bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-6 SIGNALING EXACERBATES HALLMARKS OF CHRONIC TENDON DISEASE BY STIMULATING REPARATIVE FIBROBLASTS
Authors: Stauber Tino , Moschini Greta , Hussien Amro A. , Jaeger Patrick K. , De Bock Katrien , Snedeker Jess G. 
Published: February 2023

ABSTRACTTendinopathies are debilitating diseases currently increasing in prevalence and associated costs. There is a need to deepen our understanding of the underlying cell signaling pathways to unlock effective treatments. In this work, we screen cell signaling pathways in human tendinopathies and find positively enriched IL-6/JAK/STAT signaling alongside signatures of cell populations typically activated by IL-6 in other tissues. In human tendinopathic tendons, we also confirm the strong presence and co-localization of IL-6, IL6R, and CD90, an established marker of reparative fibroblasts. To dissect the underlying causalities, we combine IL-6 knock-out mice with an explant-based assembloid model of tendon damage to successfully connect IL-6 signaling to reparative fibroblast activation and recruitment. Vice versa, we show that these reparative fibroblasts promote the development of tendinopathy hallmarks in the damaged explant upon IL-6 activation. We conclude that IL-6 activates tendon fibroblast populations which then initiate and deteriorate tendinopathy hallmarks.
CK1δ homeostasis by activity-dependent shuttling and degradation of orphan kinase
Authors: Serrano Fidel E. , Marzoll Daniela , Ruppert Bianca , Diernfellner Axel C. R. , Brunner Michael 
Published: February 2023

AbstractCasein kinase 1δ (CK1δ) is a simple monomeric enzyme involved in the regulation of a variety of functions, including signal transduction, the circadian clock, and the cell cycle. Although CK1δ is targeted by the ubiquitin ligase APC/CCdh1is not understood how CK1δ expression is regulated to support its multiple functions. Here, we show that kinase activity controls CK1δ homeostasis by coordinating two competing processes: export from the nucleus to ensure distribution of CK1δ between its assembly partners, and proteasomal degradation of unassembled CK1δ in the nucleus to keep the amount of active, potentially deleterious orphan kinase low. During mitosis, CK1δ is released from centrosomes and stabilized by (auto)phosphorylation to preserve it for the subsequent G1 phase.TeaserCompetitive nuclear export and nuclear degradation of active CK1δ ensure efficient partner interaction and keep unassembled kinase levels low.
An allele-resolved nanopore-guided tour of the human placental methylome
Authors: Kindlova Michaela , Byrne Hannah , Kubler Jade M , Steane Sarah E , Whyte Jessica M , Borg Danielle J , Clifton Vicki L , Ewing Adam D 
Published: February 2023

AbstractThe placenta is a temporary organ present during pregnancy that is responsible for coordinating all aspects of pregnancy between the mother and fetus. It has a distinct epigenetic, transcriptomic, and mutational landscape with low levels of methylation, high numbers of transcribed loci, and a high mutational burden relative to somatic tissues. We present this landscape through the application of nanopore sequencing technology to provide a more comprehensive picture of female placental genomics and methylomics along with integrated haplotype-resolved transcriptomic analyses across eight trios. Whole genome sequencing of trios allows robust phasing, permitting comprehensive genome-wide investigation of parent-of-origin methylation and transcription. This enhanced view facilitates identifications of many new differentially methylated regions (DMRs), both conserved and differing between individuals, as well as novel imprinted genes including ILDR2 and RASA1 which are potentially important for healthy placental and fetal development.
Complex waste stream valorisation through combined enzymatic hydrolysis and catabolic assimilation byPseudomonas putida
Authors: Alvarez-Gonzalez Guadalupe , Chacόn Micaela , Berepiki Adokiye , Fisher Karl , Gosalvitr Piya , Cuéllar-Franca Rosa , Dixon Neil 
Published: February 2023

