bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues
Authors: Gouldin Austin G. , Brown M. Ethan , Puetzer Jennifer L. 
Published: September 2020

AbstractPurposeIn connective tissues there is a clear link between increasing age and degeneration. Advanced glycation end-products (AGEs) are believed to play a central role. AGEs are sugar-induced non-enzymatic crosslinks which accumulate in collagen with age and diabetes, altering tissue mechanics and cellular function. Despite ample correlative evidence linking collagen glycation to tissue degeneration, little is known how AGEs impact cell-matrix interactions, limiting therapeutic options. One reason for this limited understanding is AGEs are typically induced using high concentrations of ribose which decrease cell viability, making it impossible to investigate cell-matrix interactions. The objective of this study was to develop a system to trigger AGE accumulation while maintaining cell viability.Materials and MethodsUsing cell-seeded high density collagen gels, we investigated the effect of two systems for AGE induction, ribose at low concentrations (30, 100, and 200 mM) over 15 days of culture and riboflavin (0.25 mM and 0.75mM) induced with blue light for 40 seconds (riboflavin-465 nm).ResultsWe found ribose and riboflavin-465 nm treatment produces fluorescent AGE quantities which match and/or exceed human fluorescent AGE levels for various tissues, ages, and diseases, without affecting cell viability or metabolism. Interestingly, a 40 second treatment of riboflavin-465 nm produced similar levels of fluorescent AGEs as 3 days of 100 mM ribose treatment.ConclusionsRiboflavin-465 nm is a promising method to trigger AGE crosslinks on demandin vivoorin vitrowithout impacting cell viability and offers potential for unraveling the mechanism of AGEs in age and diabetes related tissue damage.
Systematic comparison of high-throughput single-cell RNA-seq methods for immune cell profiling
Authors: Yamawaki Tracy M. , Lu Daniel R. , Ellwanger Daniel C. , Bhatt Dev , Manzanillo Paolo , Zhou Hong , Yoon Oh Kyu , Homann Oliver , Wang Songli , Li Chi-Ming 
Published: September 2020

AbstractBackgroundElucidation of immune populations with single-cell RNA-seq has greatly benefited the field of immunology by deepening the characterization of immune heterogeneity and leading to the discovery of new subtypes. However, single-cell methods inherently suffer from limitations in the recovery of complete transcriptomes due to the prevalence of cellular and transcriptional dropout events. This issue is often compounded by limited sample availability and limited prior knowledge of heterogeneity, which can confound data interpretation.ResultsHere, we systematically benchmarked seven high-throughput single-cell RNA-seq methods. We prepared 21 libraries under identical conditions of a defined mixture of two human and two murine lymphocyte cell lines, simulating heterogeneity across immune-cell types and cell sizes. We evaluate methods by their cell recovery rate, library efficiency, sensitivity, and ability to recover expression signatures for each cell type. We observed higher mRNA detection sensitivity with the 10x Genomics 5’ v1 and 3’ v3 methods. We demonstrate that these methods have fewer drop-out events which facilitates the identification of differentially-expressed genes and improves the concordance of single-cell profiles to immune bulk RNA-seq signatures.ConclusionOverall, our characterization of immune cell mixtures provides useful metrics, which can guide selection of a high-throughput single-cell RNA-seq method for profiling more complex immune-cell heterogeneity usually foundin vivo.
High throughput instrument to screen fluorescent proteins under two-photon excitation
Authors: Molina Rosana S. , King Jonathan , Franklin Jacob , Clack Nathan , McRaven Christopher , Goncharov Vasily , Flickinger Daniel , Svoboda Karel , Drobizhev Mikhail , Hughes Thomas E. 
Published: September 2020

AbstractTwo-photon microscopy together with fluorescent proteins and fluorescent protein-based biosensors are commonly used tools in neuroscience. To enhance their experimental scope, it is important to optimize fluorescent proteins for two-photon excitation. Directed evolution of fluorescent proteins under one-photon excitation is common, but many one-photon properties do not correlate with two-photon properties. A simple system for expressing fluorescent protein mutants isE. colicolonies on an agar plate. The small focal volume of two-photon excitation makes creating a high throughput screen in this system a challenge for a conventional point-scanning approach. We present an instrument and accompanying software that solves this challenge by selectively scanning each colony based on a colony map captured under one-photon excitation. This instrument, called the GIZMO, can measure the two-photon excited fluorescence of 10,000E. colicolonies in 7 hours. We show that the GIZMO can be used to evolve a fluorescent protein under two-photon excitation.
Genome-wide approaches for the identification of markers and genes associated with sugarcane yellow leaf virus resistance
Authors: Pimenta Ricardo José Gonzaga , Aono Alexandre Hild , Villavicencio Burbano Roberto Carlos , Coutinho Alisson Esdras , da Silva Carla Cristina , dos Anjos Ivan Antônio , Perecin Dilermando , de Andrade Landell Marcos Guimarães , Gonçalves Marcos Cesar , Pinto Luciana Rossini , de Souza Anete Pereira 
Published: September 2020

