bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency
Authors: Thomas Russell S , Bahadori Tina , Buckley Timothy J , Cowden John , Deisenroth Chad , Dionisio Kathie L , Frithsen Jeffrey B , Grulke Christopher M , Gwinn Maureen R , Harrill Joshua A , Higuchi Mark , Houck Keith A , Hughes Michael F , Hunter E Sidney , Isaacs Kristin K , Judson Richard S , Knudsen Thomas B , Lambert Jason C , Linnenbrink Monica , Martin Todd M , Newton Seth R , Padilla Stephanie , Patlewicz Grace , Paul-Friedman Katie , Phillips Katherine A , Richard Ann M , Sams Reeder , Shafer Timothy J , Setzer R Woodrow , Shah Imran , Simmons Jane E , Simmons Steven O , Singh Amar , Sobus Jon R , Strynar Mark , Swank Adam , Tornero-Valez Rogelio , Ulrich Elin M , Villeneuve Daniel L , Wambaugh John F , Wetmore Barbara A , Williams Antony J 
Published: March 2019

AbstractThe U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA’s Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.
Effects of nonlinear growth rates of spherical crystals and their withdrawal rate from a crystallizer on the particle-size distribution function
Authors: Makoveeva Eugenya V. , Alexandrov Dmitri V. 
Published: March 2019

In this paper, we show that the nonlinear growth rate of particles in a supersaturated solution or supercooled melt, as well as the rate of removal of crystals from the metastable liquid of a crystallizer, significantly change the size-distribution function of crystals. Taking these rates into account, we present a complete analytical solution of the integro-differential model describing the transient nucleation of solid particles and their evolution in a metastable liquid. The distribution function and metastability degree (supersaturation or supercooling) are found by means of the separation of variables and saddle-point methods. The nonlinear growth rates of crystals in supersaturated solutions and supercooled melts (single-component and binary) are summarized and compared with experimental data.
This article is part of the theme issue ‘Heterogeneous materials: metastable and non-ergodic internal structures’.
Discontinuous shear thickening in concentrated suspensions
Authors: Bossis Georges , Volkova Olga , Grasselli Yan , Gueye Oumar 
Published: March 2019

The flow of concentrated suspensions of solid particles can be suddenly blocked by the formation of a percolated network of frictional contacts above a critical value of the applied stress. Suspensions of magnetic particles coated with a superplastifier molecule were shown to produce a strong jamming transition. We find that, for these suspensions with an abrupt discontinuous shear thickening, a model using the divergence of the viscosity at a volume fraction that depends on the applied stress does not well describe the observed behaviour both below and above the critical stress. At a constant applied stress above the critical one, we have a stick–slip behaviour of the shear rate whose period can be predicted and scaled as the square root of the relaxation time of the frictional contacts. The application of a small magnetic field allows us to continuously decrease the critical shear rate, and it appears that the yield stress induced by the magnetic field does not contribute to the jamming transition. Finally, it is shown that this jamming transition also appears in the extrusion of a suspension through a die, but with a much slower dynamics than in the case of stress imposed on a rotational geometry.
This article is part of the theme issue ‘Heterogeneous materials: metastable and non-ergodic internal structures’.
Systematic identification of regulators of antibody-drug conjugate toxicity using CRISPR-Cas9 screens
Authors: Tsui C. Kimberly , Barfield Robyn M. , Fischer Curt R. , Morgens David W. , Li Amy , Smith Benjamin A. H. , Bertozzi Carolyn R. , Rabuka David , Bassik Michael C. 
Published: March 2019

AbstractAntibody-drug conjugates (ADCs) selectively deliver highly toxic chemotherapeutic agents to target antigen-expressing cells and have become an important cancer treatment in recent years. However, the molecular mechanisms by which ADCs are internalized and activated within cells remain unclear. Here we use CRISPR-Cas9 screens to identify genes that control the toxicity of ADCs. Our results demonstrate critical roles for a range of known and novel endolysosomal trafficking regulators in ADC toxicity. We identify and characterize C18orf8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Through comparative analysis of CRISPR screens with ADCs bearing a noncleavable linker versus a cleavable valine-citrulline (VC) linker, we show that a subset of late endosomal and lysosomal regulators are selectively essential for toxicity of noncleavable linker ADCs. We further show that cleavable VC linkers are rapidly processed upon internalization and therefore surprisingly appear to bypass the requirement of lysosomal delivery. Lastly, we show that inhibition of sialic acid biosynthesis sensitizes cells to ADC treatment by increasing the rate of ADC internalization. This sensitization was observed using several ADCs targeting different antigens in diverse cancer cell types, including the FDA-approved ADC trastuzumab emtansine (T-DM1) in Her2-positive breast cancer cells. Together, these results reveal novel regulators of endolysosomal trafficking, provide important insights to guide future ADC design, and identify candidate combination therapy targets as well as potential mechanisms of ADC resistance.
Single particle trajectory statistic to reconstruct chromatin organization and dynamics
Authors: Shukron O. , Seeber A. , Amitai A. , Holcman D. 
Published: March 2019

