bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Situ Microwave Fixation to Define the Terminal Rodent Brain Metabolome
Authors: Juras Jelena A. , Webb Madison B. , Young Lyndsay E.A. , Markussen Kia H. , Hawkinson Tara R. , Buoncristiani Michael D. , Bolton Kayli E. , Coburn Peyton T. , Williams Meredith I. , Sun Lisa PY. , Sanders William C. , Bruntz Ronald C. , Conroy Lindsey R. , Wang Chi , Gentry Matthew S. , Smith Bret N. , Sun Ramon C. 
Published: August 2022

ABSTRACTThe brain metabolome directly connects to brain physiology and neuronal function. Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. Therefore, challenges remain to capture an accurate snapshot of the physiological brain metabolome in healthy and diseased rodent models. To overcome this barrier, we employ a high-power focused microwave for the simultaneous euthanasia and fixation of mouse brain tissue to preserve metabolite pools prior to surgical removal and dissection of brain regions. We demonstrate exhaustion of glycogen and glucose and increase in lactate production during conventional rapid brain resection prior to preservation by liquid nitrogen that is not observed with microwave fixation. Next, microwave fixation was employed to define the impact of brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple regions of the mouse brain, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the TCA cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation to study terminal brain metabolism in rodent models.
Fibronectin-integrin α5 signaling promotes thoracic aortic aneurysm in a mouse model of Marfan syndrome
Authors: Chen Minghao , Cavinato Cristina , Hansen Jens , Tanaka Keiichiro , Ren Pengwei , Hassab Abdulrahman , Li David S. , Joshuao Eric. , Tellides George , Iyengar Ravi , Humphrey Jay D. , Schwartz Martin A. 
Published: August 2022

ABSTRACTBackgroundMarfan syndrome, caused by mutations in the gene for the extracellular matrix (ECM) glycoprotein fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM remodeling are characteristics of both non-syndromic and Marfan aneurysms. The ECM protein fibronectin (FN) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin α5β1. We investigated the role of integrin α5-specific signals in Marfan mice in which the cytoplasmic domain of integrin α5 was replaced with that of integrin α2 (denoted α5/2 chimera).MethodsWe used α5/2 chimera mouse crossed with Fbn1mgR/mgR genetic background (mgR, a mouse model of Marfan syndrome) to compare the survival rate and pathogenesis of TAAs among wild type, α5/2, mgR and α5/2; mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs allowed us to identify the molecular mechanisms by which FN affects SMCs and subsequent development of TAAs.ResultsFN was elevated in the thoracic aortas from Marfan patients, in non-syndromic aneurysms and in the mgR mouse model of Marfan syndrome. The α5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, in vitro, plating of wild-type, but not α5/2, SMCs on FN decreased contractile gene expression and activated inflammatory pathways. These effects correlated with increased NF-kB activation and immune cell infiltration in the mgR aortas, which was rescued in the α5/2 mgR aortas.ConclusionsFN-integrin α5 signaling is a significant driver of TAA in the mgR mouse model. This pathway warrants further investigation as a therapeutic target.
Robust phenotyping of highly multiplexed tissue imaging data using pixel-level clustering
Authors: Liu Candace C. , Greenwald Noah F. , Kong Alex , McCaffrey Erin F. , Leow Ke Xuan , Mrdjen Dunja , Cannon Bryan J. , Rumberger Josef Lorenz , Varra Sricharan Reddy , Angelo Michael 
Published: August 2022