AbstractA major disease affecting sugarcane, a leading sugar and energy crop, is sugarcane yellow leaf (SCYL), caused by the sugarcane yellow leaf virus (SCYLV). Despite damages caused by SCYLV, the genetic basis of resistance to this virus remains largely unknown. Several methodologies have arisen to identify molecular markers associated with SCYLV resistance, which are crucial for marker-assisted selection and understanding response mechanisms to this virus. We investigated the genetic basis of SCYLV resistance using dominant and codominant markers and genotypes of interest for breeding. A sugarcane panel inoculated with SCYLV was analyzed for SCYL symptoms, and viral titer was estimated by RT-qPCR. This panel was genotyped with 662 dominant markers and 70,888 SNPs and indels with allele proportion information. We used polyploid-adapted genome-wide association analyses and machine-learning algorithms coupled with feature selection methods to establish marker-trait associations. While each approach identified unique marker sets associated with phenotypes, convergences were observed between them, demonstrating their complementarity. Lastly, we annotated these markers, identifying genes encoding emblematic participants in virus resistance mechanisms and previously unreported candidates involved in viral responses. Our approach could accelerate sugarcane breeding targeting SCYLV resistance and facilitate studies on biological processes leading to this trait.
PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors
Authors: Milosevic Jelena , Fransson Susanne , Gulyas Miklos , Gallo-Oller Gabriel , Olsen Thale K , Treis Diana , Wickström Malin , Elfman Lotta HM , Sveinbjornsson Baldur , Hertwig Falk , Bartenhagen Christoph , Reinsbach Susanne , Wilhelm Margareta , Abel Frida , Javanmardi Niloufar , Thankaswamy-Kosalai Subazini , Eissler Nina , Kock Anna , Shi Yao , Tanino Keiji , Hehir-Kwa Jane Y , Mensenkamp Arjen , Tytgat Godelieve AM , Kanduri Chandrasekhar , Holmberg Johan , Gisselsson David , Molenaar Jan J , Jongmans Marjolijn , Fischer Matthias , Kool Marcel , Sakaguchi Kazuyasu , Baryawno Ninib , Martinsson Tommy , Johnsen John Inge , Kogner Per 
Published: September 2020

SUMMARYMajority of cancers harbor alterations of the tumor suppressorTP53. However, childhood cancers, including unfavorable neuroblastoma, often lackTP53mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulatingPPM1Dat chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded byPPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstratedPPM1Dgenetic dependency inTP53wild-type neuroblastoma cell lines, and shRNAPPM1Dknockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressingPPM1Dshowed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboringNotch1-mutations,Pten-deletions and p53-accumulation, adenocarcinomas andPHOX2B-expressing neuroblastomas establishingPPM1Das abona fideoncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.
Genome Methylation Predicts Age and Longevity of Bats
Authors: Wilkinson Gerald S. , Adams Danielle M. , Haghani Amin , Lu Ake T. , Zoller Joseph , Breeze Charles E. , Arnold Bryan D. , Ball Hope C. , Carter Gerald , Cooper Lisa Noelle , Dechmann Dina K.N. , Devanna Paolo , Fasel Nicolas J. , Galazyuk Alexander V. , Günther Linus , Hurme Edward , Jones Gareth , Knörnschild Mirjam , Lattenkamp Ella Z. , Li Caesar Z. , Mayer Frieder , Reinhardt Josephine A. , Medellin Rodrigo A. , Nagy Martina , Pope Brian , Power Megan L. , Ransome Roger D. , Teeling Emma C. , Vernes Sonja C. , Zamora-Mejías Daniel , Zhang Joshua , Horvath Steve 
Published: September 2020

AbstractExceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.
Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing
Authors: Sinjab Ansam , Han Guangchun , Treekitkarnmongkol Warapen , Hara Kieko , Brennan Patrick , Dang Minghao , Hao Dapeng , Wang Ruiping , Dai Enyu , Dejima Hitoshi , Zhang Jiexin , Bogatenkova Elena , Sanchez-Espiridion Beatriz , Chang Kyle , Little Danielle R. , Bazzi Samer , Tran Linh , Krysan Kostyantyn , Behrens Carmen , Duose Dzifa , Parra Edwin R. , Raso Maria Gabriela , Solis Luisa M. , Fukuoka Junya , Zhang Jianjun , Sepesi Boris , Cascone Tina , Byers Lauren , Gibbons Don L. , Chen Jichao , Moghaddam Seyed Javad , Ostrin Edwin J. , Rosen Daniel G. , Heymach John V. , Scheet Paul , Dubinett Steven , Fujimoto Junya , Wistuba Ignacio I. , Stevenson Christopher S. , Spira Avrum E. , Wang Linghua , Kadara Humam 
Published: September 2020

