bluuebunny/crossref_metadata_2025_split huggingface dataset:
IPMK physically binds to the SWI/SNF complex and modulates BRG1 occupancy
Authors: Beon Jiyoon , Han Sungwook , Park Seung Eun , Hyun Kwangbeom , Lee Song-Yi , Rhee Hyun-Woo , Seo Jeong Kon , Kim Jaehoon , Kim Seyun , Lee Daeyoup 
Published: September 2021

ABSTRACTInositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events including transcriptional control. In yeasts, IPMK and its IP products were known to promote the activity of SWI/SNF chromatin remodeling complex, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct linkage between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screenings and in vivo/in vitro immunoprecipitations, here we demonstrated that IPMK physically associates with native mammalian SWI/SNF complexes by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner (including promoter-TSS) in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate common gene sets, validating a functional link between IPMK and SWI/SNF complex. Together, these findings establish an importance of IPMK in promoter targeting of the SWI/SNF complex, thereby contributing to SWI/SNF-meditated chromatin accessibility and transcription.
Mitochondrial translation occurs preferentially in the peri-nuclear mitochondrial network of cultured human cells
Authors: Albus Christin , Berlinguer-Palmini Rolando , Caroline Caroline , McFarlane Fiona , Savu Elisabeta-Ana , Lightowlers Robert N. , Chrzanowska-Lightowlers Zofia M. , Zorkau Matthew 
Published: September 2021

AbstractHuman mitochondria are highly dynamic organelles, fusing and budding to maintain reticular networks throughout many cell types. Although extending to the extremities of the cell, the majority of the network is concentrated around the nucleus in most of the commonly cultured cell lines. This organelle harbours its own genome, mtDNA, with a different gene content to the nucleus, but the expression of which is critical for maintaining oxidative phosphorylation. Recent advances in click chemistry have allowed us to visualise sites of mitochondrial protein synthesis in intact cultured cells. We show that the majority of translation occurs in the peri-nuclear region of the network. Further analysis reveals that whilst there is a slight peri-nuclear enrichment in the levels of mitoribosomal protein and mitochondrial rRNA, it is not sufficient to explain this substantial heterogeneity in distribution of translation. Finally, we also show that in contrast, a mitochondrial mRNA does not show such a distinct gradient in distribution. These data suggest that the relative lack of translation in the peripheral mitochondrial network is not due to an absence of mitoribosomes or an insufficient supply of the mt-mRNA transcripts.
Revealing spatio-temporal dynamics with long-term trypanosomatid live-cell imaging
Authors: Muniz Richard S. , Campbell Paul C. , Sladewski Thomas E. , Renner Lars D. , de Graffenried Christopher L. 
Published: September 2021

AbstractTrypanosoma brucei, the causative agent of human African trypanosomiasis, employs a flagellum for dissemination within the parasite’s mammalian and insect hosts.T. bruceicells are highly motile in culture and must be able to move in all three dimensions for reliable cell division. These characteristics have made long-term microscopic imaging of liveT. bruceicells challenging, which has limited our understanding of a variety of important cell-cycle events. To address this issue, we have devised an imaging approach that confines cells to small volumes that can be imaged continuously for up to 24 h. This system employs cast agarose microwells generated using a PDMS stamp that can be made with different dimensions to maximize cell viability and imaging quality. Using this approach, we have imaged individualT. bruceithrough multiple rounds of cell division with high spatial and temporal resolution. We have employed this method to study the differential rate ofT. bruceidaughter cell division and show that the approach is compatible with loss-of-function experiments such as small molecule inhibition and RNAi. We have also developed a strategy that employs in-well “sentinel” cells to monitor potential toxicity due to imaging. This live-cell imaging method will provide a novel avenue for studying a wide variety of cellular events in trypanosomatids that have previously been inaccessible.ImportanceTrypanosoma bruceicauses severe diseases that affect humans and livestock in Sub-Saharan Africa. Efficient strategies for manipulating theT. bruceigenome have provided a wealth of information about protein localization and function in diverse cellular processes. However, employing live-cell imaging for phenotypic analysis inT. bruceiremains a significant challenge because immobilization of this highly motile parasite rapidly leads to morphologic defects and cell death. While fixed-cell imaging can provide snapshots of cellular events, it cannot provide the direct causal link or precise timing of events that comes from watching a living cell change over time. Our strategy using agarose microwells now allows long-term live cellT. bruceiimaging with a simple apparatus that can be adapted for a wide range of experimental conditions.
Effect of sodium silicate on drinking water biofilm development
Authors: Munoz Sebastian , Trueman Benjamin F. , Li Bofu , Gagnon Graham A. 
Published: September 2021