AbstractWhile technologies for multiplexed imaging have provided an unprecedented understanding of tissue composition in health and disease, interpreting this data remains a significant computational challenge. To understand the spatial organization of tissue and how it relates to disease processes, imaging studies typically focus on cell-level phenotypes. However, images can capture biologically important objects that are outside of cells, such as the extracellular matrix. Here, we developed a pipeline, Pixie, that achieves robust and quantitative annotation of pixel-level features using unsupervised clustering and show its application across a variety of biological contexts and multiplexed imaging platforms. Furthermore, current cell phenotyping strategies that rely on unsupervised clustering can be labor intensive and require large amounts of manual cluster adjustments. We demonstrate how pixel clusters that lie within cells can be used to improve cell annotations. We comprehensively evaluate pre-processing steps and parameter choices to optimize clustering performance and quantify the reproducibility of our method. Importantly, Pixie is open source and easily customizable through a user-friendly interface.
Modulation of adaptive immune responses by Akkermansia muciniphila is restricted to an early life window in NOD mice
Authors: Maddux Sarah , Lubin Jean-Bernard , Green Jamal , Flores Julia , Rozich Isaiah , Duranova Tereza , Planet Paul J. , Silverman Michael A. 
Published: August 2022

AbstractEarly life microbiota drive immune system development and influence risk for immune dysfunction later in life, including the development of type 1 diabetes (T1D). Which specific early-life microbes modulate diabetes risk and the timing of these critical interactions are not well understood. To address this gap in knowledge, we screened for microbes that induce systemic IgG1 responses in young NOD mice. We isolated a strain of Akkermansia muciniphila that potently induces systemic IgG1 antibodies and peripheral regulatory T cells (pTregs). Since this mucus-degrading commensal protects NOD mice from T1D and is associated with lower risk of developing T1D in children, we investigated how A. muciniphila impacts early-life host-commensal interactions using gnotobiotic NOD mice colonized with a defined 9-member bacterial consortium that models the early life microbiome. We find that A. muciniphila potently induces pTregs and enhances antibody responses to other commensal microbes. Remarkably, these effects only occur when A. muciniphila colonizes NOD mice prior to weaning, establishing that the specific window of exposure to A. muciniphila shapes adaptive immune system development in diabetes-susceptible NOD mice. This time dependence provides important evidence that early-life exposure may enhance microbiota-based therapies to prevent T1D.One Sentence SummaryAkkermansia muciniphila induces peripheral Tregs and enhances antibody responses to itself and other commensals during an early life window.
Transcriptome-Wide Gene-Gene Interaction Association Study Elucidates Pathways and Functional Enrichment of Complex Traits
Authors: Evans Luke M. , Arehart Christopher H. , Grotzinger Andrew D. , Mize Travis J. , Brasher Maizy S. , Stitzel Jerry A. , Ehringer Marissa A. , Hoeffer Charles A. 
Published: August 2022

AbstractIt remains unknown to what extent gene-gene interactions contribute to complex traits. Here, we introduce a new approach using predicted gene expression to perform exhaustive transcriptome-wide interaction studies (TWISs) for multiple traits across all pairs of genes expressed in several tissue types. Using imputed transcriptomes, we simultaneously reduce the computational challenge and improve interpretability and statistical power. We discover and replicate several interaction associations, and find several hub genes with numerous interactions. We also demonstrate that TWIS can identify novel associated genes because genes with many or strong interactions have smaller single-locus model effect sizes. Finally, we develop a method to test gene set enrichment of TWIS associations (E-TWIS), finding numerous pathways and networks enriched in interaction associations. Epistasis is likely widespread, and our procedure represents a tractable framework for beginning to explore gene interactions and identify novel genomic targets.
Cereblon controls the timing of muscle differentiation in Ciona embryos
Authors: Long Juanjuan , Mariossi Andrea , Cao Chen , Levine Michael , Lemaire Laurence A. 
Published: August 2022

