bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolvin D3 controls mouse and human nociceptive functions and preclinical progression of psoriasis
Authors: Lee Sang Hoon , Tonello Raquel , Im Sang-Taek , Jeon Hawon , Park Jeongsu , Ford Zachary , Davidson Steve , Kim Yong Ho , Park Chul-Kyu , Berta Temugin 
Published: July 2019

SummaryPsoriasis is a chronic inflammatory skin disease caused by a complex interplay between the immune and nervous systems. Here, we found that resolvin D3 (RvD3) significantly prevented both skin inflammation and itch in a preclinical animal model of psoriasis induced by repeated applications of imiquimod. We also found that RvD3 anti-psoriatic effects resulted from the inhibition of nociceptive functions, which inhibition was replicated in human nociceptive neurons. We conclude that RvD3 and targeting nociceptive functions are promising strategies to treat psoriasis.
Less is more: Coarse-grained integrative modeling of large biomolecular assemblies with HADDOCK
Authors: Roel-Touris Jorge , Don Charleen G. , Honorato Rodrigo V. , Rodrigues João P.G.L.M , Bonvin Alexandre M.J.J. 
Published: July 2019

ABSTRACTPredicting the 3D structure of protein interactions remains a challenge in the field of computational structural biology. This is in part due to difficulties in sampling the complex energy landscape of multiple interacting flexible polypeptide chains. Coarse-graining approaches, which reduce the number of degrees of freedom of the system, help address this limitation by smoothing the energy landscape, allowing an easier identification of the global energy minimum. They also accelerate the calculations, allowing to model larger assemblies. Here, we present the implementation of the MARTINI coarse-grained force field for proteins into HADDOCK, our integrative modelling platform. Docking and refinement are performed at the coarse-grained level and the resulting models are then converted back to atomistic resolution through a distance restraints-guided morphing procedure. Our protocol, tested on the largest complexes of the protein docking benchmark 5, shows an overall ~7-fold speed increase compared to standard all-atom calculations, while maintaining a similar accuracy and yielding substantially more near-native solutions. To showcase the potential of our method, we performed simultaneous 7 body docking to model the 1:6 KaiC-KaiB complex, integrating mutagenesis and hydrogen/deuterium exchange data from mass spectrometry with symmetry restraints, and validated the resulting models against a recently published cryo-EM structure.
Hippocampal Subfield Volumes in Abstinent Men and Women with a History of Alcohol Use Disorder
Authors: Sawyer Kayle S. , Adra Noor , Salz Daniel M. , Kemppainen Maaria I. , Ruiz Susan M. , Harris Gordon J. , Oscar-Berman Marlene 
Published: July 2019

AbstractAlcohol use disorder (AUD) has been associated with abnormalities in hippocampal volumes, but these relationships have not been fully explored with respect to sub-regional volumes, nor in association with individual characteristics such as gender differences, age, and memory. The present study examined the impact of those variables in relation to hippocampal subfield volumes in abstinent men and women with a history of AUD. Using Magnetic Resonance Imaging at 3 Tesla, we obtained brain images from 67 participants (31 women) with AUD and 63 healthy control (NC) participants (30 women) without AUD. We used Freesurfer 6.0 to segment the hippocampus into 12 regions. These were imputed into mixed models to examine the relationships of brain volume with AUD group, gender, age, drinking history, and memory. The AUD group had approximately 5% smaller CA1, hippocampal tail, and molecular layer regions than the NC group. Age was negatively associated with volumes for the AUD group in the hippocampal tail, subiculum, and presubiculum. The relationships for delayed and immediate memory with hippocampal tail volume differed for AUD and NC groups: Higher scores were associated with smaller volumes in the AUD group, but larger volumes in the NC group. Length of sobriety was associated with decreasing CA1 volume in women (0.02% per year) and increasing volume size in men (0.03% per year). These findings confirm and extend evidence that AUD, gender, age, and abstinence differentially impact volumes of component parts of the hippocampus. The course of abstinence on CA1 volume differed for men and women, and the differential relationships of subregional volumes to age and memory could indicate a distinction in the impact of AUD on functions of the hippocampal tail.
High-throughput identification of MHC class I binding peptides using an ultradense peptide array
Authors: Haj Amelia K. , Breitbach Meghan E. , Baker David A. , Mohns Mariel S. , Moreno Gage K. , Wilson Nancy A. , Lyamichev Victor , Patel Jigar , Weisgrau Kim L. , Dudley Dawn M. , O’Connor David H. 
Published: July 2019

