bluuebunny/crossref_metadata_2025_split huggingface dataset:
PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments
Authors: Léveillé Mélissa , Besse-Patin Aurèle , Jouvet Nathalie , Gunes Aysim , Jeromson Stewart , Khan Naveen P. , Sczelecki Sarah , Baldwin Cindy , Dumouchel Annie , Correia Jorge , Jannig Paulo , Boulais Jonathan , Ruas Jorge L. , Estall Jennifer L. 
Published: July 2019

ABSTRACTLiver is regularly exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1α is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation. However, it is not known how PGC-1α integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants expressed from different promoters. Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1α proteins in regulating hepatic metabolism and inflammatory signaling downstream of TNFα. PGC-1α1 and PGC-1α4 were expressed in hepatocytes and expression analysis uncovered shared and isoform-specific roles for these variants linked to metabolism and inflammation. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα signaling revealed that PGC-1α4 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models illustrated that PGC-1α4 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNFα or LPS. This was in contrast to PGC-1α1, which reduced the expression of a wide inflammatory gene network, but did not prevent liver cell death in response to the cytokine. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to metabolism and inflammation and identify PGC-1α4 as an important mitigator of apoptosis.
Analysis of the Human Connectome Data Supports the Notion of A “Common Model of Cognition” for Human and Human-Like Intelligence Across Domains
Authors: Stocco Andrea , Sibert Catherine , Steine-Hanson Zoe , Koh Natalie , Laird John E. , Lebiere Christian J. , Rosenbloom Paul 
Published: July 2019

AbstractThe Common Model of Cognition (CMC) is a recently proposed, consensus architecture intended to capture decades of progress in cognitive science on modeling human and human-like intelligence. Because of the broad agreement around it and preliminary mappings of its components to specific brain areas, we hypothesized that the CMC could be a candidate model of the large-scale functional architecture of the human brain. To test this hypothesis, we analyzed functional MRI data from 200 participants and seven different tasks that cover a broad range of cognitive domains. The CMC components were identified with functionally homologous brain regions through canonical fMRI analysis, and their communication pathways were translated into predicted patterns of effective connectivity between regions. The resulting dynamic linear model was implemented and fitted using Dynamic Causal Modeling, and compared against six alternative brain architectures that had been previously proposed in the field of neuroscience (three hierarchical architectures and three hub-and-spoke architectures) using a Bayesian approach. The results show that, in all cases, the CMC vastly outperforms all other architectures, both within each domain and across all tasks. These findings suggest that a common set of architectural principles that could be used for artificial intelligence also underpins human brain function across multiple cognitive domains.
Metabolic Modeling Elucidates the Transactions in the Rumen Microbiome and the Shifts upon Virome Interactions
Authors: Islam Mohammad Mazharul , Fernando Samodha C. , Saha Rajib 
Published: July 2019

AbstractThe complex microbial ecosystem within the bovine rumen plays a crucial role in host nutrition, health, and environmental impact. However, little is known about the interactions between the functional entities within the system, which dictates the community structure and functional dynamics and host physiology. With the advancements in high-throughput sequencing and mathematical modeling,in silicogenome-scale metabolic analysis promises to expand our understanding of the metabolic interplay in the community. In an attempt to understand the interactions between microbial species and the phages inside rumen, a genome-scale metabolic modeling approach was utilized by using key members in the rumen microbiome (a bacteroidete, a firmicute, and an archaeon) and the viral phages associated with them. Individual microbial host models were integrated into a community model using multi-level mathematical frameworks. An elaborate and heuristics-based computational procedure was employed to predict previously-unknown interactions involving the transfer of fatty acids, vitamins, coenzymes, amino acids, and sugars among the community members. While some of these interactions could be inferred by the available multi-omic datasets, our proposed method provides a systemic understanding of why these occur and how these affect the dynamics in a complex microbial ecosystem. To elucidate the functional role of the virome on the microbiome, local alignment search was used to identify the metabolic functions of the viruses associated with the hosts. The incorporation these functions demonstrated the role of viral auxiliary metabolic genes in relaxing the metabolic bottlenecks in the microbial hosts and complementing the inter-species interactions. Finally, a comparative statistical analysis of different biologically significant community fitness criteria identified the variation in flux space and robustness of metabolic capacities of the community members. Our elucidation of metabolite exchange among three members of rumen microbiome shows how their genomic differences and interactions with the viral strains shape up a highly sophisticated metabolic interplay and explains how such interactions across kingdoms can cause metabolic and compositional shifts in the community and affect the health, nutrition, and pathophysiology of the ruminant animal.
DNA and RNA-SIP revealNitrospira spp.as key drivers of nitrification in groundwater-fed biofilters
Authors: Gülay Arda , Fowler Jane , Tatari Karolina , Thamdrup Bo , Albrechtsen Hans-Jørgen , Al-Soud Waleed Abu , Sørensen Søren J. , Smets Barth F. 
Published: July 2019