AbstractChromatin organization remains complex and far from understood. We discuss here recent statistical methods to extract biophysical parameters from in vivo single particle trajectories of loci to reconstruct chromatin reorganization in response to cellular stress such as DNA damages. We look at the methods to analyze both single loci as well as multiple loci tracked simultaneously and explain how to quantify and describe chromatin motion using a combination of extractable parameters. These parameters can be converted into information about chromatin dynamics and function. Furthermore, we discuss how the time scale of recurrent motion of a locus can be extracted and converted into local chromatin dynamics. We also discuss the effect of various sampling rates on the estimated parameters. Finally, we discuss polymer methods based on cross-linkers that account for minimal loop constraints hidden in tracked loci, that reveal chromatin organization at the 250nmspatial scale. We list and refer to some algorithm packages that are now publicly available. To conclude, chromatin organization and dynamics at hundreds of nanometers can be reconstructed from locus trajectories and predicted based on polymer models.
Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ
Authors: Law Pui-Pik , Chan Ping-Kei , McEwen Kirsten , Zhi Huihan , Liang Bing , Naruse Chie , Asano Masahide , Tan-Un Kian-Cheng , Chan Godfrey Chi-Fung , Festenstein Richard 
Published: March 2019

SummarySex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1γ). To determine whether this sex-regulatory effect of HP1γ was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1γ. Strikingly, HP1γ was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1γ gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease.
Small RNA expression pattern in multiply inbred lines and their hybrids of maize embryo
Authors: Liu Yong-Xin 
Published: March 2019

AbstractHeterosis, also known as hybrid vigor or transgression, is the phenomenon wherein an F1 hybrid produced from crossing two cultivars of the same or different species shows superior phenotypes. Heterosis in maize has been found and applied in breeding for more than one hundred years. However, its underlying molecular mechanisms are still poorly understood. To investigate whether small RNAs (sRNAs) participate in the regulation of heterosis, we profiled the sRNA expression patterns in the germ seeds of five inbred lines and theirs three F1 hybrids using high-throughput sequencing technology. The sequencing result show maize sRNAs are enriched in 22-nt length. Nearly 90% of 22-nt small RNA dominated clusters (SRCs) are in repeat regions, which mainly originated from Gypsy and Copia in retrotransposon. About 25% differentially expressed SRCs exist between parents, and hybrid gain almost all differentially expressed 22-nt SRCs. Twenty-four-nt sRNA also enriched in maize, which showed great sequence diversity and overall low expression across the genome. More than half of 24-nt SRCs originate from repeat, and 80% of them come from DNA transposon. Nearly 30% of 24-nt SRCs located in genes or their flanking regions, especially in flanking regions of “lipid metabolic process” and “macromolecule modification” related genes. Several thousands 24-nt SRCs are paternal or maternal specific expressed, and hybrids gain only half of differentially expressed 24-nt SRCs. Hundreds of 24-nt SRCs show high parent or above high parent expression pattern in different hybrids, and them mainly from Tourist, haT, and CACTA in DNA transposon and enrich nearby “tRNA aminoacylation for protein translation” related genes. Also, some 21-nt SRCs show conserved expression pattern in low parent. They were enriched in anti-sense region of some genes, which functions are about oxidative phosphorylation and translation. miRNAs have a global downregulated tendency in hybrids. zma-miR408-5p, zma-miR1432-5p and zma-miR528-5p are significant downregulated in each hybrid, and this phenomenon may cause their target genes more stable and contribute to hybrid vigor. Taken together, our results illustrated that sRNAs may contribute to heterosis at the very early stage of seed germination through repressing of retrotransposon activity, regulation gene activity at gene and genic flanking regions, and promotion some gene expressions by downregulated miRNAs.
Computational Design of Myristoylated Cell Penetrating Peptides Targeting Oncogenic K-Ras.G12D at the Effector Binding Membrane Interface
Authors: Li Zhenlu , Buck Matthias 
Published: March 2019