ABSTRACTLittle is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24 which mediates pro-tumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment.Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution of LUAD from the lung that comprise high-potential targets for early interception.
Loss of Fgf-responsive Pea3 transcription factors results in ciliopathy-associated phenotypes during early zebrafish development
Authors: McFaul Matt E. , Hart Neta , Draper Bruce W. 
Published: September 2020

AbstractFGF signaling is used reiteratively during development and elicits several different responses, such as cell proliferation, differentiation, or migration. We parsed the complex FGF intracellular response by creating triple homozygous mutants in the Pea3 subgroup of ETS transcription factors, designated3etvmutants. The Pea3 proteins Etv4 and Etv5 are expressed in areas of FGF activity; however, their role in FGF signal transduction as either positive or negative modulators of FGF activity was unclear. Using3etvmutants, we found these genes act redundantly and have phenotypes consistent with known FGF defects in inner ear, pectoral fin, and posterior mesoderm development. Additionally, we uncovered a novel role for the FGF/Pea3 pathway during body axis straightening.3etvlarvae develop a curly-tail up (CTU) phenotype that we linked to mis-regulation of the polycystin and urotensin pathways, which have opposing actions to ensure a straight body orientation along the dorsal-ventral axis. We find that the Etv4/5 transcription factors act as positive regulators of FGF signaling and propose a model where Etv4/5 are required for cilia function downstream of Fgf8a.Summary StatementPea3 transcription factor triple mutants reveal a role for FGF signaling in balancing polycystin and urotensin signaling to achieve a straight body axis.
Asymmetric Functional Gradients in the Human Subcortex
Authors: Guell Xavier , Schmahmann Jeremy D , Gabrieli John DE , Ghosh Satrajit S , Geddes Maiya R 
Published: September 2020

ABSTRACTA central principle in our understanding of cerebral cortical organization is that homotopic left and right areas are functionally linked to each other, and also connected with structures that share similar functions within each cerebral cortical hemisphere. Here we refer to this concept as interhemispheric functional symmetry (IHFS). While multiple studies have described the distribution and variations of IHFS in the cerebral cortex, descriptions of IHFS in the subcortex are largely absent in the neuroscientific literature. Further, the proposed anatomical basis of IHFS is centered on callosal and other commissural tracts. These commissural fibers are present in virtually all cerebral cortical areas, but almost absent in the subcortex. There is thus an important knowledge gap in our understanding of subcortical IHFS. What is the distribution and variations of subcortical IHFS, and what are the anatomical correlates and physiological implications of this important property in the subcortex? Using fMRI functional gradient analyses in a large dataset (Human Connectome Project, n=1003), here we explored IHFS in human thalamus, lenticular nucleus, cerebellar cortex, and caudate nucleus. Our detailed descriptions provide an empirical foundation upon which to build hypotheses for the anatomical and physiological basis of subcortical IHFS. Our results indicate that direct or driver cerebral cortical afferent connectivity, as opposed to indirect or modulatory cerebral cortical afferent connectivity, is associated with stronger subcortical IHFS in thalamus and lenticular nucleus. In cerebellar cortex and caudate, where there is no variability in terms of either direct vs. indirect or driver vs. modulatory cerebral cortical afferent connections, connectivity to cerebral cortical areas with stronger cerebral cortical IHFS is associated with stronger IHFS in the subcortex. These two observations support a close relationship between subcortical IHFS and connectivity between subcortex and cortex, and generate new testable hypotheses that advance our understanding of subcortical organization.
Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer
Authors: Orouji Elias , Raman Ayush T. , Singh Anand K. , Sorokin Alexey , Arslan Emre , Ghosh Archit K. , Schulz Jonathan , Terranova Christopher J. , Tang Ming , Maitituoheti Mayinuer , Callahan S. Carson , Tomczak Katarzyna J. , Jiang Zhiqin , Davis Jennifer S. , Ghosh Sukhen , Lee Hey Min , Reyes-Uribe Laura , Chang Kyle , Liu Yushua , Chen Huiqin , Azhdarnia Ali , Morris Jeffrey S. , Vilar Eduardo , Carmon Kendra S. , Kopetz Scott , Rai Kunal 
Published: September 2020