AbstractNitrification, the oxidative process converting ammonia to nitrite and nitrate, is driven by microbes and plays a central role in the global nitrogen cycle. Our earlier metagenomics,amoA-amplicon, andamoA-qPCR based investigations of groundwater-fed biofilters indicated a consistently high abundance of comammoxNitrospira, and we hypothesized that these non-classical nitrifiers drive ammonia-N oxidation. Hence, we used DNA and RNA stable isotope probing (SIP) coupled with 16S rRNA amplicon sequencing to identify the active members in the biofilter community when subject to a continuous supply of NH4+or NO2−in the presence of13C-HCO3−(labelled) or12C-HCO3−(unlabelled). Allylthiourea (ATU) and sodium chlorate were added to inhibit autotrophic ammonia- and nitrite-oxidizing bacteria, respectively. Our results confirmed that lineage IINitrospiradominated ammonium oxidation in the biofilter community. A total of 78 (8 in RNA-SIP and 70 in DNA-SIP) and 96 (25 in RNA-SIP and 71 in DNA-SIP)Nitrospiraphylotypes (at 99% 16S rRNA sequence similarity) were identified as complete ammonia- and nitrite-oxidizing, respectively. We also detected significant HCO3−uptake byAcidobacteria subgroup10, Pedomicrobium, Rhizobactera, andAcidovoraxunder conditions that favoured ammonium oxidation. CanonicalNitrospiraalone drove nitrite oxidation in the biofilter community, and activity of archaeal ammonia oxidizing taxa was not detected in the SIP fractions. This study provides the firstin-situevidence of ammonia oxidation by comammoxNitrospirain an ecologically relevant complex microbiome.
Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma
Authors: Iyer Aishwarya , Hennessey Dylan , O’Keefe Sandra , Patterson Jordan , Wang Weiwei , Ka-Shu Wong Gane , Gniadecki Robert 
Published: July 2019

AbstractMycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T-cell. However, this concept does not explain the key characteristics of MF such as the debut with multiple, widespread skin lesions or inability of skin directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here we have used whole exome sequencing approach to detect and quantify TCRα, -β and -γ clonotypes in tumor cell clusters microdissected from MF lesions. This method allows us to calculate the tumor cell fraction of the sample and therefore an unequivocal identification of the TCR clonotypes as neoplastic. Analysis of TCR sequences from 29 patients with MF stage I-IV proved existence of multiple T-cell clones within the tumor cell fraction, with a considerable variation between patients and between lesions from the same patient (median 11 clones, range 2-80 clones/sample). We have also detected multiple neoplastic clones in the peripheral blood in all examined patients. Based on these findings we propose that circulating neoplastic T-cell clones continuously replenish the lesions of MF thus increasing their heterogeneity by a mechanism analogous to the consecutive tumor seeding. We hypothesize that circulating neoplastic clones might be a promising target for therapy and could be exploited as a potential biomarker in MF.
Paradoxically sparse chemosensory tuning in broadly-integrating external granule cells in the mouse accessory olfactory bulb
Authors: Zhang Xingjian , Meeks Julian P. 
Published: July 2019

AbstractThe accessory olfactory bulb (AOB) is a critical circuit in the mouse accessory olfactory system (AOS), but AOB processing is poorly understood compared to the main olfactory bulb (MOB). We used 2-photon GCaMP6f Ca2+ imaging in an ex vivo preparation to study the chemosensory tuning of AOB external granule cells (EGCs), an interneuron population hypothesized to broadly integrate from mitral cells (MCs). We measured MC and EGC tuning to natural chemosignal blends and monomolecular ligands, finding that EGC tuning was far sparser than MC tuning. Simultaneous patch-clamp electrophysiology and Ca2+ imaging indicated that this was only partially explained by lower GCaMP6f-to-spiking ratios in EGCs compared to MCs. Ex vivo patch-clamp recordings revealed that EGC subthreshold responsivity was broad, but monomolecular ligand responses were insufficient to elicit spiking. These results indicate that EGC spiking is selectively engaged by chemosensory blends, suggesting different roles for EGCs than analogous interneurons in the MOB.
TraceMontage: a Method for Merging Multiple Independent Neuronal Traces
Authors: Dizaji Aslan S , Walker Logan A , Cai Dawen 
Published: July 2019

