bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metalign: Efficient alignment-based metagenomic profiling via containment min hash
Authors: LaPierre Nathan , Alser Mohammed , Eskin Eleazar , Koslicki David , Mangul Serghei 
Published: January 2020

AbstractWhole-genome shotgun sequencing enables the analysis of microbial communities in unprecedented detail, with major implications in medicine and ecology. Predicting the presence and relative abundances of microbes in a sample, known as “metagenomic profiling”, is a critical first step in microbiome analysis. Existing profiling methods have been shown to suffer from poor false positive or false negative rates, while alignment-based approaches are often considered accurate but computationally infeasible. Here we present a novel method, Metalign, that addresses these concerns by performing efficient alignment-based metagenomic profiling. We use a containment min hash approach to reduce the reference database size dramatically before alignment and a method to estimate organism relative abundances in the sample by resolving reads aligned to multiple genomes. We show that Metalign achieves significantly improved results over existing methods on simulated datasets from a large benchmarking study, CAMI, and performs well onin vitromock community data and environmental data from the Tara Oceans project. Metalign is freely available athttps://github.com/nlapier2/Metalign, along with the results and plots used in this paper, and a docker image is also available athttps://hub.docker.com/repository/docker/nlapier2/metalign.
The human and mouse synaptome architecture of excitatory synapses show conserved features
Authors: Curran Olimpia E. , Qiu Zhen , Smith Colin , Grant Seth G. N. 
Published: January 2020

AbstractLarge-scale mapping of the location of synapses and their molecular properties in the mouse has shown that diverse synapse types are spatially distributed across the brain. The diversity of synapses is known as the synaptome and the spatial distribution as the synaptome architecture. Synaptome maps in the mouse show each brain region has a characteristic compositional signature. The signature can store behavioral representations and is modified in mouse genetic models of human disease. The human synaptome remains unexplored and whether it has any conserved features with the mouse synaptome is unknown.As a first step toward creating a human synaptome atlas, we have labelled and imaged synapses expressing the excitatory synapse protein PSD95 in twenty human brain regions in four phenotypically normal individuals. We quantified the number, size and intensity of approximately a billion individual synaptic puncta and compared their regional distributions. We found that each region showed a distinct signature of synaptic puncta parameters. Comparison of brain regions showed the synaptome of cortical and hippocampal structures were similar but distinct to the synaptome of cerebellum and brainstem. Comparison of human and mouse synaptome revealed conservation of synaptic puncta parameters, hierarchical organization of brain regions and network architecture. These data show that the synaptome of humans and mouse share conserved features despite the 1000-fold difference in brain size and 90 million years since a common ancestor. This first draft human synaptome atlas illustrates the feasibility of generating a systematic atlas of the human synaptome in health and disease.
Accurate and Versatile 3D Segmentation of Plant Tissues at Cellular Resolution
Authors: Wolny Adrian , Cerrone Lorenzo , Vijayan Athul , Tofanelli Rachele , Vilches Barro Amaya , Louveaux Marion , Wenzl Christian , Steigleder Susanne , Pape Constantin , Bailoni Alberto , Duran-Nebreda Salva , Bassel George , Lohmann Jan U. , Hamprecht Fred A. , Schneitz Kay , Maizel Alexis , Kreshuk Anna 
Published: January 2020

ABSTRACTQuantitative analysis of plant and animal morphogenesis requires accurate segmentation of individual cells in volumetric images of growing organs. In the last years, deep learning has provided robust automated algorithms that approach human performance, with applications to bio-image analysis now starting to emerge. Here, we present PlantSeg, a pipeline for volumetric segmentation of plant tissues into cells. PlantSeg employs a convolutional neural network to predict cell boundaries and graph partitioning to segment cells based on the neural network predictions. PlantSeg was trained on fixed and live plant organs imaged with confocal and light sheet microscopes. PlantSeg delivers accurate results and generalizes well across different tissues, scales, and acquisition settings. We present results of PlantSeg applications in diverse developmental contexts. PlantSeg is free and open-source, with both a command line and a user-friendly graphical interface.
Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation
Authors: Fang Celestia , Wang Zhenjia , Han Cuijuan , Safgren Stephanie L. , Helmin Kathryn A. , Adelman Emmalee R. , Eagen Kyle P. , Gaspar-Maia Alexandre , Figueroa Maria E. , Singer Benjamin D. , Ratan Aakrosh , Ntziachristos Panagiotis , Zang Chongzhi 
Published: January 2020

