bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Practical Haplotype Graph, a platform for storing and using pangenomes for imputation
Authors: Bradbury PJ , Casstevens T , Jensen SE , Johnson LC , Miller ZR , Monier B , Romay MC , Song B , Buckler ES 
Published: August 2021

AbstractMotivationPangenomes provide novel insights for population and quantitative genetics, genomics, and breeding not available from studying a single reference genome. Instead, a species is better represented by a pangenome or collection of genomes. Unfortunately, managing and using pangenomes for genomically diverse species is computationally and practically challenging. We developed a trellis graph representation anchored to the reference genome that represents most pangenomes well and can be used to impute complete genomes from low density sequence or variant data.ResultsThe Practical Haplotype Graph (PHG) is a pangenome pipeline, database (PostGRES & SQLite), data model (Java, Kotlin, or R), and Breeding API (BrAPI) web service. The PHG has already been able to accurately represent diversity in four major crops including maize, one of the most genomically diverse species, with up to 1000-fold data compression. Using simulated data, we show that, at even 0.1X coverage, with appropriate reads and sequence alignment, imputation results in extremely accurate haplotype reconstruction. The PHG is a platform and environment for the understanding and application of genomic diversity.AvailabilityAll resources listed here are freely available. The PHG Docker used to generate the simulation results ishttps://hub.docker.com/as maizegenetics/phg:0.0.27. PHG source code is athttps://bitbucket.org/bucklerlab/practicalhaplotypegraph/src/master/. The code used for the analysis of simulated data is athttps://bitbucket.org/bucklerlab/phg-manuscript/src/master/. The PHG database of NAM parent haplotypes is in the CyVerse data store (https://de.cyverse.org/de/) and named /iplant/home/shared/panzea/panGenome/PHG_db_maize/phg_v5Assemblies_20200608.db.Contactpjb39@cornell.edu
MS-driven metabolic alterations are recapitulated in iPSC-derived astrocytes
Authors: Ghirotto Bruno , Oliveira Danyllo F. , Cipelli Marcella , Basso Paulo J. , de Lima Jean , Breda Cristiane N. S. , Ribeiro Henrique C. , Silva Camille C. C. , Hiyane Meire I. , Caldini Elia G. , Sussulini Alessandra , Kowaltowski Alicia J. , Oliveira Enedina M. L. , Zatz Mayana , Câmara Niels O. S. 
Published: August 2021

ABSTRACTObjectiveAstrocytes play a significant role in the pathology of Multiple Sclerosis (MS). Nevertheless, for ethical reasons, most of the studies in these cells were performed on the Experimental Autoimmune Encephalomyelitis model. As there are significant differences between human and mouse cells, we aimed here to better characterize astrocytes from patients with MS (PwMS), focusing mainly on mitochondrial function and cell metabolism.MethodsWe obtained and characterized induced pluripotent stem cell (iPSC)-derived astrocytes from three PwMS and three unaffected controls and performed functional assays including electron microscopy, flow cytometry, cytokine measurement, gene expression, in situ respiration, and metabolomics.ResultsWe detected several differences in MS astrocytes including: (i) enrichment of genes associated with mitophagy and neurodegeneration, (ii) increased mitochondrial fission and decreased mitochondrial to nuclear DNA ratio, indicating disruption of mitochondrial content, (iii) increased production of superoxide and MS-related proinflammatory chemokines, (iv) increased electron transport capacity and proton leak, in line with the increased oxidative stress, and (v) a distinct metabolic profile, with a deficiency in amino acid catabolism and increased sphingolipid metabolism, which have already been linked to MS.InterpretationTo our knowledge, this is the first study thoroughly describing the metabolic profile of iPSC-derived astrocytes from PwMS, and validating this model as a powerful tool to study disease mechanisms and to perform non-invasive drug targeting assays in vitro. Our findings recapitulate several disease features described in patients and provide new mechanistic insights into the metabolic rewiring of astrocytes in MS, which could be targeted in future therapeutic studies.
Aberrant accumulation of NIK promotes tumorigenicity by dysregulating post-translational modifications in breast cancer
Authors: Hayashi Yusuke , Nakayama Jun , Yamamoto Mizuki , Maekawa Masashi , Watanabe Shinya , Higashiyama Shigeki , Inoue Jun-ichiro , Yamamoto Yusuke , Semba Kentaro 
Published: August 2021