AbstractThe use of biomass and organic waste as a feedstock for the production of fuels, chemicals and materials offers great potential to support the transition to net-zero and circular economic models. However, such renewable feedstocks are often complex, highly heterogeneous, and subject to geographical and seasonal variability, creating supply-chain inconsistency that impedes adoption. Towards addressing these challenges, the development of engineered microorganisms equipped with the ability to flexibly utilise complex, heterogenous substrate compositions for growth and bio-production would be greatly enabling. Here we show through careful strain selection and metabolic engineering, that Pseudomonas putida can be employed to permit efficient co-utilisation of highly heterogeneous substrate compositions derived from hydrolysed mixed municipal-like waste fractions, with remarkable resilience to compositional variability. To further illustrate this, one pot enzymatic pre-treatments of the five most abundant, hydrolytically labile, mixed waste feedstocks was performed – including food, plastic, organic, paper and cardboard, and textiles – for growth and synthesis of exemplar bio-products by engineered P. putida. Finally, prospective life cycle assessment and life cycle costing illustrated the climate change and economic advantage, respectively, of using the waste-derived feedstock for biomanufacturing compared to conventional waste treatment options. This work demonstrates the potential for expanding the treatment strategies for mixed municipal waste to include engineered microbial bio-production platforms that can accommodate variability in feedstock inputs to synthesise a range of chemical and material outputs.
Phosphoproteomics of cellular mechanosensing reveals NFATC4 as a regulator of myofibroblast activity
Authors: Mattner Laura F. , Zeng Zhen , Mayr Christoph H. , Ansari Meshal , Wei Xin , Asgharpour Sara , Wasik Anita A. , Kneidinger Nikolaus , Stoleriu Mircea-Gabriel , Behr Jürgen , Polleux Julien , Yildirim Ali Önder , Burgstaller Gerald , Mann Matthias , Schiller Herbert B. 
Published: February 2023

AbstractFeedback connections between tissue stiffness and cellular contractile forces can instruct cell identity and activity via a process referred to as mechanosensing. Specific phosphoproteome changes during mechanosensing are poorly characterized. In this work, we chart the global phosphoproteome dynamics of primary human lung fibroblasts sensing the stiffness of injury relevant fibronectin coated Poly(dimethylsiloxane) substrates. We discovered a key signaling threshold at a Young’s modulus of eight kPa stiffness, above which cells activated a large number of pathways including RhoA, CK2A1, PKA, AMPK, AKT1, and Hippo-YAP1/TAZ mediated signaling. Time-resolved phosphoproteomics of cell spreading on stiff substrates revealed the temporal dynamics of these stiffness-sensitive signaling pathways. ECM substrate stiffness above eight kPA induced fibroblast contractility, cytoskeletal rearrangements, ECM secretion, and a fibroblast to myofibroblast transition. Our data indicate that phosphorylation of the transcriptional regulator NFATC4 at S213/S217 enhances myofibroblast activity, which is the key hallmark of fibrotic diseases. NFATC4 knock down cells display reduced stiffness induced collagen secretion, cell contractility, nuclear deformation and invasion, suggesting NFATC4 as a novel target for antifibrotic therapy.SynopsisHow tissue stiffness regulates identity and activity of tissue fibroblasts is unclear. Mass spectrometry based analysis of tissue stiffness dependent phosphoproteome changes reveals how primary lung fibroblasts sense the mechanical properties of their environment and identifies NFATC4 as a novel regulator of the stiffness dependent transition of fibroblasts to ECM secreting myofibroblasts.Mass spectrometry analysis reveals the signaling landscape of fibroblast mechanosensingTime-resolved phosphoproteomic analysis of cell spreading on fibronectinNFATC4 regulates myofibroblast collagen secretion, cell contractility and invasion
Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B cell fate decisions and yields T cell-depleted lymphomas
Authors: Li Jie , Chin Christopher R. , Ying Hsia-Yuan , Meydan Cem , Teater Matthew R. , Xia Min , Farinha Pedro , Takata Katsuyoshi , Chu Chi-Shuen , Rivas Martin A. , Chadburn Amy , Steidl Christian , Scott David W. , Roeder Robert G. , Mason Christopher E. , Béguelin Wendy , Melnick Ari M. 
Published: February 2023