AbstractBackgroundThe ability to reconstruct neuronal networks, local microcircuits, or the entire connectome is a central goal of modern neuroscience. Recently, advancements in sample preparation (e.g., sample expansion and Brainbow labeling) and optical (e.g., confocal and light sheet) techniques have enabled the imaging of increasingly large neural systems with high contrast. Tracing neuronal structures from these images proves challenging, however, necessitating tools that integrate multiple neuronal traces, potentially derived by various methods, into one combined (montaged) result.New MethodHere, we present TraceMontage, an ImageJ/Fiji plugin for the combination of multiple neuron traces of a single image, either redundantly or non-redundantly. Internally, it uses graph theory to connect topological patterns in the 3-D spatial coordinates of neuronal trees. The software generates a single output tracing file containing the montage traces of the input tracing files and provides several measures of consistency analysis among multiple tracers.Results and Comparison to existing method(s)To our knowledge, our software is the first dedicated method for the combination of tracing results. Combining multiple tracers increases the accuracy and speed of tracing of densely-labeled samples by harnessing collaborative effort. This utility is demonstrated using fluorescence microscope images from the hippocampus and primary visual cortex (V1) in Brainbow-labeled mice.ConclusionsTraceMontageprovides researchers the ability to combine neuronal tracing data generated by either the same or different method(s). As datasets become larger, the ability to trace images in this parallel manner will help connectomics scale to increasingly larger neural systems.
Rhes, a Striatal-Enriched Protein, Promotes Mitophagy Via Nix
Authors: Sharma Manish , Ramirez Jarquin Uri Nimrod , Rivera Oscar , Karantzis Melissa , Eshraghi Mehdi , Shahani Neelam , Sharma Vishakha , Tapia Ricardo , Subramaniam Srinivasa 
Published: July 2019

AbstractElimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here we discovered that Rhes, a striatal-enriched protein, is a major regulator of mitophagy in the striatum. Rhes predominantly interact with dysfunctional mitochondria and degrades them via mitophagy, and this function is exacerbated by the striatal toxin, 3-nitropropionic acid (3-NP). 3-NP induces mitochondrial swelling, loss of cristae and neuronal cell death only in WT but not Rhes KO striatum. Mechanistically, Rhes disrupts the mitochondrial membrane potential (ΔΨm) and interacts with mitophagy receptor, Nix. In Nix KO cells, Rhes fails to disrupt ΔΨmor eliminate dysfunctional mitochondria. Moreover, Rhes travels to the neighboring cell and associates with dysfunctional mitochondria via Nix. Collectively, Rhes is a major regulator of mitophagy via Nix which may determine striatal vulnerability in the brain.
Standardizing the determination and interpretation ofPcritin fishes
Authors: Reemeyer Jessica E. , Rees Bernard B. 
Published: July 2019

AbstractFor most fishes, there is an oxygen level, the critical oxygen tension (Pcrit), below which oxygen consumption (MO2) becomes dependent upon ambient oxygen partial pressure (PO2). We compare multiple curve-fitting approaches to estimatePcritof the Gulf killifish,Fundulus grandis, during closed and intermittent-flow respirometry. The traditional approach fitting two line segments ofMO2versusPO2produced high and variable estimates ofPcrit. Nonlinear regression using hyperbolic or Weibull functions resulted in either variablePcritestimates or, in some cases, failed to converge upon meaningful solutions.Pcritdetermined as thePO2whenMO2equals standard metabolic rate (SMR) based upon a linear relationship ofMO2andPO2at lowPO2were consistent across fish and experimental trials. Therefore, we recommend that Pcrit specifically refer to thePO2below which SMR cannot be maintained. Its determination, therefore, requires accurate measurement of SMR.
Pericyte Bridges in Homeostasis and Hyperglycemia: Reconsidering Pericyte Dropout and Microvascular Structures
Authors: Corliss Bruce A. , Ray H. Clifton , Doty Richard , Mathews Corbin , Sheybani Natasha , Fitzgerald Kathleen , Prince Remi , Kelly-Goss Molly , Murfee Walter L. , Chappell John , Owens Gary , Yates Paul , Peirce Shayn M. 
Published: July 2019