AbstractSodium silicates have been studied for sequestration of iron, coagulation, and corrosion control, but their impact on biofilm formation has not been documented in detail. This study investigated the impact of sodium silicate corrosion control on biomass accumulation in drinking water systems in comparison to orthophosphate, a common corrosion inhibitor. Biofilm growth was measured by determining ATP concentrations, and the bacterial community was characterized using 16S ribosomal RNA (rRNA) sequencing. A pilot-scale study with cast-iron pipe loops, annular reactors (ARs), and polycarbonate coupons demonstrated significantly lower biofilm ATP concentrations in the sodium silicate-treated AR than the orthophosphate-treated AR when the water temperature exceeded 20°C. However, an elevated sodium silicate dose (48 mg L-1 of SiO2) disturbed and dispersed the biofilm formed inside the AR, resulting in elevated effluent ATP concentrations. Two separate experiments confirmed that biomass accumulation was higher in the presence of orthophosphate at high water temperatures (20°C) only. No significant differences were identified in biofilm ATP concentrations at lower water temperatures (below 20°C). Differences in bacterial communities between the orthophosphate- and sodium silicate-treated systems were not statistically significant, even though orthophosphate promoted higher biofilm growth. However, the genera Halomonas and Mycobacterium—which include opportunistic pathogens—were present at greater relative abundances in the orthophosphate-treated system compared to the sodium silicate system.Graphical abstractOrthophosphate promotes more biofilm growth in comparison to sodium silicates at water temperatures above 20°C.Water impact statementSodium silicates have been used in drinking water treatment for decades, both as sequestrants and as corrosion inhibitors. However, their impact on biofilm formation is poorly understood, and this risks drinking water quality. This study aims to further clarify the effects of corrosion inhibitors on biofilm development, including inhibitors that are not phosphate-based.
Gram-negative bacterial infection increases lung cancer metastasis via Toll-like receptor activation and increased cancer cell proliferation post-tumor adhesion
Authors: Rayes Roni F. , Wilson Marnie Goodwin , Gowing Stephen D. , Bourdeau France , Giannias Betty , Camilleri-Broet Sophie , Fiset Pierre-Olivier , Najmeh Sara , Spicer Jonathan D. , Ferri Lorenzo E. , Cools-Lartigue Jonathan J. 
Published: September 2021

AbstractBackgroundLung cancer is a leading cause of death partially due to high recurrence rates after surgical resection. Clinical data suggest that post-operative infections may increase the risk of recurrence. Our previous work indicated that increased adhesion of circulating tumors in the context of infection is partially responsible for this phenotype. However, cancer metastasis is a multi-step process, and it is likely that other events following tumor adhesion also play a role.MethodsIn vivo intrasplenic injection of murine lung cancer cells into wild type (WT) and Toll-like receptor 4 knockout (TLR4-/-) mice followed by cecal-ligation and puncture (CLP) as a model of post-operative infection or sham surgery were used. H&E staining and immunohistochemistry analysis of Ki67+ cells in the livers of those mice were performed. In vitro proliferation assays were performed on human lung cancer cells using combinations of TLR blockade.ResultsWe found a 5-fold increase in hepatic metastases in WT CLP mice compared to WT sham mice. TLR4-/- CLP mice had a significant decreased tumor burden compared to WT CLP mice. This indicated an important mechanistic role for the TLR4-initiated host response to gram negative infection post-tumor cell adhesion. By analyzing the livers of those mice, we observed an increase in proliferation of tumor micrometastases in vivo in WT CLP mice as compared to WT sham mice. Here again, CLP TLR4 -/- mice had significantly fewer replicating micrometastases than CLP WT mice. Indeed, we found that direct stimulation of lung cancer cells with heat-inactivated E.Coli resulted in increased proliferation of tumor growth in vitro. These effects were partially abrogated by tumor TLR4 blockade; combined TLR2, 4 and 5 blockades led to a more prominent decrease. Conditioned media from bronchoalveolar epithelial cells treated with lipopolysaccharide lead to increased lung cancer proliferation; these changes were reversed with TLR blockade, indicating that the host response to infection is TLR mediated.ConclusionsOverall, these results imply a more complex mechanistic role of post-operative infection in metastasis. From a clinical standpoint, this evidence strengthens the case for the use of TLR blockade as a potential therapeutic target in the prevention of metastasis.
VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis
Authors: Watson Sarah , LaVigne Collette , Xu Lin , Murchison Whitney , Surdez Didier , Rakheja Dinesh , Tirode Franck , Delattre Olivier , Amatruda James , Kendall Genevieve 
Published: September 2021

