. The sudden appearance of a highly infectious SARS-CoV-2 presents a major cause for concern that should motivate stronger international efforts to identify the source and prevent near future re-emergence. Any existing pools of SARS-CoV-2 progenitors would be particularly dangerous if similarly well adapted for human transmission. To look for clues regarding intermediate hosts, we analyze recent key findings relating to how SARS-CoV-2 could have evolved and adapted for human transmission, and examine the environmental samples from the Wuhan Huanan seafood market. Importantly, the market samples are genetically identical to human SARS-CoV-2 isolates and were therefore most likely from human sources. We conclude by describing and advocating for measured and effective approaches implemented in the 2002-2004 SARS outbreaks to identify lingering population(s) of progenitor virus.
RootNet: A Convolutional Neural Networks for Complex Plant Root Phenotyping from High-Definition Datasets
Authors: Yasrab Robail , Pound Michael P , French Andrew P , Pridmore Tony P 
Published: May 2020

AbstractPlant phenotyping using machine learning and computer vision approaches is a challenging task. Deep learning-based systems for plant phenotyping is more efficient for measuring different plant traits for diverse genetic discoveries compared to the traditional image-based phenotyping approaches. Plant biologists have recently demanded more reliable and accurate image-based phenotyping systems for assessing various features of plants and crops. The core of these image-based phenotyping systems is structural classification and features segmentation. Deep learning-based systems, however, have shown outstanding results in extracting very complicated features and structures of above-ground plants. Nevertheless, the below-ground part of the plant is usually more complicated to analyze due to its complex arrangement and distorted appearance. We proposed a deep convolutional neural networks (CNN) model named “RootNet” that detects and pixel-wise segments plant roots features. The feature of the proposed method is detection and segmentation of very thin (1-3 pixels wide roots). The proposed approach segment high definition images without significantly sacrificing pixel density, it leads to more accurate root type detection and segmentation results. It is hard to train CNNs with high definition images due to GPU memory limitations. The proposed patch-based CNN training setup makes use of the entire image (with maximum pixel desisity) to recognize and segment give root system efficiently. We have used wheat (Triticum aestivum L.) seedlings dataset, which consists of wheat roots grown in visible pouches. The proposed system segments are given root systems and save it to the Root System Markup Language (RSML) for future analysis. RootNet trained on the dataset mentioned above along with popular semantic segmentation architectures, and it achieved a benchmark accuracy.
Impact of sustained TGFβ receptor inhibition on chromatin accessibility and gene expression in cultured human endometrial MSC
Authors: Lucciola Raffaella , Vrljicak Pavle , Filby Caitlin , Darzi Saeedeh , Gurung Shanti , Muter Joanne , Ott Sascha , Brosens Jan J , Gargett Caroline E 
Published: May 2020

AbstractEndometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansionin vitro. A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes pharmacological expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFβ-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFβ-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction ofRARB, encoding retinoic acid receptor beta (RARβ). Selective RARβ inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture.Significance statementCycling human endometrium is a rich source of adult stem/progenitor cells that could be exploited for clinical purposes. Small molecules, such as A83-01, that modulate cell identity may open new avenues to maintain the functional properties of eMSC upon expansion in culture. By integrating complementary genome-wide profiling techniques, we mapped the dynamic changes in chromatin landscape and gene expression in response to prolonged A83-01 treatment of eMSC. Our findings provide new insights into the mechanisms of action of TGFβ-R inhibition that may lead to the development of more targeted pharmacological approaches for MSC expansion.
MSCquartets 1.0: Quartet methods for species trees and networks under the multispecies coalescent model in R
Authors: Rhodes John A. , Baños Hector , Mitchell Jonathan D. , Allman Elizabeth S. 
Published: May 2020

AbstractMSCquartetsis an R package for species tree hypothesis testing, inference of species trees, and inference of species networks under the Multispecies Coalescent model of incomplete lineage sorting. Input for these analyses are collections of metric or topological locus trees which are then summarized by the quartets displayed on them. Results of hypothesis tests at user-supplied levels are displayed in a simplex plot by color-coded points. The package includes the QDC and WQDC algorithms for topological and metric species tree inference, and the NANUQ algorithm for level-1 topological species network inference, all of which give statistically consistent estimators under the model.
Computational verification of large logical models – application to the prediction of T cell response to checkpoint inhibitors
Authors: Hernandez Céline , Thomas-Chollier Morgane , Naldi Aurélien , Thieffry Denis 
Published: May 2020

ABSTRACTAt the crossroad between biology and mathematical modelling, computational systems biology can contribute to a mechanistic understanding of high-level biological phenomenon. But as knowledge accumulates, the size and complexity of mathematical models increase, calling for the development of efficient dynamical analysis methods. Here, we propose the use of two approaches for the development and analysis of complex cellular network models.A first approach, called “model verification” and inspired by unitary testing in software development, enables the formalisation and automated verification of validation criteria for whole models or selected sub-parts. When combined with efficient analysis methods, this approach is suitable for continuous testing, thereby greatly facilitating model development.A second approach, called “value propagation”, enables efficient analytical computation of the impact of specific environmental or genetic conditions on the dynamical behaviour of some models.We apply these two approaches to the delineation and the analysis of a comprehensive model for T cell activation, taking into account CTLA4 and PD-1 checkpoint inhibitory pathways. While model verification greatly eases the delineation of logical rules complying with a set of dynamical specifications, propagation provides interesting insights into the different potential of CTLA4 and PD-1 immunotherapies.Both methods are implemented and made available in the all-inclusive CoLoMoTo Docker image, while the different steps of the model analysis are fully reported in two companion interactive jupyter notebooks, thereby ensuring the reproduction of our results.
PSGL-1 inhibits the virion incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins and impairs virus attachment and infectivity
Authors: He Sijia , Waheed Abdul A. , Hetrick Brian , Dabbagh Deemah , Akhrymuk Ivan V. , Kehn-Hall Kylene , Freed Eric O. , Wu Yuntao 
Published: May 2020

AbstractP-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks virus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1+cells.