ABSTRACTThalidomide has a dark history as a teratogen, but in recent years it has been shown to function as a chemotherapeutic agent. Thalidomide binds cereblon, a component of E3 ubiquitin ligase complex and modifies its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here, we employ the simple proto-vertebrate model, Ciona intestinalis, to address this question. We observed a “hotspot” of Crbn expression in the developing tail muscles and identify its enhancer containing both Myod activator sites and a Snail repressive element. Overexpression of Crbn in tail muscles decreases expression of contractility genes. We suggest that this reduction is due to premature degradation of Tbx6. Drug inhibition studies using lenalidomide, a derivative of thalidomide, lead to a striking increase of Crbn expression. This autofeedback regulation could be induced by neomorphic degradation of Snail, contributing to the efficacy of lenalidomide in treating metastatic melanoma. In summary, our analysis of Crbn suggests that its normal function in Ciona is to time expression of contractility genes during muscle differentiation thereby ensuring coordination of tail morphogenesis and hatching of swimming tadpoles.
Virtual screening for the discovery of novel urease inhibitors of rumen bacterial urease
Authors: Zhao Shengguo , Togtokhbayar Norovsambuu , Narantuya Baatar 
Published: August 2022

AbstractInhibition of urea hydrolysis by rumen bacterial urease can improve the efficiency of dietary nitrogen utilization in animal production and decrease nitrogen pollution into the environment. The three dimensional structure of urease from the ruminal bacterium Ruminococcus albus 8 (RaUrease) was resolved by comparison with the crystal structure of urease from Helicobacter pylori (HpUrease, PDB ID 1E9Z) using Modeller. A reliable structure of RaUrease was generated using molecular dynamics simulation for 20 ns with the AMBER force field using the Gromacs system, and the stereochemical quality of the protein model was evaluated. On the basis of binding energies (<-9.8 kcal mol-1), 12 commercially available agents were selected as potential urease inhibitors. Characterization of the RaUrease-binding site for the compound with the highest predicted inhibitory activity indicated that van der Waals forces were more important than hydrogen bonds for rumen bacterial urease binding. The results of the present study may help design novel urease inhibitors for ruminants and alleviate nitrogen pollution derived from livestock production.
Translation control by maternal Nanog promotes oocyte maturation and early embryonic development
Authors: He Mudan , Jiao Shengbo , Ye Ding , Wang Houpeng , Sun Yonghua 
Published: August 2022

AbstractMany maternal mRNAs are translationally repressed during oocyte maturation and spatio-temporally activated during early embryogenesis, which is critical for oocyte and early embryo development. By analyzing maternal mutants of nanog (Mnanog) in zebrafish, we demonstrated that Nanog tightly controls translation of maternal mRNA during oocyte maturation via transcriptional repression of eukaryotic translation elongation factor 1 alpha 1, like 2 (eef1a1l2). Loss of maternal Nanog led to defects of egg maturation, increased endoplasmic reticulum (ER) stress, and an activated unfold protein response (UPR), which was caused by elevated translational activity. We further demonstrated that Nanog, as a transcriptional repressor, represses the transcription of eefl1a1l2 by directly binding to the eef1a1l2 promoter during oocyte maturation. More importantly, depletion of eef1a1l2 in nanog mutant females effectively rescued the elevated translational activity in oocytes, egg quality defects, and embryonic defects of Mnanog embryos. Thus, our study demonstrates that maternal Nanog regulates oocyte maturation and early embryogenesis though translational control of maternal mRNA via a novel mechanism, in which Nanog acts as a transcriptional repressor to suppress transcription of eef1a1l2.
Homeodomain-less MEIS1 suppresses CUL3-dependent ATOH1 degradation to regulate cerebellar granule cell development
Authors: Owa Tomoo , Shiraishi Ryo , Adachi Toma , Miyashita Satoshi , Ichijo Kentaro , Nishioka Tomoki , Taya Shinichiro , Kaibuchi Kozo , Hoshino Mikio 
Published: August 2022