AbstractClinical sequencing efforts are uncovering numerous fusion genes in childhood solid tumors, yet few methods exist to delineate fusion-oncogenes from structural changes of unknown significance. One such novel fusion gene is VGLL2-NCOA2, which was described by us and others in patients with congenital sarcomas but has lacked functional validation. To determine if this fusion is an oncogene, and how it is driving disease, we developed a vertebrate zebrafish model and mouse allograft model of human VGLL2-NCOA2 driven sarcomagenesis. We found that VGLL2-NCOA2 is indeed an oncogene and is sufficient to generate mesenchymal tumors that recapitulate the human disease at the histological and transcriptional level. Zebrafish VGLL2-NCOA2 tumors display features of arrested skeletal muscle development, and a subset transcriptionally cluster with somitogenesis in developing embryos. By comparing tumor and embryonic gene expression signatures, we identified developmentally regulated targets that VGLL2-NCOA2 potentially leverages for tumorigenesis. These targets highlight the core biology of the disease and could represent therapeutic opportunities. Specifically, a RAS family GTPase, arf6/ARF6, involved in actin remodeling and rapid cycling of endocytic vesicles at the plasma membrane, is highly expressed during zebrafish somitogenesis and in VGLL2-NCOA2 tumors. In zebrafish tumors, arf6 protein is highly expressed and is absent from mature skeletal muscle. In VGLL2-NCOA2 mouse allograft models and patient tumors, ARF6 mRNA is overexpressed as compared to skeletal muscle or normal controls. More broadly, ARF6 is overexpressed in adult and pediatric sarcoma subtypes as compared to mature skeletal muscle. Overall, our cross-species comparative oncology approach provides evidence that VGLL2-NCOA2 is an oncogene which leverages developmental programs for tumorigenesis, and that one of these programs, the reactivation or persistence of arf6/ARF6, could represent a therapeutic opportunity.
Divergent encoding of active avoidance behavior in corticostriatal and corticolimbic projections
Authors: Kajs Bridget L. , Loewke Adrienne C. , Dorsch Jeffrey M. , Vinson Leah T. , Gunaydin Lisa A. 
Published: September 2021

ABSTRACTActive avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of projection-defined dmPFC subpopulations during active avoidance learning remains unexplored. Here we utilized fiber photometry to record from the dmPFC and its downstream projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in mice. We examined neural activity during conditioned stimulus (CS) presentations, active avoidance, and cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased activity during avoidance and decreased activity during cued freezing. Finally, dmPFC-DMS and dmPFC-BLA projections showed divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA showing decreased activity during active avoidance. Our results identify differential prefrontal encoding of active and passive coping behaviors in the same behavioral paradigm and demonstrate divergent encoding of active avoidance in projection-specific dmPFC subpopulations.
Hypoxia promotes a perinatal-like progenitor state in the adult murine epicardium
Authors: Sayed Angeliqua , Turoczi Szimonetta , Soares-da-Silva Francisca , Marazzi Giovanna , Hulot Jean-Sébastien , Sassoon David , Valente Mariana 
Published: September 2021

AbstractThe epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fate. We found that in vivo exposure of mice to physiological hypoxia induced adult epicardial cells to re-enter the cell cycle and to express a subset of developmental genes. Multiplex transcriptional profiling revealed a lineage relationship between epicardial cells and smooth muscle, stromal, and endothelial fates, and that physiological hypoxia promoted an endothelial cell fate. In vitro analyses of purified epicardial cells showed that cell growth and subsequent differentiation is dependent upon hypoxia, and that resident epicardial cells retain progenitor identity in the adult mammalian heart with self-renewal and multilineage differentiation potential. These results point to a source of progenitor cells in the adult heart that can promote heart revascularization, providing an invaluable in vitro model for further studies.
Cdc48 targets INQ-localized Mrc1 to facilitate recovery from replication stress
Authors: Colding Camilla , Autzen Jacob , Pfander Boris , Lisby Michael 
Published: September 2021