ABSTRACTThe extent and function of chromatin state aberrations during colorectal cancer (CRC) progression is not completely understood. Here, by comprehensive epigenomic characterization of 56 tumors, adenomas, and their matched normal tissues, we define the dynamics of chromatin states during the progression of colorectal cancer. H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumor-specific enhancers for crucial oncogenes, such asASCL2andFZD10, was crucial for excessive proliferation. Consistently, combination of MEK plus bromodomain (BET) inhibition was found to have synergistic effects in CRC patient-derived xenograft (PDX) models. Probing inter-tumor heterogeneity, we identified four distinct enhancer subtypes (EpiC), three of which correlate well with previously defined transcriptomic subtypes (CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, and TGFβi) for three EPIC groups. Our data suggest that the dynamics of active enhancer underlies colorectal cancer progression and the patient-specific active enhancer patterns govern their unique gene expression patterns which can be leveraged for precision combination therapy.
Expansion and accelerated evolution of 9-exon odorant receptors inPolistespaper wasps
Authors: Legan Andrew W. , Jernigan Christopher M. , Miller Sara E. , Fuchs Matthieu F. , Sheehan Michael J. 
Published: September 2020

ABSTRACTIndependent origins of sociality in bees and ants are associated with independent expansions of particular odorant receptor (OR) gene subfamilies. In ants, one clade within the OR gene family, the 9-exon subfamily, has dramatically expanded. These receptors detect cuticular hydrocarbons (CHCs), key social signaling molecules in insects. It is unclear to what extent 9-exon OR subfamily expansion is associated with the independent evolution of sociality across Hymenoptera, warranting studies of taxa with independently derived social behavior. Here we describe odorant receptor gene family evolution in the northern paper wasp,Polistes fuscatus, and compare it to four additional paper wasp species spanning ~40 million years of divergence. We find 200 functional OR genes inP. fuscatusmatching predictions from neuroanatomy, and more than half of these are in the 9-exon subfamily. Lineage-specific expansions of 9-exon subfamily ORs are tandemly arrayed inPolistesgenomes and exhibit a breakdown in microsynteny relative to tandem arrays in other OR subfamilies. There is evidence of episodic positive diversifying selection shaping ORs in expanded subfamilies, including 9-exon, E, H, and L, but 9-exon ORs do not stand out as selectively diversified amongPolistesspecies. Accelerated evolution has resulted in lower amino acid similarity and highdN/dS among 9-exon ORs compared to other OR subfamilies. Patterns of OR evolution withinPolistesare consistent with 9-exon OR function in CHC perception by combinatorial coding, with both selection and drift contributing to interspecies differences in copy number and sequence.
CyDAP–A fluorescent probe for cytosolic dopamine detection
Authors: Jeng Jing-Yi , Sun Lee , Wang Jia-Chi , Lin Cheng-Yuan , Hung Chih-Ping , Chu Li-An , Chang Hui-Yun , Chiang Ann-Shyn , Sang Tzu-Kang 
Published: September 2020

AbstractDopamine (DA) is an essential neurotransmitter modulating motor and cognitive functions. Several neurological disorders, including Parkinson’s disease (PD) and drug addiction, are the result of DA system dysfunction; however, it remains incomplete understood of why DA neuron is selectively more vulnerable than other neurons. Here we utilize the spectral feature of human MAO B (monoamine oxidase B) to design a genetic-amenable, GFP-based fluorescent probe CyDAP. Upon genetic and pharmacological manipulations to elevate the cytosolic DA levels in cells andDrosophilamodels, CyDAP shows enhanced GFP emission, suggesting this probe is feasible for DA detection. Furthermore, we observe that expressing human α-Synuclein inDrosophilaelicited GFP emission from CyDAP, suggesting a link between cytosolic DA imbalance and regional vulnerability in PD context. Importantly, CyDAP can detect the change of cytosolic DA in liveDrosophilabrains, as demonstrated by time-lapse and the 4D light-sheet confocal recording. CyDAP may serve as a tool for evaluating metabolic deregulation of DA in brain models of PD and other DA system-related psychiatric disorders.
Combination of deep neural network with attention mechanism enhances the explainability of protein contact prediction
Authors: Chen Chen , Wu Tianqi , Guo Zhiye , Cheng Jianlin 
Published: September 2020

AbstractDeep learning has emerged as a revolutionary technology for protein residue-residue contact prediction since the 2012 CASP10 competition. Considerable advancements in the predictive power of the deep learning-based contact predictions have been achieved since then. However, little effort has been put into interpreting the black-box deep learning methods. Algorithms that can interpret the relationship between predicted contact maps and the internal mechanism of the deep learning architectures are needed to explore the essential components of contact inference and improve their explainability. In this study, we present an attention-based convolutional neural network for protein contact prediction, which consists of two attention mechanism-based modules: sequence attention and regional attention. Our benchmark results on the CASP13 free-modeling (FM) targets demonstrate that the two attention modules added on top of existing typical deep learning models exhibit a complementary effect that contributes to predictive improvements. More importantly, the inclusion of the attention mechanism provides interpretable patterns that contain useful insights into the key fold-determining residues in proteins. We expect the attention-based model can provide a reliable and practically interpretable technique that helps break the current bottlenecks in explaining deep neural networks for contact prediction.