AbstractPost-translational modifications and mRNA translation are frequently altered in human cancers. However, investigations to understand their roles in the cancer progression mechanism remain insufficient. In this research, we explored protein levels altered by translational or post-translational regulation by analyzing transcriptome and western blotting data of the highly malignant breast cancer cell lines. From these analyses, NIK was found to be upregulated at the protein level to predominantly activate the non-canonical NF-κB pathway in a breast cancer cell line. Furthermore, the increase in NIK protein production was attributed to the dysregulation of ubiquitin-proteasome system caused by a decrease in the translation of cIAP1. NIK upregulation contributed to tumorigenicity by regulating the expression of inflammatory response-related genes. Collectively, our study suggests that NIK is post-translationally modified and has the potential to be a therapeutic target and diagnostic marker for breast cancer.
The mechanical regulation of RNA binding protein hnRNPC in the failing heart
Authors: Martino Fabiana , Varadarajan Nandan Mysore , Perestrelo Ana Rubina , Hejret Vaclav , Durikova Helena , Horvath Vladimir , Cavalieri Francesca , Caruso Frank , Albihlal Waleed S. , Gerber André P. , O’Connell Mary A. , Vanacova Stepanka , Pagliari Stefania , Forte Giancarlo 
Published: August 2021

ABSTRACTCardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by re-expressing fetal contractile proteins via transcriptional and post-transcriptional processes, like alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is upregulated and relocates to the sarcomeric Z-disk upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates to the translation machinery. Alterations in hnRNPC expression and localization can be mechanically determined and affect the AS of numerous mRNAs involved in mechanotransduction and cardiovascular diseases, like Hippo pathway effector YAP1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by impacting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNAs homeostasis mechanoregulation in pathological conditions.
Stress Evaluation of Various Breeding Environments in Mouse
Authors: Lee Gwang-Hoon , Choi Hye-Yoon , Jo Woori , Kim Kil-Soo 
Published: August 2021

AbstractLaboratory animals are raised in a fixed space during the study period and are environmentally bound. Laboratory animal may be under stress on the constrained environment, which changes physiological indicators, affecting the reproducibility and accuracy of animal study. Therefore, reducing animal stress by providing proper breeding environment and environmental enrichment can be the basis for animal study. In this study, the stress level was assessed according to the mouse breeding environment. According to the results of the experiment, it was determined that the individual ventilation cage had less cortisol concentration in serum and body weight increased in the individual ventilation cage than individual isolated cage, when providing environmental enrichment rather than group breeding or not providing environmental enrichment. The results will provide appropriate guidelines for laboratory animal welfare.
Age-related neural dedifferentiation for individual stimuli: An across-participant pattern similarity analysis
Authors: Koen Joshua D. 
Published: August 2021

AbstractAge-related neural dedifferentiation – reductions in the regional specificity and precision of neural representations – is proposed to compromise the ability of older adults to form sufficiently distinct neural representations to support episodic memory encoding. The computational model that spurred investigations of age-related neural dedifferentiation initially characterized this phenomenon as a reduction in the specificity of neural patterns for individual items or stimuli. Most investigations have focused on reductions in neural differentiation for patterns of neural activity associated with category level information, such as reduced neural selectivity between categories of visual stimuli (e.g., scenes, objects, and faces). Here, I report a novel across-participant pattern similarity analysis method to measure neural distinctiveness for individual stimuli that were presented to participants on a single occasion. Measures of item level pattern similarity during encoding showed a graded positive subsequent memory effect in younger, with no significant subsequent memory effect in older adults. These results suggest that age-related reductions in the distinctiveness of neural patterns for individual stimuli during age differences in memory encoding. Moreover, a measure of category level similarity demonstrated a significant subsequent memory effect associated with item recognition (regardless of an object source memory detail), whereas the effect in older was associated with source memory. These results converge with predictions of computational models of dedifferentiation showing age-related reductions in the distinctiveness of neural patterns across multiple levels of representation.
Three-dimensional microenvironment regulates gene expression, function, and tight junction dynamics of iPSC-derived blood-brain barrier microvessels
Authors: Linville Raleigh M. , Sklar Matthew B. , Grifno Gabrielle N. , F. Nerenberg Renée , Zhou Justin , Ye Robert , DeStefano Jackson G. , Guo Zhaobin , Jha Ria , Jamieson John J. , Zhao Nan , Searson Peter C. 
Published: August 2021