AbstractBackgroundThe three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, there is no hitherto a comprehensive survey of genome-wide CTCF binding patterns across different human cancers.ResultsTo dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions in patient samples, but not always with DNA methylation changes or sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events are induced by oncogenic transcription factors and exhibit enhancer activities. We validate these findings in T-cell acute lymphoblastic leukemia and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena.ConclusionsCancer-specific CTCF binding events are not always associated with DNA methylation changes or mutations, but can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.
Kctd15 regulates nephron segment development by repressing Tfap2a activity
Authors: Chambers Brooke E. , Clark Eleanor G. , Gatz Allison E. , Wingert Rebecca A. 
Published: January 2020

AbstractA functional vertebrate kidney relies on structural units called nephrons, which are epithelial tubules that contain a sequence of segments each expressing a distinct repertoire of solute transporters. To date, the transcriptional codes driving regional specification, solute transporter program activation, and terminal differentiation of segment populations remain poorly understood. We demonstrate for the first time that the KCTD15 paralogs,kctd15aandkctd15b, function in concert to restrict distal early (DE)/thick ascending limb (TAL) segment lineage assignment in the developing zebrafish pronephros by repressing Tfap2a activity. During renal ontogeny, expression of these factors co-localized withtfap2ain distal tubule precursors.kctd15loss primed nephron cells to adopt distal fates by driving expansions inslc12a1,kcnj1a.1, andstc1marker expression. These phenotypes were resultant of Tfap2a hyperactivity, wherekctd15a/b-deficient embryos exhibited increased abundance of this transcription factor. Interestingly,tfap2areciprocally promotedkctd15transcription, unveiling a circuit of autoregulation operating in nephron progenitors. Concomitantkctd15bknockdown withtfap2aoverexpression produced genetic synergy and further expanded the DE population. Our study provides strong evidence that a transcription factor-repressor feedback module employs tight regulation of Tfap2a and Kctd15 kinetics to control nephron segment fate choice and differentiation during kidney development.
A role for reward valuation in the serotonergic modulation of impulsivity
Authors: Desrochers Stephanie S. , Lesko Emma , Magalong Valerie M. , Balsam Peter D. , Nautiyal Katherine M. 
Published: January 2020

AbstractImpulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is integral to understanding and treating disorders with dysregulated impulsive behavior. Our approach was to first determine what behavioral and cognitive phenotypes are associated with increased impulsive behavior, and then probe if they could causally contribute to increasing impulsivity. We used a mouse model for disordered impulsivity - mice lacking the serotonin 1B receptor (5-HT1BR) which have deficits specific to impulsive action, and not other components of impulsive behavior. Here we report, that in addition to increased impulsive action, mice lacking expression of 5-HT1BR also have increased goal-directed responding and motivation, with no differences in extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression did show an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more to cues that predict reward, compared to controls. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action is a result of increased reward valuation. Taken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Additionally this work supports a role for reward valuation as an important substrate in impulsive action which may drive clinically-relevant increases in impulsivity.
ChronicStaphylococcus aureusinfection is cured by theory-driven therapy
Authors: Papaxenopoulou Lito A. , Zhao Gang , Khailaie Sahamoddin , Katsoulis-Dimitriou Konstantinos , Schmitz Ingo , Medina Eva , Hatzikirou Haralampos , Meyer-Hermann Michael 
Published: January 2020

SUMMARYStaphylococcus aureusis considered a dangerous pathogen due to its ability to evade the immune system and resist multiple antibiotics. These evasive strategies lead to difficult-to-treat chronic infections and abscesses in internal organs including kidneys, which are associated with the expansion of myeloid-derived suppressor cells (MDSCs) and their suppressive effect on T cells. Here, we developed a mathematical model of chronicS. aureusinfection that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies to eradicateS. aureus. We quantifiedin silicoa therapeutic protocol with heat-killedS. aureus(HKSA), which we testedin vivo. Contrary to conventional administration of heat-killed bacteria as vaccination prior to infection, we administered HKSA as treatment, when the hosts were already chronically infected. Our treatment cured all chronicallyS. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during ongoing, chronic infection without any use of standard treatments that involve antibiotics, MDSC-targeting drugs (chemotherapy), or procedures such as abscess drainage. This study is a proof-of-principle for a treatment protocol against chronicS. aureusinfection and renal abscesses by repurposing heat-killed treatments, guided and quantified by mathematical modelling. Our mathematical model further explains why previous treatment with inactivatedS. aureusadministered to long-term infected human patients has not led to cure. Overall, our results can have direct relevance to the design of human therapeutics against chronicS. aureusinfections.In briefA theory-driven treatment protocol with heat-killedS. aureuseradicatesS. aureus, reduces MDSCs, and reverses T-cell dysfunctionin vivo.Graphical abstract
ER-Anchored Transcription Factors bZIP17 and bZIP60 Regulate Triterpene Saponin Biosynthesis inMedicago truncatula1[OPEN]
Authors: Ribeiro Bianca , Erffelinck Marie-Laure , Colinas Maite , Williams Clara , Van Hamme Evelien , Lacchini Elia , De Clercq Rebecca , Perassolo Maria , Goossens Alain 
Published: January 2020