AbstractRational vaccine development and evaluation requires identifying and measuring the magnitude of epitope-specific CD8 T cell responses. However, conventional CD8 T cell epitope discovery methods are labor-intensive and do not scale well. Here, we accelerate this process by using an ultradense peptide array as a high-throughput tool for screening peptides to identify putative novel epitopes. In a single experiment, we directly assess the binding of four common Indian rhesus macaque MHC class I molecules – Mamu-A1*001, -A1*002, -B*008, and -B*017 – to approximately 61,000 8-mer, 9-mer, and 10-mer peptides derived from the full proteomes of 82 simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) isolates. Many epitope-specific CD8 T cell responses restricted by these four MHC molecules have already been identified in SIVmac239, providing an ideal dataset for validating the array; up to 64% of these known epitopes are found in the top 192 SIVmac239 peptides with the most intense MHC binding signals in our experiment. To assess whether the peptide array identified putative novel CD8 T cell epitopes, we validated the method by IFN-γ ELISPOT assay and found three novel peptides that induced CD8 T cell responses in at least two Mamu-A1*001-positive animals; two of these were validated byex vivotetramer staining. This high-throughput identification of peptides that bind class I MHC will enable more efficient CD8 T cell response profiling for vaccine development, particularly for pathogens with complex proteomes where few epitope-specific responses have been defined.
Functional localization of the frontal eye fields in the common marmoset using microstimulation
Authors: Selvanayagam Janahan , Johnston Kevin D. , Schaeffer David J. , Hayrynen Lauren K. , Everling Stefan 
Published: July 2019

AbstractThe frontal eye field (FEF) is a critical region for the deployment of overt and covert spatial attention. While investigations in the macaque continue to provide insight into the neural underpinnings of the FEF, due to its location within a sulcus the macaque FEF is virtually inaccessible to electrophysiological techniques such as high-density and laminar recordings. With a largely lissencephalic cortex, the common marmoset (Callithrix jacchus) is a promising alternative primate model for studying FEF microcircuitry. Putative homologies have been established with the macaque FEF on the basis of cytoarchitecture and connectivity, however physiological investigation in awake, behaving marmosets is necessary to physiologically locate this area. Here we addressed this gap using intracortical microstimulation in a broad range of frontal cortical areas in marmosets. We implanted marmosets with 96-channel Utah arrays and applied microstimulation trains while they freely viewed video clips. We evoked short-latency fixed vector saccades at low currents (<50 μA) in areas 45, 8aV, 8C and 6DR. We observed a topography of saccade direction and amplitude consistent with findings in macaques and humans; we observed small saccades in ventrolateral FEF and large saccades combined with contralateral neck and shoulder movements encoded in dorsomedial FEF. Our data provide compelling evidence supporting homology between marmoset and macaque FEF and suggest the marmoset is a useful primate model for investigating FEF microcircuitry and its contributions to oculomotor and cognitive functions.Significance StatementThe frontal eye field (FEF) is a critical cortical region for overt and covert spatial attention. The microcircuitry of this area remains poorly understood, as in the macaque, the most commonly used model, it is embedded within a sulcus and is inaccessible to modern electrophysiological and optical imaging techniques. The common marmoset is a promising alternative primate model due to its lissencephalic cortex and potential for genetic manipulation. However, evidence for homologous cortical areas in this model remains limited and unclear. Here we applied microstimulation in frontal cortical areas in marmosets to physiologically identify the FEF. Our results provide compelling evidence for a frontal eye field in the marmoset, and suggest that the marmoset is a useful model for FEF microcircuitry.
Monotonous behavior with 2-propanol converts into reentrant transition with 1-propanol: Higher-order structure of DNA
Authors: Ma Y. , Yoshikawa Y. , Yoshikawa K. 
Published: July 2019