ABSTRACTMutations affecting enhancer chromatin regulatorsCREBBPandKMT2Dare highly co-occurrent in germinal center (GC)-derived lymphomas and other tumors, even though regulating similar pathways. Herein, we report that combined haploinsufficiency ofCrebbpandKmt2d(C+K) indeed accelerated lymphomagenesis. C+K haploinsufficiency induced GC hyperplasia by altering cell fate decisions, skewing B cells away from memory and plasma cell differentiation. C+K deficiency particularly impaired enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for immunoregulatory and differentiation genes. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Notably, C+K lymphomas in mice and humans manifested significantly reduced CD8+T-cell abundance. Hence, deficiency of C+K cooperatively induced an immune evasive phenotype due at least in part to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions.SIGNIFICANCEAlthough CREBBP and KMT2D have similar enhancer regulatory functions, they are paradoxically co-mutated in lymphomas. We show that their combined loss causes specific disruption of super-enhancers driving immune synapse genes. Importantly, this leads to reduction of CD8 cells in lymphomas, linking super-enhancer function to immune surveillance, with implications for immunotherapy resistance.
Hemodynamics in Patients with Aortic Coarctation: A Comparison ofin vivo4D-Flow MRI and FSI Simulation
Authors: Nair Priya J. , Pfaller Martin R. , Dual Seraina A. , Loecher Michael , McElhinney Doff B. , Ennis Daniel B. , Marsden Alison L. 
Published: February 2023

AbstractThe analysis of quantitative hemodynamics provides information for the diagnosis and treatment planning in patients with aortic coarctation (CoA). Patient-specific computational fluid dynamics (CFD) simulations reveal detailed hemodynamic information, but their agreement with the clinical standard 4D-Flow magnetic resonance imaging (MRI) needs to be characterized. This work directly comparesin vivoCFD fluid-structure interaction (FSI) simulations against 4D-Flow MRI in patients with CoA (N=5). 4D-Flow MRI-derived flow waveforms and cuff blood pressure measurements were used to tune the boundary conditions for the FSI simulations. Flow rates from 4D-Flow MRI and FSI were compared at cross-sections in the ascending aorta (AAo), CoA and descending aorta (DAo). Qualitative comparisons showed an overall agreement of flow patterns in the aorta between the two methods. TheR2values for the flow waveforms in the AAo, CoA, and DAo were 0.97, 0.84 and 0.81 respectively, representing a strong correlation between 4DFlow MRI measurements and FSI results. This work characterizes the use of patient-specific FSI simulations in quantifying and analyzing CoA hemodynamics to inform CoA treatment planning.
Lifelong molecular consequences of high Glucocorticoids exposure during development
Authors: Choi Min-Kyeung , Cook Alex , Mungikar Kanak , Eachus Helen , Tochwin Anna , Linke Matthias , Gerber Susanne , Ryu Soojin 
Published: February 2023

AbstractEarly life stress (ELS) is one of the strongest risk factors for developing psychiatric disorders in humans. As conserved key stress hormones of vertebrates, glucocorticoids (GCs) are thought to play an important role in mediating the effects of ELS exposure in shaping adult phenotypes. In this process, early exposure to high level of GCs may induce molecular changes that alter developmental trajectory of an animal and primes differential adult responses. However, comprehensive characterization of identities of molecules that are targeted by developmental GC exposure is currently lacking. In our study, we describe lifelong molecular consequences of high level of developmental GC exposure using an optogenetic zebrafish model. First, we developed a new double-hit stress model using zebrafish by combining exposure to a high endogenous GC level during development and acute adulthood stress exposure. Our results establish that similar to ELS-exposed humans and rodents, developmental GC exposed zebrafish model shows altered behavior and stress hypersensitivity in adulthood. Second, we generated time-series gene expression profiles of the brains in larvae, in adult, and upon stress exposure to identify molecular alterations induced by high developmental GC exposure at different developmental stages. Third, we identify a set of GC-primed genes that show altered expression upon acute stress exposure only in animals exposed to a high developmental GC. Interestingly, our datasets of GC primed genes are enriched in risk factors identified for human psychiatric disorders. Lastly, we identify potential epigenetic regulatory elements and associated post-transcriptional modifications following high developmental GC exposure. Thus, we present a translationally relevant zebrafish model for studying stress hypersensitivity and alteration of behavior induced by exposure to elevated GC levels during development. Our study provides comprehensive datasets delineating potential molecular targets underlying the impact of developmental high GC exposure on adult responses.
In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction
Authors: D’Alessandro Angelo , Nouraie S. Mehdi , Zhang Yingze , Cendali Francesca , Gamboni Fabia , Reisz Julie A. , Zhang Xu , Bartsch Kyle W. , Galbraith Matthew D. , Gordeuk Victor R. , Gladwin Mark T 
Published: February 2023