ABSTRACTTriterpene saponins (TS) are a structurally diverse group of metabolites that are widely distributed in plants. They primarily serve as defense compounds and their production is often triggered by biotic stresses through signaling cascades that are modulated by phytohormones such as the jasmonates (JA). Two JA-modulated basic helix-loop-helix (bHLH) transcription factors (TFs), TRITERPENE SAPONIN BIOSYNTHESIS ACTIVATING REGULATOR 1 (TSAR1) and TSAR2, have been previously identified as direct activators of TS biosynthesis in the model legumeMedicago truncatula. Here, we report on the involvement of the core endoplasmic reticulum (ER) stress basic leucine zipper (bZIP) TFs bZIP17 and bZIP60 in the regulation of TS biosynthesis. Expression and processing ofM. truncatulabZIP17 and bZIP60 proteins was altered in roots with perturbed TS biosynthesis or treated with JA. Accordingly, such roots displayed an altered ER network structure.M. truncatulabZIP17 and bZIP60 proteins were shown to be capable of interfering with the TSAR-mediated transactivation of TS biosynthesis genes, particularly under ER stress conditions, when they translocate from the ER to the nucleus. Furthermore, the inhibitory role of ER stress bZIP TFs in the regulation of JA-dependent terpene biosynthetic pathways appears to be widespread in the plant kingdom, as we demonstrate that it also occurs in the regulation of monoterpene indole alkaloid biosynthesis in the medicinal plantCatharanthus roseus. We postulate that activation of ER stress bZIP TFs provides the plant with a mechanism to balance metabolic activities and thereby adequately govern modulation of growth, development and defense processes in defined stress situations.One sentence summaryER stress bZIP transcription factors can interfere with the activity of jasmonate-inducible bHLH transcription factors to modulate the elicitation of plant specialized metabolism in stress conditions.
Elucidating the complex organization of neural micro-domains in the locustSchistocerca gregariausing dMRI
Authors: Shahid S.S. , Kerskens C.M. , Burrows M. , Witney A.G. 
Published: January 2020

AbstractTo understand brain function it is necessary to characterize both the underlying structural connectivity between neurons and the physiological integrity of these connections. Previous research exploring insect brain connectivity has used microscopy techniques, but this methodology is time consuming and cannot be applied to living animals and so cannot be used to understand dynamic physiological processes. The relatively large brain of the desert locust,Schistercera gregaria(Forksȧl) is ideal for exploring a novel methodology; diffusion magnetic resonance imaging (dMRI) for the characterization of neuronal connectivity in an insect brain. The diffusion-weighted imaging (DWI) data were acquired on a preclinical system using a customised multi-shell diffusion MRI scheme. Endogenous imaging contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. The application of micro-MRI and dMRI modelling to the locust brain provides a novel means of identifying anatomical regions and connectivity in an insect brain. Furthermore, quantitative imaging indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA) could, in future, be used to quantify longitudinal structural changes in neuronal connectivity due to environmental stressors or ageing.
Hydroxyl carlactone derivatives are predominant strigolactones inArabidopsis
Authors: Yoneyama Kaori , Akiyama Kohki , Brewer Philip B. , Mori Narumi , Kawada Miyuki , Haruta Shinsuke , Nishiwaki Hisashi , Yamauchi Satoshi , Xie Xiaonan , Umehara Mikihisa , Beveridge Christine A. , Yoneyama Koichi , Nomura Takahito 
Published: January 2020

ABSTRACTStrigolactones (SLs) regulate important aspects of plant growth and stress responses. Many diverse types of SL occur in plants, but a complete picture of biosynthesis remains unclear. InArabidopsis thaliana, we have demonstrated that MAX1, a cytochrome P450 monooxygenase, converts carlactone (CL) into carlactonoic acid (CLA), and that LBO, a 2-oxoglutarate-dependent dioxygenase, converts methyl carlactonoate (MeCLA) into a metabolite called [MeCLA+16] Da. In the present study, feeding experiments with deuterated MeCLAs revealed that [MeCLA+16] Da is hydroxymethyl carlactonoate (1’-HO-MeCLA). Importantly, this LBO metabolite was detected in plants. Interestingly, other related compounds, methyl 4-hydroxycarlactonoate (4-HO-MeCLA) and methyl 16-hydroxycarlactonoate (16-HO-MeCLA) were also found to accumulate inlbomutants. 3-HO-, 4-HO- and 16-HO-CL were detected in plants, but their expected corresponding metabolites, HO-CLAs, were absent inmax1mutants. These results suggest that HO-CL derivatives are predominant SLs inArabidopsis, produced through MAX1 and LBO.
Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: implications for disease modeling and therapeutic development
Authors: Weiss Alison R. , Liguore William A. , Domire Jacqueline S. , Button Dana , McBride Jodi L. 
Published: January 2020