AbstractGranule cell progenitors (GCPs) and granule cells (GCs) in the cerebellum are excellent models for studying the differentiation of neural progenitors into neurons. Although gradual degradation of ATOH1 protein in GCPs leads to their differentiation into GCs, the underlying regulatory mechanism is unclear. We show that a homeodomain-less isoform of MEIS1 (MEIS1-HdL) regulates ATOH1 degradation and GCP differentiation in a transcriptional regulation-independent manner. BMP signaling phosphorylates Ser328 of ATOH1 via ERK. CUL3 was identified as an E3-ligase that polyubiquitinates Ser328 phosphorylated ATOH1, leading to ATOH1 degradation. MEIS1-HdL and full-length MEIS1 form a trimeric complex with CUL3 and COP9 signalosome that inhibits ATOH1 ubiquitination and degradation. MEIS1-HdL is exclusively expressed in GCPs and suppresses ATOH1 degradation and GCP differentiation into GCs, despite high BMP signaling activities in the cells. Our study provides insight into the precise regulatory machinery of the degradation of the pivotal protein ATOH1 and differentiation of neural progenitors.
Direct access to millions of mutations by Whole Genome Sequencing of an oilseed rape mutant population
Authors: Jhingan Srijan , Kumar Avneesh , Harloff Hans-Joachim , Dreyer Felix , Abbadi Amine , Beckmann Katrin , Obermeier Christian , Jung Christian 
Published: August 2022

AbstractInduced mutations are an essential source of genetic variation in plant breeding. EMS mutagenesis has been frequently applied, and mutants have been detected by phenotypic or genotypic screening of large populations. In this study, a rapeseed M2 population was derived from M1 parent cultivar “Express” treated with EMS. Whole genomes were sequenced from fourfold (4x) pools of 1,988 M2 plants representing 497 M2 families. Detected mutations were not evenly distributed and displayed distinct patterns across the 19 chromosomes with lower mutation rates towards the ends. Mutation frequencies ranged from 32/Mb to 48/Mb. On average, 284,442 single nucleotide polymorphisms per M2 DNA pool were found resulting from EMS mutagenesis. 55% were C→T and G→A transitions, characteristic for EMS induced (‘canonical’) mutations, whereas the remaining SNPs were ‘non-canonical’ transitions (15%) or transversions (30%). Additionally, we detected 88,725 high confidence insertions and deletions (InDels) per pool. On average, each M2 plant carried 39,120 canonical mutations, corresponding to a frequency of one mutation per 23.6 kb. Roughly 82% of such mutations were located either 5 kb upstream or downstream (~56%) of gene coding regions or within intergenic regions (26%). The remaining 18% were located within regions coding for genes. All mutations detected by whole-genome sequencing could be verified by comparison with known mutations. Furthermore, all sequences are accessible via the online tool “EMS Brassica” (http://www.emsbrassica.plantbreeding.uni-kiel.de/), which enables direct identification of mutations in any target sequence. The sequence resource described here will further add value for functional gene studies in rapeseed breeding.
Mixed-integer linear programming models for the type-II resource-constrained assembly line balancing problem
Authors: Michels Adalberto Sato , Costa Alysson M. 
Published: August 2022

Purpose
Resource-constrained assembly lines are widely found in industries that manufacture complex products. In such lines, tasks may require specific resources to be processed. Therefore, decisions on which tasks and resources will be assigned to each station must be made. When the number of available stations is fixed, the problem’s main goal becomes the minimisation of cycle time (type-II version). This paper aims to explore this variant of the problem that lacks investigation in the literature.

Design/methodology/approach
In this paper, the authors propose mixed-integer linear programming (MILP) models to minimise cycle time in resource-constrained assembly lines, given a limited number of stations and resources. Dedicated and alternative resource types for tasks are considered in different scenarios.

Findings
Besides, past modelling decisions and assumptions are questioned. The authors discuss how they were leading to suboptimal solutions and offer a rectification.

Practical implications
The proposed models and data set fulfil more practical concerns by taking into account characteristics found in real-world assembly lines.