AbstractA number of small inhibitors have been developed in the recent years to target the cancer driving protein, K-Ras. In this study we propose and design a novel way of targeting oncogenic K-Ras4B.G12D with myristoylated cell penetrating peptides which become membrane anchored and lock the protein into an inactive state. In all atom molecular dynamics simulations such peptides associate with K-Ras4B exclusively at the effector binding region, which, in turn, expected to hinder the binding of down-stream effector proteins (e.g. C-Raf). The myristoylated R9 (Arg9) peptide strongly locks K-Ras4B.G12D into orientations that are unfavorable for effector binding. After breaking the cyclic structure and myristoylation, a cell penetrating peptide cyclorasin 9A5, which was designed for targeting the Ras: Raf interface, is also found to be effective in targeting the Ras: membrane interface. The myristoylated peptides likely have high cell permeability due to their mixed cationic/hydrophobic character at the N-terminus, while simultaneously the subsequent multiple charges help to maintain a strong association of the peptide with the K-Ras4B.G12D effector binding lobe. Targeting protein-membrane interfaces is starting to attract attention very recently, thanks to our understanding of the signaling mechanism of an increased number of peripheral membrane proteins. The strategy used in this study has potential applications in the design of drugs against K-Ras4B driven cancers. It also provides insights into the general principles of targeting protein-membrane interfaces.
Structured Inhibitory Activity Dynamics During Learning
Authors: Arriaga Moises , Han Edward B. 
Published: March 2019

AbstractHippocampal network activity is tightly regulated by local inhibitory interneurons. Suppression of inhibition has been proposed to accelerate learning by enhancing network activity and plasticity; however, the activity dynamics of hippocampal interneurons during learning remain poorly understood. Furthermore, it is unknown if individual interneurons are stochastically suppressed across different learning episodes, mirroring the random remapping of place cells, or if instead they exhibit consistent patterns of activity suppression. These critical properties define how inhibition shapes and controls learning at a network level. To uncover the functional circuit dynamics of inhibition during novelty-induced learning, we recorded calcium activity from hippocampal CA1 interneurons using two-photon imaging as mice learned a virtual reality (VR) goal-directed spatial navigation task in new visual contexts. Here we focused on dendrite-targeting somatostatin-expressing interneurons (SOM-ints), which powerfully control burst firing and synaptic plasticity in excitatory neurons. We found robust activity suppression in SOM-ints upon exposure to novel virtual environments; activity then recovered over repeated exposures to the novel environment as the animal learned goal locations. At a population level, we found a continuum of activity suppression, from interneurons strongly suppressed to moderately activated during learning. Surprisingly, each interneuron exhibited a stable level of activity modulation: when animals were switched into a second novel environment, the magnitude of activity suppression was strongly correlated across remapping sessions. This work reveals dynamic inhibition suppression triggered by novel environments and the gradual return of inhibition with learning. Furthermore, unlike the stochastic remapping of place cells, inhibitory networks display a stable activity structure across learning episodes. This functional inhibitory circuit architecture suggests that individual interneurons play specialized and stereotyped roles during learning, perhaps by differentially regulating pyramidal subnetworks specialized for plasticity and stability.
Molecular evolution guided functional analyses reveals Nucleobindin-1 as a canonical E-box binding protein promoting Epithelial-to-Mesenchymal transition (EMT)
Authors: Sinha Sansrity , Pattnaik Siddhart , Aradhyam Gopala Krishna 
Published: March 2019

AbstractCalcium binding proteins (CBPs) function in response to changes in intracellular calcium (Ca2+) levels by modulating intracellular signaling pathways. Calcium sensors, including Nucleobindins (Nucb1/2) undergo Ca2+-binding induced conformational changes and bind to target proteins. Nucleobindins possess additional uncharacterized domains including partly characterized EF-hands. We study the molecular evolution of Nucleobindins in eukaryotes emphasizing on the N-terminal DNA binding domain (DBD) that emerged as a result of domain insertion event in Nucb1/2 domain-scaffold in an ancestor to the opisthokonts. Our results fromin silicoanalyses and functional assays revealed that DBD of Nucb1 binds to canonical E-box sequences and triggers cell epithelial-mesenchymal transition (EMT). Thus, post gene duplication, Nucb1 has emerged as unconventional Ca2+-binding transcriptional regulators that can induce EMT.HighlightsNucleobindins emerged from prokaryotic EF-hand containing protein.The DNA-binding domain was gained in these in opisthokonts.Gene duplication in ancestor of euteleostomes, lead to emergence of Nucb1/2.Nucb1 emerged as a canonical E-box binding protein promoting EMT
Probing Allosteric Coupling of a Constitutively Open Mutant of the Ion Channel KcsA using Solid State NMR
Authors: Sun Zhiyu , Xu Yunyao , Zhang Dongyu , McDermott Ann E 
Published: March 2019