AbstractDiabetic retinopathy threatens the vision of a third of diabetic patients. Progression of the disease is attributed to the dropout of pericytes, a cell type that enwraps and stabilizes the microvasculature. In tandem with this presumptive pericyte dropout, there is enriched formation of structures assumed to be remnants of collapsed or regressed vessels, previously classified as acellular capillaries, string vessels, and basement membrane bridges. Instead of endothelial cells, we show that pericytes colocalize with basement membrane bridges, and both bridging structures are enriched by cell-specific knockout of KLF4 and reversibly enriched with elevation of Ang-2, PDGF-BB, and blood sugar. Our data suggests that pericyte counts from retinal digests have misclassified pericyte bridges as endothelial structures and have exaggerated the role of pericyte loss in DR progression. In vivo imaging of corneal limbal vessels demonstrates pericyte migration off-vessel, implicating pericyte movement in formation of pericyte bridges and pathogenesis of diabetic retinopathy.
Spectral cues are necessary to encode azimuthal auditory space in the mouse superior colliculus
Authors: Ito Shinya , Si Yufei , Feldheim David A. , Litke Alan M. 
Published: July 2019

AbstractSound localization plays a critical role in animal survival. Three cues can be used to compute sound direction: interaural timing differences (ITDs), interaural level differences (ILDs) and the direction-dependent spectral filtering by the head and pinnae (spectral cues). Little is known about how spectral cues contribute to the neural encoding of auditory space. Here we report on auditory space encoding in the mouse superior colliculus (SC). We show that the mouse SC contains neurons with spatially-restricted receptive fields (RFs) that form an azimuthal topographic map. We found that frontal RFs require spectral cues and lateral RFs require ILDs. The neurons with frontal RFs have frequency tunings that match the spectral structure of the specific head and pinna filter for sound coming from the front. These results demonstrate that patterned spectral cues in combination with ILDs give rise to the topographic map of azimuthal auditory space.
Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases
Authors: Dornan Gillian L. , Stariha Jordan T.B. , Rathinaswamy Manoj K. , Powell Cameron J. , Boulanger Martin J. , Burke John E. 
Published: July 2019

SummaryThe class IA PI3Ks are key signalling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders. Mutations in the p85α regulatory subunit encoded byPIK3R1can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations activate both the p110α/p110δ catalytic subunits. We find that the oncogenic Q572* truncation ofPIK3R1disrupts all inhibitory inputs, with p110α being hyper-activated compared to p110δ. In addition, we find that the R649W mutation in the cSH2 ofPIK3R1decreases sensitivity to activation by receptor tyrosine kinases. This work reveals novel insight into isoform specific regulation of p110s by p85α.Highlights- An oncogenic variant of p85α, Q572*, leads to hyper-activation of p110α compared to p110δ- HDX-MS revealed that Q572* leads to disruption of all inhibitory interfaces in p110α- A SHORT syndrome mutation in p85α leads to decreased sensitivity to RTKs for p110α/δ
Modeling the Interplay between Photosynthesis, CO2Fixation, and the Quinone Pool in a Purple Non-Sulfur Bacterium
Authors: Alsiyabi Adil , Immethun Cheryl , Saha Rajib 
Published: July 2019

AbstractRhodopseudomonas palustrisCGA009 is a purple non-sulfur bacterium (PNSB) that can fix CO2and nitrogen or break down organic compounds for its carbon and nitrogen requirements. Light, inorganic, and organic compounds can all be used for its source of energy. Excess electrons produced during its metabolic processes can be exploited to produce hydrogen gas or biodegradable polyesters (polyhydroxybutyrate). A genome-scale metabolic model of the bacterium was reconstructed to study the interactions between photosynthesis, carbon dioxide fixation, and the redox state of the quinone pool. A comparison of model-predicted flux values with publishedin vivoMFA fluxes resulted in predicted errors of 5-19% across four different growth substrates. The model predicted the presence of an unidentified sink responsible for the oxidation of excess quinols generated by the TCA cycle. Furthermore, light-dependent energy production was found to be highly dependent on the rate of quinol oxidation. Finally, the extent of CO2fixation was predicted to be dependent on the amount of ATP generated through the electron transport cycle, with excess ATP going toward the energy-demanding CBB pathway. Based on this analysis, it is hypothesized that the quinone redox state acts as a feed-forward controller of the CBB pathway, signaling the amount of ATP available.
Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago
Authors: Natri Heini , Bobowik Katalina S. , Kusuma Pradiptajati , Darusallam Chelzie Crenna , Jacobs Guy S. , Hudjashov Georgi , Lansing J. Stephen , Sudoyo Herawati , Banovich Nicholas E. , Cox Murray P. , Gallego Romero Irene 
Published: July 2019

AbstractIndonesia is the world’s fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10% of tested genes are differentially expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating with nearby CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by very local environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.