AbstractThe blood-brain barrier (BBB) plays a pivotal role in brain health and disease. In the BBB, brain microvascular endothelial cells (BMECs) are connected by tight junctions which regulate paracellular transport, and express specialized transporter systems which regulate transcellular transport. However, existingin vitromodels of the BBB display variable physiological accuracy across a wide range of characteristics including gene/protein expression and barrier function. Here, we use an isogenic family of fluorescently-labeled iPSC-derived BMEC-like cells (iBMECs) and brain pericyte-like cells (iPCs) within two-dimensional confluent monolayers (2D) and three-dimensional (3D) tissue-engineered microvessels to explore how 3D microenvironment regulates gene expression and function of thein vitroBBB. We show that 3D microenvironment (shear stress, cell-ECM interactions, and cylindrical geometry) increases BBB phenotype and endothelial identity, and alters angiogenic and cytokine responses in synergy with pericyte co-culture. Tissue-engineered microvessels incorporating junction-labeled iBMECs enable study of the real-time dynamics of tight junctions during homeostasis and in response to physical and chemical perturbations.
Transposable element diversity remains high in gigantic genomes
Authors: Haley Ava Louise , Mueller Rachel Lockridge 
Published: August 2021

ABSTRACTTransposable elements (TEs) are repetitive sequences of DNA that replicate and proliferate throughout genomes. Taken together, all the TEs in a genome form a diverse community of sequences, which can be studied to draw conclusions about genome evolution. TE diversity can be measured using models for ecological community diversity that consider species richness and evenness. Several models predict TE diversity decreasing as genomes expand because of selection against ectopic recombination and/or competition among TEs to garner host replicative machinery and evade host silencing mechanisms. Salamanders have some of the largest vertebrate genomes and highest TE loads. Salamanders of the genus Plethodon, in particular, have genomes that range in size from 20 to 70 Gb. Here, we use Oxford Nanopore sequencing to generate low-coverage genomic sequences for four species of Plethodon that encompass two independent genome expansion events, one in the eastern clade (P. cinereus, 29.3 Gb vs. P. glutinosus, 38.9 Gb) and one in the western clade (P. vehiculum, 46.4 Gb vs P. idahoensis, 67.0 Gb). We classified the TEs in these genomes and found ~52 TE superfamilies, accounting for 27-32% of the genomes. We calculated Simpson’s and Shannon’s diversity indices to quantify overall TE diversity. In both pairwise comparisons, the diversity index values for the smaller and larger genome were almost identical. This result indicates that, when genomes reach extremely large sizes, they maintain high levels of TE diversity at the superfamily level, in contrast to predictions made by previous studies on smaller genomes.
Pattern separation and tuning shift in human sensory cortex underlie fear memory
Authors: You Yuqi , Novak Lucas R. , Clancy Kevin , Li Wen 
Published: August 2021

ABSTRACTAnimal research has recognized the role of the sensory cortex in fear memory and two key underlying mechanisms—pattern separation and tuning shift. We interrogated these mechanisms in the human sensory cortex in an olfactory differential conditioning study with a delayed (9-day) retention test. Combining affective appraisal and olfactory psychophysics with functional magnetic resonance imaging (fMRI) multivoxel pattern analysis and voxel-based tuning analysis over a linear odor-morphing continuum, we confirmed affective and perceptual learning and memory and demonstrated associative plasticity in the human olfactory (piriform) cortex. Specifically, the piriform cortex exhibited immediate and lasting enhancement in pattern separation (between the conditioned stimuli/CS and neighboring non-CS) and late-onset yet lasting tuning shift towards the CS, especially in anxious individuals. These findings highlight an evolutionarily conserved sensory cortical system of fear memory, which can underpin sensory encoding of fear/threat and confer a sensory mechanism to the neuropathophysiology of anxiety.
Successive remodeling of IgG glycans using a solid-phase enzymatic platform
Authors: Hsu Yen-Pang , Verma Deeptak , Sun Shuwen , McGregor Caroline , Mangion Ian , Mann Benjamin F. 
Published: August 2021