AbstractTransmembrane allosteric coupling is a feature of many critical biological signaling events. Here we test whether transmembrane allosteric coupling controls the mean open time of the prototypical potassium channel KcsA in the context of C-type inactivation. Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH. Numerous studies have suggested that this proton binding also prompts a conformational switch leading to a loss of affinity for potassium ions at the selectivity filter and therefore to channel inactivation. We tested this mechanism for inactivation using a KcsA mutant (H25R/E118A) that has the pH gate open across a broad range of pH values. We present solid-state NMR measurements of this open mutant at neutral pH to probe the affinity for potassium at the selectivity filter. The potassium binding affinity in the selectivity filter of this mutant, 81 mM, is about 4 orders of magnitude weaker than that of wild type KcsA at neutral pH and is comparable to the value for wild type KcsA at low pH (pH ∼ 3.5). This result strongly supports our assertion that the open pH gate allosterically effects the potassium binding affinity of the selectivity filter. In this mutant the protonation state of a glutamate residue (E120) in the pH sensor is sensitive to potassium binding, suggesting that this mutant also has flexibility in the activation gate and is subject to transmembrane allostery.Significance statementInactivation of potassium channels controls mean open times and provides exquisite control over biological processes. In the highly conserved C-type inactivation process, opening of the activation gate causes subsequent inactivation. We test whether the open state of the channel simply has a poor ability to bind the K+ion. Previously, activated and inactivated states were stabilized using truncations or a significant pH drop. Here, we use the H25R/E118A constitutively open mutant of KcsA and also observe a large drop in potassium binding affinity. This provides strong evidence that channel opening causes an allosteric loss of ion affinity, and that the central feature of this universal channel inactivation process is loss of ion affinity at the selectivity filter.
The AAA+ ATPase TorsinA polymerizes into hollow tubes with a helical periodicity of 8.5 subunits per turn
Authors: Demircioglu F. Esra , Zheng Weili , McQuown Alexander J. , Maier Nolan , Watson Nicki , Cheeseman Iain M. , Denic Vladimir , Egelman Edward H. , Schwartz Thomas U. 
Published: March 2019

AbstractTorsinA is an ER-resident AAA+ ATPase, whose single residue deletion of glutamate E303 results in the genetic neuromuscular disease primary dystonia. TorsinA is a highly unusual AAA+ ATPase in that it needs an external activator. Also, it appears not to thread a peptide substrate through a narrow central channel, in contrast to its closest structural homologs. Here, we examined the oligomerization of TorsinA to get closer to a molecular understanding of the still enigmatic function of it. We observe TorsinA to form helical filaments, which we analyzed by cryo-electron microscopy using helical reconstruction. The 4.4 Å structure reveals long hollow tubes with a helical periodicity of 8.5 subunits per turn, and an inner cavity of ∼4 nm diameter. We further show that the protein is able to induce tubulation of membranes in vitro, an observation that may reflect an entirely new characteristic of AAA+ ATPases. We discuss the implications of these observations for TorsinA function.
Novel Organ-Specific Genetic Factors for Quantitative Resistance to Late Blight in Potato
Authors: Juyo Rojas Deissy Katherine , Soto Sedano Johana Carolina , Ballvora Agim , Léon Jens , Mosquera Vásquez Teresa 
Published: March 2019

AbstractPotato,Solanum tuberosum, is one of the highest consumed food in the world, being the basis of the diet of millions of people. The main limiting and destructive disease of potato is late blight, caused byPhytophtora infestans. Here, we present a multi-environmental analysis of the response toP. infestansusing an association panel of 150 accessions ofS. tuberosumGroup Phureja, evaluated in two localities in Colombia. Disease resistance data were merged with a genotyping matrix of 83,862 SNPs obtained by 2b-restriction site–associated DNA and Genotyping by sequencing approaches into a Genome-wide association study. We are reporting 16 organ-specific QTL conferring resistance to late blight. These QTL explain from 13.7% to 50.9% of the phenotypic variance. Six and ten QTL were detected for resistance response in leaves and stem, respectively.In silicoanalysis revealed 15 candidate genes for resistance to late blight. Four of them have no functional genome annotation, while eleven candidate genes code for diverse proteins, including one leucine-rich repeat kinase.