ABSTRACTIn the present study, we measured the changes in the higher-order structure of genomic DNA molecules in the presence of alcohols through single-DNA observation by use of fluorescence microscopy, with particular focus on the different effects of 1-propanol and 2-propanol. The results showed that, with an increasing concentration of 1-propanol, DNA exhibits reentrant conformational transitions from an elongated coil to a folded globule, and then to an unfolded state. On the other hand, with 2-propanol, DNA exhibits monotonous shrinkage into a compact state. Thus, DNA molecules are more effectively condensed/precipitated with 2-propanol than with 1-propanol. The propanol isomers also had different effects on the changes in the secondary structure of DNA, as revealed by circular dichroism (CD) measurements. With 1-propanol, DNA maintains a B-form secondary structure. An A-like conformation appears with the addition of 2-propanol.STATEMENT OF SIGNIFICANCECurrently, 2-propanol has most often been used as the solvent to extract and purify genomic DNA molecules from living cells, according the protocols in molecular biology and biochemistry. Unfortunately, the reason why usage of 2-propanol is recommended instead of ethanol and 1-propanol has never been explained in a clear manner. We believe that the new insight based on chemical physics point of view would play an important role for the development of current chemical procedures/treatments adapted on an empirical basis.
Multiplexed Single Ion Mass Spectrometry Improves Measurement of Proteoforms and Their Complexes
Authors: Kafader Jared O. , Melani Rafael D. , Durbin Kenneth R. , Ikwuagwu Bon , Early Bryan P. , Fellers Ryan T. , Beu Steven C. , Zabrouskov Vlad , Makarov Alexander A. , Maze Joshua T. , Shinholt Deven L. , Yip Ping F. , Tullman-Ercek Danielle , Senko Michael W. , Compton Philip D. , Kelleher Neil L. 
Published: July 2019

AbstractA new Orbitrap-based single ion analysis procedure is shown to be possible by determining the direct charge on numerous measurements of individual protein ions to generate true mass spectra. The deployment of an Orbitrap system for charge detection enables the characterization of highly complicated mixtures of proteoforms and their complexes in both denatured and native modes of operation, revealing information not obtainable by traditional measurement of an ensemble of ions.
Recognition of histone H3 methylation states by the PHD1 domain of histone demethylase KDM5A
Authors: Longbotham James E , Kelly Mark J S , Galonić Fujimori Danica 
Published: July 2019

AbstractPHD reader domains are chromatin binding modules often responsible for the recruitment of large protein complexes that contain histone modifying enzymes, chromatin remodelers and DNA repair machinery. A majority of PHD domains recognize N–terminal residues of histone H3 and are sensitive to the methylation state of Lys4 in histone H3 (H3K4). Histone demethylase KDM5A, an epigenetic eraser enzyme that contains three PHD domains, is often overexpressed in various cancers and its demethylation activity is allosterically enhanced when its PHD1 domain is bound to the H3 tail. The allosteric regulatory function of PHD1 expands roles of reader domains, suggesting unique features of this chromatin interacting module. Our previous studies determined the H3 binding site of PHD1, although it remains unclear how the H3 tail interacts with the N–terminal residues of PHD1 and how PHD1 discriminates against H3 tails with varying degrees of H3K4 methylation. Here we have determined the solution structure of apo and H3 bound PHD1. We observe conformational changes occurring in PHD1 in order to accommodate H3, which interestingly binds in a helical conformation. We also observe differential interactions of binding residues with differently methylated H3K4 peptides (me0, me1, me2 or me3), providing a rational for this PHD1 domain’s preference for lower methylation states of H3K4. We further assessed the contributions of various H3 interacting residues in the PHD1 domain to the binding of H3 peptides. The structural information of the H3 binding site could provide useful information to aid development of allosteric small molecule modulators of KDM5A.
Contextual Classifications of Cancer Driver Genes
Authors: Chandrashekar Pramod , Ahmadinejad Navid , Wang Junwen , Sekulic Aleksandar , Egan Jan B. , Asmann Yan W. , Maley Carlo , Liu Li 
Published: July 2019