AbstractThe success of glycoprotein-based drugs in various disease treatments has become widespread. Frequently, therapeutic glycoproteins exhibit a heterogeneous array of glycans that are intended to mimic human glycopatterns. While immunogenic responses to biologic drugs are uncommon, enabling exquisite control of glycosylation with minimized microheterogeneity would improve their safety, efficacy and bioavailability. Therefore, close attention has been drawn to the development of glycoengineering strategies to control the glycan structures. With the accumulation of knowledge about the glycan biosynthesis enzymes, enzymatic glycan remodeling provides a potential strategy to construct highly ordered glycans with improved efficiency and biocompatibility. In this study, we quantitatively evaluate more than 30 enzymes for glycoengineering immobilized immunoglobulin G, an impactful glycoprotein class in the pharmaceutical field. We demonstrate successive glycan remodeling in a solid-phase platform, which enabled IgG glycan harmonization into a series of complex-type N-glycoforms with high yield and efficiency while retaining native IgG binding affinity.SignificanceGlycosylation plays critical functional and structural roles in protein biology. However, our understanding of how discrete glycan structures affect protein behaviors remains extremely limited due to the naturally occurring microheterogeneity. Through the use of characterized glycoengineering enzyme combination, we report a solid-phase glycan remodeling (SPGR) platform that enables efficient IgG glycan harmonization into several glycoforms of interest with high biocompatibility to the substrates. It provides an efficient strategy to screen the biological behavior of distinct glycoforms, building a fundamental understanding of glycosylation.
A base-resolution panorama of the in vivo impact of cytosine methylation on transcription factor binding
Authors: Hernandez-Corchado Aldo , Najafabadi Hamed S. 
Published: August 2021

ABSTRACTWhile methylation of CpG dinucleotides is traditionally considered antagonistic to the DNA-binding activity of most transcription factors (TFs), recent in vitro studies have revealed a more complex picture, suggesting that over a third of TFs may preferentially bind to methylated sequences. Expanding these in vitro observations to in vivo TF binding preferences, however, is challenging, as the effect of methylation of individual CpG sites cannot be easily isolated from the confounding effects of DNA accessibility and regional DNA methylation. As a result, the in vivo methylation preferences of most TFs remain uncharacterized.Here, we introduce joint accessibility-methylation-sequence (JAMS) models, which connect the strength of the binding signal observed in ChIP-seq to the DNA accessibility of the binding site, regional methylation level, DNA sequence, and base-resolution cytosine methylation. We show that JAMS models quantitatively explain the TF binding strength, recapitulate cell type-specific TF binding, and have high precision for inferring intra-motif methylation effects. Analysis of 2209 ChIP-seq experiments resulted in high-confidence JAMS models for 260 TFs, revealing that 45% of TFs are inhibited by intra-motif methylation in vivo. In contrast, only 16 TFs (6%) preferentially bind to methylated sites, including 11 novel methyl-binding TFs that are mostly from the multi-zinc finger family of TFs.Our study substantially expands the repertoire of in vivo methyl-binding TFs, but also suggests that most TFs that prefer methylated CpGs in vitro present themselves as methylation agnostic in vivo, potentially due to the balancing effect of competition with other methyl-binding proteins.
Enhancement of the immunogenicity of a Mycobacterium tuberculosis fusion protein using ISCOMATRIX and PLUSCOM nano-adjuvants after nasal administration in mice
Authors: Avarvand Arshid Yousefi , Meshkat Zahra , Khademi Farzad , Aryan Ehsan , Sankian Mojtaba , Tafaghodi Mohsen 
Published: August 2021