Originality/value
The proposed MILP models are applied to an existing data set, results are compared against a constraint programming model, and new optimal solutions are obtained. Moreover, a data set extension is proposed due to the simplicity of the current one and instances up to 70 tasks are optimally solved.
Technology and solution-driven trends in sustainable aviation
Authors: Rohacs Daniel 
Published: August 2022

PurposeThe primary driver of future aviation has recently been sustainability. The rapid development of radically new, disruptive technologies and solutions should be regularly evaluated to maintain the desired trends in sustainable aviation. The purpose of this research can be listed as follows: (i) to propose a sustainable performance index and methodology (ii) to evaluate the new technologies and solutions, and (iii) apply them to evaluate the effect of technologies and solutions under development.Design/methodology/approachThis paper introduces a total sustainable performance index for evaluating the sustainability; demonstrates its applicability to future development processes; recognizes the supporting new technologies and solutions by implementing their identification, evaluation and selection processes; and defines the major trends and drivers maintaining the sustainability of the future aviation.FindingsThis study has resulted in a proposed new “total sustainable performance index,” and methodology of identifying key drivers that allow defining the technology and solution-driven trends, and defines the major trends and listed technologies and solutions that may have a determining role in given trends.Research limitations/implicationsThere are dilemmas on taking into account the positive effects of aviation on the economy and society that may overwrite the costs and limited information about the foresight on new technologies and solutions.Practical implicationsIt depends on access to required inputs.Social implicationsTwo-way effects of solid expectations of society on the possible greening of aviation can be listed as the social implication of this research.Originality/valueThe proposed “total sustainability performance index” totally evaluates sustainability, including a penalty, considering the policy (regulation) and interest of future generations.
What motivates people to continuously engage in online task-oriented check-ins? The role of perceived social presence
Authors: Sun Wenzheng , Liu Hong , Wen Nainan 
Published: August 2022

PurposeOnline task-oriented check-ins (i.e. OTOCs) are popular means of tracking personal progress in certain fields. This study focused on the use of OTOC platforms and explored the predictors of individuals' continuing usage intention.Design/methodology/approachA model was proposed to understand Chinese users' continuous intention of OTOCs based on the UTAUT framework. Perceived social presence was also incorporated as a predictor of continuance intention of OTOC platforms. A survey of 397 users of the OTOC platforms was conducted in Nanjing, China.FindingsPerformance expectancy, hedonic motivation, and habit had direct, positive influence on the continuous use intention, whereas effort expectancy and social influence were not significant predictors of continuance intention of OTOCs. Perceived social presence was a significant, indirect predictor of intention to continuously use the OTOCs, and the relationship was mediated by performance expectancy, hedonic motivation, and habit.Originality/valueThis study distinguished OTOCs from other modes of self-tracking and extended the UTAUT framework by incorporating perceived social presence as a predictor of continuous technology use in the context of OTOCs. This study also provided a deeper understanding of the interrelations between the explanatory variables of the model that have been identified as robust in previous literature on technology use.
Enhancing project stakeholder communication under insufficient knowledge of project management concepts
Authors: Zwikael Ofer , Salmona Michelle , Meredith Jack , Zarghami Seyed Ashkan 
Published: August 2022

PurposeAlthough the literature is clear on what comprises effective project stakeholder management, communication between key stakeholders and project managers is often ineffective. Research is silent on stakeholders' insufficient knowledge of project management terminology, which is a barrier for such effective communication. This paper aims to identify the project management concepts that key stakeholders should understand to improve effective communication.Design/methodology/approachThis paper employs a three-step research design. In the first step, based on threshold concept theory, the authors identify the key project management concepts through interviews with 20 project management practitioners, trainers and trainees. In the second step, the authors confirm the findings from the first step and identify effective approaches to enhance project stakeholders' communication through seven additional interviews with project stakeholders. In the third step, the authors construct a functional model of the research findings by employing a system-level modeling tool.FindingsThis research identifies five project management threshold concepts (TC) that are challenging for project stakeholders to understand (1) project benefits, (2) the iron triangle, (3) the critical path, (4) uncertainty and (5) project leadership. Following these knowledge barriers, the paper proposes unique approaches to develop effective project stakeholder communication.Originality/valueThis paper advances project stakeholder management research by identifying knowledge barriers and providing project managers with more effective approaches to better engage with their stakeholders.