AbstractDespite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood cells (RBCs)in vivo. The current study evaluates the RBC metabolome of 587 subjects with sickle cell sickle cell disease (SCD) from the WALK-PHaSST clinical cohort. The set includes hemoglobin SS, hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events, and HbF related to hydroxyurea therapy. Here we explore the modulating effects of genotype, age, sex, severity of hemolysis, and hydroxyurea and transfusion therapy on sickle RBC metabolism. Data - collated in an online portal – show that the Hb SS genotype is associated with significant alterations of RBC acylcarnitines, pyruvate, sphingosine 1-phosphate, creatinine, kynurenine and urate metabolism. Surprisingly, the RBC metabolism of SC RBCs is dramatically different from SS, with all glycolytic intermediates significantly elevated in SS RBCs, with the exception of pyruvate. This result suggests a metabolic blockade at the ATP-generating phosphoenolpyruvate to pyruvate step of glycolysis, which is catalyzed by redox-sensitive pyruvate kinase. Increasing in vivo concentrations of HbA improved glycolytic flux and normalized the HbS erythrocyte metabolome. An unexpectedly limited metabolic effect of hydroxyurea and HbF was observed, possibly related to the modest induction of HbF in this cohort. The metabolic signature of HbS RBCs correlated with the degree of steady state hemolytic anemia, cardiovascular and renal dysfunction and mortality.Key pointsIn vivo dysregulation of RBC metabolism by HbS is evaluated by metabolic profiling of 587 patients with variable HbA, HbC and HbF levels;RBC acyl-carnitines, urate, pyruvate metabolism, S1P, kynurenine relate to hemolysis and cardiorenal dysfunction, respond to transfusion;
Threshold inclusion size triggers conversion of huntingtin to prion-like state that is reversible in newly born cells
Authors: Asgarkhani Leila , Khandakar Ibrahim , Pakan Rachel , Swayne Theresa C. , Emtage Lesley 
Published: February 2023

AbstractAggregation of mutant Huntingtin protein (mHtt) leads to neuronal cell death and human disease. We investigated the effect of inclusion formation on yeast cells. Previous work indicates that mHtt protein moves both in and out of inclusions, potentially undergoing refolding in the inclusion. However, the sustained influx of unfolded protein into an inclusion leads to a dramatic change from a phase-separated body to an irregular, less soluble form at a threshold inclusion size. Altered morphology was associated with a prion-like seeding that accelerated inclusion growth despite loss of soluble cytoplasmic protein. The structural change abolished exchange of material between the inclusion and the cytosol and resulted in early cell death. Affected cells continued to divide occasionally, giving rise to daughters with a similar phenotype. Most newly born cells were able to reverse the prion-like aggregation, restoring both soluble cytoplasmic protein and a normal inclusion structure.
Nuclear Myosin 1 regulates platelet activation and immune response in mice
Authors: Venit Tomas , Percipalle Piergiorgio 
Published: February 2023