ABSTRACTFunctions of cancer driver genes depend on cellular contexts that vary substantially across tissues and organs. Distinguishing oncogenes (OGs) and tumor suppressor genes (TSGs) for each cancer type is critical to identifying clinically actionable targets. However, current resources for context-aware classifications of cancer drivers are limited. In this study, we show that the direction and magnitude of somatic selection of missense and truncating mutations of a gene are suggestive of its contextual activities. By integrating these features with ratiometric and conservation measures, we developed a computational method to categorize OGs and TSGs using exome sequencing data. This new method, named genes under selection in tumors (GUST) shows an overall accuracy of 0.94 when tested on manually curated benchmarks. Application of GUST to 10,172 tumor exomes of 33 cancer types identified 98 OGs and 179 TSGs, >70% of which promote tumorigenesis in only one cancer type. In broad-spectrum drivers shared across multiple cancer types, we found heterogeneous mutational hotspots modifying distinct functional domains, implicating the synchrony of convergent and divergent disease mechanisms. We further discovered two novel OGs and 28 novel TSGs with high confidence. The GUST program is available at https://github.com/liliulab/gust. A database with pre-computed classifications is available at https://liliulab.shinyapps.io/gust
Genetic and environmental canalization are not associated among altitudinally varying populations ofDrosophila melanogaster
Authors: Pesevski Maria , Dworkin Ian 
Published: July 2019

AbstractOrganisms are exposed to environmental and mutational effects influencing both mean and variance of phenotypes. Potentially deleterious effects arising from this variation can be reduced by the evolution of buffering (canalizing) mechanisms, ultimately reducing phenotypic variability. As such, there has been interest regarding the plausible conditions that enable canalizing mechanisms to evolve. Under some models, the circumstances under which genetic canalization evolves is limited, despite apparent empirical evidence for it. It has been argued that canalizing mechanisms for mutational effects may evolve as a correlated response to environmental canalization (the congruence model). Yet, empirical evidence has not consistently supported the prediction of a correlation between genetic and environmental canalization. In a recent study, a population ofDrosophila melanogasteradapted to high altitude showed evidence of genetic decanalization relative to those from low-altitudes. Using strains derived from these populations, we tested if they also varied for environmental canalization, rearing them at different temperatures. Using wing morphology, we quantified size, shape, cell (trichome) density and frequencies of mutational defects. We observed the expected differences in wing size and shape, cell density and mutational defects between the high- and low-altitude populations. However, we observed little evidence for a relationship between a number of measures of environmental canalization with population or with visible defect frequency. Our results do not support the predicted association between genetic and environmental canalization.
Deep learning-based cross-classifications reveal conserved spatial behaviors within tumor histological images
Authors: Noorbakhsh Javad , Farahmand Saman , pour Ali Foroughi , Namburi Sandeep , Caruana Dennis , Rimm David , Soltanieh-ha Mohammad , Zarringhalam Kourosh , Chuang Jeffrey H. 
Published: July 2019

AbstractHistopathological images are a rich but incompletely explored data type for studying cancer. Manual inspection is time consuming, making it challenging to use for image data mining. Here we show that convolutional neural networks (CNNs) can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors. We develop CNN architectures to analyze 27,815 hematoxylin and eosin slides from The Cancer Genome Atlas for tumor/normal, cancer subtype, and mutation classification. Our CNNs are able to classify tumor/normal status of whole slide images (WSIs) in 19 cancer types with consistently high AUCs (0.995±0.008), as well as subtypes with lower but significant accuracy (AUC 0.87±0.1). Remarkably, tumor/normal CNNs trained on one tissue are effective in others (AUC 0.88±0.11), with classifier relationships also recapitulating known adenocarcinoma, carcinoma, and developmental biology. Moreover, classifier comparisons reveal intra-slide spatial similarities, with average tile-level correlation of 0.45±0.16 between classifier pairs. Breast cancers, bladder cancers, and uterine cancers have spatial patterns that are particularly easy to detect, suggesting these cancers can be canonical types for image analysis. Patterns for TP53 mutations can also be detected, with WSI self- and cross-tissue AUCs ranging from 0.65-0.80. Finally, we comparatively evaluate CNNs on 170 breast and colon cancer images with pathologist-annotated nuclei, finding that both cellular and intercellular regions contribute to CNN accuracy. These results demonstrate the power of CNNs not only for histopathological classification, but also for cross-comparisons to reveal conserved spatial biology.
A ciliary BBSome-ARL-6-PDE6D pathway trafficks RAB-28, a negative regulator of extracellular vesicle biogenesis
Authors: Akella Jyothi S. , Carter Stephen P. , Rizvi Fatima , Nguyen Ken C.Q. , Tsiropoulou Sofia , Moran Ailís L. , Silva Malan , Kennedy Breandán N. , Hall David H. , Barr Maureen M. , Blacque Oliver E. 
Published: July 2019