ABSTRACTRecently, AAV2.retro, a new capsid variant capable of efficient retrograde transport in brain, was generated in mice using a directed evolution approach. However, it remains unclear to what degree transport will be recapitulated in the substantially larger and more complex nonhuman primate (NHP) brain. Here, we compared the biodistribution of AAV2.retro with its parent serotype, AAV2, in adult macaques following delivery into the caudate and putamen, brain regions which comprise the striatum. While AAV2 transduction was primarily limited to the injected brain regions, AAV2.retro transduced cells in the striatum and in dozens of cortical and subcortical regions with known striatal afferents. We then evaluated the capability of AAV2.retro to deliver disease-related gene cargo to biologically-relevant NHP brain circuits by packaging a fragment of human mutantHTT, the causative gene mutation in Huntington’s disease. Following intra-striatal delivery, pathological mHTT-positive protein aggregates were distributed widely among cognitive, motor, and limbic cortico-basal ganglia circuits. Together, these studies demonstrate strong retrograde transport of AAV2.retro in NHP brain, highlight its utility in developing novel NHP models of brain disease and suggest its potential for querying circuit function and delivering therapeutic genes in the brain, particularly where treating dysfunctional circuits, versus single brain regions, is warranted.
Quantitative Method for Assessing the Role of Lysine & Arginine Post-Translational Modifications in Nonalcoholic Steatohepatitis
Authors: Robinson Aaron E. , Binek Aleksandra , Venkatraman Vidya , Searle Brian C. , Holewinski Ronald J. , Rosenberger George , Parker Sarah J. , Basisty Nathan , Xie Xueshu , Lund Peder J. , Saxena Gautam , Mato José M. , Garcia Benjamin A. , Schilling Birgit , Lu Shelly C. , Van Eyk Jennifer E. 
Published: January 2020

AbstractProteoforms containing post-translational modifications (PTMs) represent a degree of functional diversity only harnessed through analytically precise simultaneous quantification of multiple PTMs. Here we present a method to accurately differentiate an unmodified peptide from its PTM-containing counterpart through data-independent acquisition-mass spectrometry, leveraging small precursor mass windows to physically separate modified peptidoforms from each other during MS2 acquisition. We utilize a lysine and arginine PTM-enriched peptide assay library and site localization algorithm to simultaneously localize and quantify seven PTMs including mono-, di-, and tri-methylation, acetylation, and succinylation in addition to total protein quantification in a single MS run without the need to enrich experimental samples. To evaluate biological relevance, this method was applied to liver lysate from differentially methylated non-alcoholic steatohepatitis (NASH) mouse models. We report altered methylation and acetylation together with total protein changes drive the novel hypothesis of a regulatory function of PTMs in protein synthesis and mRNA stability in NASH.Graphical Abstract
Robust classification of Immune Subtypes in Cancer
Authors: Gibbs David L 
Published: January 2020

AbstractAs part of the ‘immune landscape of cancer’, six immune subtypes were defined which describe a categorization of tumor-immune states. A number of phenotypic variables were found to associate with immune subtypes, such as nonsilent mutation rates, regulation of immunomodulator genes, and cytokine network structures. An ensemble classifier based on XGBoost is introduced with the goal of classifying tumor samples into one of six immune subtypes. Robust performance was accomplished through feature engineering; quartile-levels, binary gene-pair features, and gene-set-pair features were computed for each sample independently. The classifier is robust to software pipeline and normalization scheme, making it applicable to any expression data format from raw count data to TPMs since the classification is essentially based on simple binary gene-gene level comparisons within a given sample. The classifier is available as an R package or part of the CRI iAtlas portal.Code / Tool availabilitySource Codehttps://github.com/Gibbsdavidl/ImmuneSubtypeClassifierWeb App Toolhttps://www.cri-iatlas.org/
Skd3 (humanCLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations
Authors: Cupo Ryan R. , Shorter James 
Published: January 2020

ABSTRACTCells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (humanCLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health.