AbstractBackgroundTuberculosis (TB), a contagious disease caused by Mycobacterium tuberculosis (M. tuberculosis), remains a health problem worldwide and this infection has the highest mortality rate among bacterial infections. Current studies suggest that intranasal administration of new tuberculosis vaccines could enhance the immunogenicity of M. tuberculosis antigens. Hence, we aim to evaluate the protective efficacy and immunogenicity of HspX/EsxS fusion protein of M. tuberculosis along with ISCOMATRIX and PLUSCOM nano-adjuvants and MPLA through the intranasal administration in mice model.MethodsIn present study, the recombinant fusion protein was expressed in Escherichia coli and purified and used to prepare different nanoparticle formulations in combination with ISCOMATRIX and PLUSCOM nano-adjuvants and MPLA. Mice were intranasally vaccinated with each formulation three times at an interval of 2 weeks. Finally, IFN-γ, IL-4. IL-17 and TGF-β concentration in supernatant of cultured splenocytes of vaccinated mice as well as serum titers of IgG1 and IgG2a and sIgA titers in nasal lavage were determined.ResultsAccording to obtained results, intranasally vaccinated mice with formulations containing ISCOMATRIX and PLUSCOM nano-adjuvants and MPLA could effectively induced IFN-γ and sIgA responses. Moreover, both HspX/EsxS/ISCOMATRIX/MPLA and HspX/EsxS/PLUSCOM/MPLA and their BCG booster formulation could strongly stimulate the immune system and enhance the immunogenicity of M. tuberculosis antigens.ConclusionThe results demonstrate the potential of HspX/EsxS-fused protein in combination with ISCOMATRIX, PLUSCOM and MPLA after nasal administration in enhancing immune response against of M. tuberculosis antigens. So, nasal immunization with these formulations, could induce immune responses and considered as new TB vaccine or as BCG booster.
Mechanistic basis for SNX27-Retromer coupling to ESCPE-1 in promoting endosomal cargo recycling
Authors: Simonetti Boris , Guo Qian , Gimenez-Andres Manuel , Chen Kai-En , Moody Edmund R.R. , Evans Ashley J. , Danson Chris M. , Williams Tom A. , Collins Brett M. , Cullen Peter J. 
Published: August 2021

ABSTRACTSorting nexin-27 (SNX27)-Retromer is an endosomal sorting complex that orchestrates endosome-to-plasma membrane recycling of hundreds of internalized receptors, channels and transporters, enzymes and adhesion molecules. While SNX27-Retromer is essential for development, subtle functional defects are observed in human disease, most notably neurodegenerative and neurological disorders. Achieving a thorough mechanistic dissection of SNX27-Retromer is central to understanding endosomal sorting in health and disease. Here we combine biochemical, structural and cellular analyses to establish the mechanistic basis through which SNX27-Retromer couples to the membrane tubulating ESCPE-1 complex (Endosomal SNX-BAR sorting complex for promoting exit 1). We show that a conserved surface in the FERM (4.1/ezrin/radixin/moesin) domain of SNX27 directly binds acidic-Asp-Leu-Phe (aDLF) motifs in the disordered amino-termini of the SNX1 and SNX2 subunits of ESCPE-1. This interaction hands-over SNX27-Retromer captured integral membrane proteins into ESCPE-1 tubular profiles to promote their cell surface recycling. Through phylogenetic analysis, we reveal that SNX27:Retromer:ESCPE-1 assembly evolved in a stepwise manner during the early evolution of metazoans, which reflects the increasing complexity of endosomal sorting from the ancestral opisthokont to modern animals.
Preclinical models of human multiple myeloma subgroups
Authors: Winkler Wiebke , Díaz Carlota Farré , Blanc Eric , Napieczynska Hanna , Langner Patrick , Werner Marvin , Walter Barbara , Wollert-Wulf Brigitte , Yasuda Tomoharu , Heuser Arnd , Beule Dieter , Mathas Stephan , Anagnostopoulos Ioannis , Rosenwald Andreas , Rajewsky Klaus , Janz Martin 
Published: August 2021

AbstractMultiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated subgroup-specific MM models by the GC B cell-specific co-activation of Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NFκB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency and bone lesions. The transgenic plasma cells could be propagated in vivo and showed transcriptional profiles resembling their human counterparts. Thus, we show that Ccnd1 and MMSET cooperate with NFκB in MM pathogenesis, considering for the first time the genetic heterogeneity of MM for the generation of preclinical models.