ABSTRACTCilia both receive and send information, the latter in the form of extracellular vesicles (EVs). EVs are nano-communication devices that cells shed to influence cell, tissue, and organism behavior. Mechanisms driving ciliary EV biogenesis and environment release are almost entirely unknown. Here, we show that the ciliary G-protein RAB28, associated with human autosomal recessive cone-rod dystrophy, negatively regulates EV levels in the sensory organs of Caenorhabditis elegans. We also find that sequential targeting of lipidated RAB28 to periciliary and ciliary membranes is highly dependent on the BBSome and PDE6D, respectively, and that BBSome loss causes excessive and ectopic EV production. Our data indicate that RAB28 and the BBSome are key in vivo regulators of EV production at the periciliary membrane. Our findings also suggest that EVs control sensory organ homeostasis by mediating communication between ciliated neurons and glia, and that defects in ciliary EV biogenesis may contribute to human ciliopathies.
Rising insecticide potency outweighs falling application rate to make US farmland increasingly hazardous to insects
Authors: Douglas Margaret R. , Sponsler Douglas B. , Lonsdorf Eric V. , Grozinger Christina M. 
Published: July 2019

AbstractEach year, millions of kilograms of insecticides are applied to crops in the US. While insecticide use supports food, fuel, and fiber production, it can also threaten non-target organisms, a concern underscored by mounting evidence of widespread insect decline. Nevertheless, answers to basic questions about the spatiotemporal patterns of insecticide use remain elusive, due in part to the inherent complexity of insecticide use, and exacerbated by the dispersed nature of the relevant data, divided between several government repositories. Here, we integrate these public datasets to generate county-level annual estimates of total ‘insect toxic load’ (honey bee lethal doses) for insecticides applied in the US between 1997-2012, calculated separately for oral and contact toxicity. To explore the underlying drivers of the observed changes, we divide insect toxic load into the components of extent (area treated) and intensity (application rate x potency). We show that while contact-based insect toxic load remained relatively steady over the period of our analysis, oral-based insect toxic load increased roughly 9-fold, with reductions in application rate outweighed by disproportionate increases in potency (toxicity/kg) and increases in extent. This pattern varied markedly by region, with the greatest increases seen in Heartland and Northern Great Plains regions, likely driven by use of neonicotinoid seed treatments in corn and soybean. In this “potency paradox,” US farmland has become more hazardous to insects despite lower volumes of insecticides applied, raising serious concerns about insect conservation and highlighting the importance of integrative approaches to pesticide use monitoring.Significance statementPrevious analyses disagree about whether US insecticide use is increasing or decreasing, a question of significant importance given the putative role of insecticides in recent insect declines. We integrated information from multiple national databases to estimate ‘insect toxic load’ (represented as honey bee lethal doses) of the agricultural insecticides applied in each US county from 1997 to 2012, and factors responsible for its change. Across the US, insect toxic load – calculated on the basis of oral toxicity – increased 9-fold. This increase was due to increases in the potency (toxicity/kg) of insecticides applied and in the area treated; the volume of insecticides applied declined. Toxic load increased most dramatically in regions where neonicotinoid seed treatments for field crops are commonly used.