AbstractDNA replication stress is a source of genome instability and a replication checkpoint has evolved to enable fork stabilisation and completion of replication during stress. Mediator of the replication checkpoint 1 (Mrc1) is the primary mediator of this response in Saccharomyces cerevisiae. Mrc1 is partially sequestered in the intranuclear quality control compartment (INQ) upon methyl methanesulfonate (MMS)-induced replication stress. Here we show that Mrc1 re-localizes from the replication fork to INQ during replication stress. Sequestration of Mrc1 in INQ is facilitated by the Btn2 chaperone and the Cdc48 segregase is required to release Mrc1 from INQ during recovery from replication stress. Consistently, we show that Cdc48 colocalizes with Mrc1 in INQ and we find that Mrc1 is recognized by the Cdc48 cofactors Ufd1 and Otu1, which contribute to clearance of Mrc1 from INQ. Our findings suggest that INQ localization of Mrc1 and Cdc48 function to facilitate replication stress recovery by transiently sequestering the replication checkpoint mediator Mrc1 and explains our observation that Btn2 and Cdc48 are required for efficient replication restart following MMS-induced replication stress.
Blood flow modeling reveals improved collateral artery performance during mammalian heart regeneration
Authors: Anbazhakan Suhaas , Rios Coronado Pamela E. , Sy-Quia Ana Natalia L. , Seow Anson , Hands Aubrey M. , Zhao Mingming , Dong Melody L. , Pfaller Martin , Raftrey Brian C. , Cook Christopher K. , Bernstein Daniel , Nieman Koen , Pașca Anca M. , Marsden Alison L. , Red-Horse Kristy 
Published: September 2021

AbstractCollateral arteries are a vessel subtype that bridges two artery branches, forming a natural bypass that can deliver blood flow downstream of an occlusion. These bridges in the human heart are associated with better outcomes during coronary artery disease. We recently found that their rapid development in neonates supports heart regeneration, while the non-regenerative adult heart displays slow and minimal collateralization. Thus, inducing robust collateral artery networks could serve as viable treatment for cardiac ischemia, but reaching this goal requires more knowledge on their developmental mechanisms and functional capabilities. Here, we use whole-organ imaging and 3D computational fluid dynamics (CFD) modeling to identify the spatial architecture of and predict blood flow through collaterals in neonate and adult hearts. We found that neonate collaterals are more numerous, larger in diameter, and, even when similar in size/number, are predicted to more effectively re-perfuse an occluded coronary network when compared to adults. CFD analysis revealed that collaterals perform better in neonates because of decreased differential pressures along their coronary artery tree. Furthermore, testing of various collateral configurations indicated that larger, more proximal collaterals are more beneficial than many smaller ones, identifying a target architecture for therapeutic interventions. Morphometric analysis revealed how the coronary artery network expands during postnatal growth. Vessel diameters do not scale with cardiac muscle growth. Instead, the coronary tree expands solely by adding additional branches of a set length, a burst of which occurs during murine puberty. Finally, we compared mouse structural and functional data to human hearts. Surprisingly, fetal human hearts possessed a very large number of small, but mature, smooth muscle cell covered collaterals while angiogram data indicated adult patients with chronic coronary occlusions contained at least two. Comparing size ratios with modeled mouse data suggested low re-perfusion capabilities of the embryonic collaterals but higher functional benefits of those in diseased adults. Our unique interdisciplinary approach allowed us to quantify the functional significance of collateral arteries during heart regeneration and repair–a critical step towards realizing their therapeutic potential.
Migrant workers in precarious employment
Authors: Zhang Hui , Nardon Luciara , Sears Greg J. 
Published: September 2021

PurposeVarious forms of precarious employment create barriers to the integration and inclusion of migrant workers in receiving countries. The purpose of this paper is to review extant research in employment relations and management to identify key factors that contribute to migrant workers' precarious employment and highlight potential avenues for future research.Design/methodology/approachThe authors conducted a narrative literature review drawing on 38 academic journal articles published between 2005 and 2020.FindingsThe authors’ review suggests that macro- and meso-level factors contribute to the precarious employment conditions of migrant workers. However, there is a limited articulation of successful practices and potential solutions to reduce migrant work precarity and exclusion. The literature on migrant workers' precarious employment experience is primarily focused on low-skilled sector (e.g. agriculture, hospitality, domestic care) jobs. In addition, few studies have explored the role of worker characteristics, such as gender, class, ethnicity, race and migration status, in shaping the experience of migrant workers in precarious employment.Practical implicationsThe results of this research highlight the importance of engaging multilevel actors in addressing migrant employment precarity, including policymakers, employers and employment agencies.Originality/valueThis research contributes to a growing conversation of migrant employment precarity by highlighting the heterogeneity of migrant groups and calling for the use of intersectional lenses to understand migrant workers' experiences of precarious employment.