AbstractCellular differentiation involves a complex series of events associated with change in cellular shape, function and proliferative capacity. This process is mostly regulated by specific expression of multiple genes which guide the cell through the differentiation process but also ensure proper function of terminal cell types. Over the last decade, the role of cellular metabolism on maintaining pluripotency of stem cells and subsequent differentiation is getting more attention as there is a direct link between the metabolic status of cells and their differentiation potential. We have recently shown that deletion of Nuclear Myosin 1 (NM1) leads to a molecular switch from oxidative phosphorylation to glycolysis and subsequent tumorigenesis in mice. In the present study, we explored the role of NM1 during differentiation of hematopoietic progenitor stem cells to terminal blood and bone marrow stromal cells. Remarkably, we found that NM1 deletion leads to differential expression of genes associated with platelet activation, immune system response and osteoclast differentiation with glycolysis-dependent processes being upregulated while oxidative phosphorylation-dependent processes being generally suppressed in bone marrow tissue isolated from NM1 knock-out mice. The study provides novel insights into the underlying mechanisms of hematopoietic differentiation and suggests that NM1 is a potential therapeutic target for blood-related disorders.
Coopetition configuration and performance of international joint ventures for high-speed rail projects
Authors: Niu Yanliang , Li Huimin , Luo Xiaowei , Deng Xiaopeng 
Published: February 2023

PurposeMembers in the international joint ventures (IJVs) for high-speed rail (HSR) projects usually engage in coopetition interactions to create common benefits (CB) and simultaneously safeguard private benefits (PB). Previous studies of coopetition and performance using variance-based methods usually ignore the combinational influence of diverse coopetition constructs on performance, which can be effectively compensated by adopting a configuration perspective. Therefore, this research aims to ascertain various combinations of three coopetition constructs (coopetition relationship, coopetition capability and coopetition strategy) that lead to high IJVs’ performance through a configuration approach.Design/methodology/approachFirst, the research framework of coopetition configuration was established, and the key constructs were operationalized, which were validated by expert interviews. Then the information on 12 HSR IJVs was collected and quantified through nine rounds of interviews and a questionnaire survey. Later, the fuzzy-set qualitative comparative analysis (fsQCA) was applied to explore what coopetition configurations benefit the CB or PB achievement.FindingsConfiguration results indicate that six coopetition configurations lead to CB outcome and seven configurations lead to PB outcome. Based on the results, coopetition contexts are divided into four categories: firm-based coopetition, project-based coopetition, firm-project-based coopetition and none-based coopetition. Then, a selection scheme for coopetition strategies in various contexts has been developed. The results also show that the core conditions mostly appear in the coopetition relationships and coopetition strategies dimensions, and the optimal coopetition strategies vary in different contexts.Originality/valueThis study enhances the theoretical understanding of coopetition in HSR IJVs and assists relative HSR industrialists, as well as the mega infrastructure project managers, in IJVs’ implementation. The configuration perspective of this paper also contributes to a systemic and holistic view of coopetition in HSR IJVs.
Green human resource management: the role of positive levers of control and environmental performance measures in managing performance
Authors: Baird Kevin , Tung Amy 
Published: February 2023

PurposeThis study focuses on the role of green human resource management (GHRM) practices through providing an empirical insight into the mediating role of the use of environmental performance measures (EPMs) in the association between Simons’ (1995) positive levers of control (beliefs and the interactive use of controls) with environmental and organisational performance.Design/methodology/approachA survey questionnaire was distributed to 577 chief financial officers within Australian manufacturing organisations who were randomly chosen from the OneSource online database.FindingsThe use of operational EPMs is found to mediate the association between the use of the positive levers of control with two of the four dimensions of environmental performance (resource usage and stakeholder interaction), and non-financial performance (through stakeholder interaction). In addition, the use of management EPMs mediates the association between the use of the positive levers of control with the regulatory compliance dimension of environmental performance. The findings highlight the importance of GHRM practices, in particular, the need for managers to focus on the positive levers of control and using operational EPMs and management EPMs to a greater extent.Originality/valueThe study contributes to the limited empirical research examining GHRM practices, highlighting the importance of EPMs and integrating such measures with internal control mechanisms, specifically beliefs and the interactive use of controls.