bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trans-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease
Authors: Yang Guoyi , Mason Amy M , Gill Dipender , Schooling C Mary , Burgess Stephen 
Published: September 2023

Structured abstractBackgroundPlasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation.ObjectivesWe tested the hypothesis that different plasma LDL-cholesterol lowering pathways have distinct effects on biliary cholesterol and thereby risk of gallstone disease.MethodsThis Mendelian randomization (MR) study used data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). First, drug-target MR and colocalization analyses were performed to investigate plasma LDL-cholesterol lowering therapies on gallstone disease. Second, clustered MR and pathway analyses were performed to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease.ResultsFor a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower risk of gallstone disease (odds ratio 0.72 [95% confidence interval 0.62, 0.83]) but PCSK9 inhibitors and mipomersen were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease, with evidence for ancestry-and sex-specific associations. Among variants predicting lower plasma LDL-cholesterol, those associated with lower risk of gallstone disease were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters.ConclusionsDifferent plasma LDL-cholesterol lowering pathways may have opposing effects on risk of gallstone disease. Notably, statins may reduce risk of gallstone disease.Condensed abstractWe hypothesized that different plasma LDL-cholesterol lowering pathways have distinct effects on risk of gallstone disease. We performed drug-target and clustered Mendelian randomization (MR) analyses, using data from the UK Biobank, FinnGen and Biobank Japan. Genetic mimics of statins were associated with lower risk of gallstone disease, but PCSK9 inhibitors and mipomersen were associated with higher risk. Clustered MR identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease. This genetic study supports that different plasma LDL-cholesterol lowering pathways have opposing effects on risk of gallstone disease and statins may reduce risk of gallstone disease.
Gut microbiota promotes enteroendocrine cell maturation and mitochondrial function
Authors: Alsudayri Alfahdah , Perelman Shane , Chura Annika , Brewer Melissa , McDevitt Madelyn , Drerup Catherine , Ye Lihua 
Published: September 2023

AbstractThe enteroendocrine cells (EECs) in the intestine are crucial for sensing ingested nutrients and regulating feeding behavior. The means by which gut microbiota regulates the nutrient-sensing EEC activity is unclear. Our transcriptomic analysis of the EECs from germ-free (GF) and conventionalized (CV) zebrafish revealed that commensal microbiota colonization significantly increased the expression of many genes that are associated with mitochondrial function. Using in vivo imaging and 3D automated cell tracking approach, we developed new methods to image and analyze the EECs’ cytoplasmic and mitochondrial calcium activity at cellular resolution in live zebrafish. Our data revealed that during the development, shortly after gut microbiota colonization, EECs briefly increased cytoplasm and mitochondrial Ca2+, a phenomenon we referred to as “EEC awakening”. Following the EEC awakening, cytoplasmic Ca2+levels but not mitochondrial Ca2+level in the EECs decreased, resulting in a consistent increase in the mitochondrial-to-cytoplasmic Ca2+ratio. The increased mitochondrial-to-cytoplasmic Ca2+ratio is associated with the EEC maturation process. In immature EECs, we further discovered that their mitochondria are evenly distributed in the cytoplasm. When EECs mature, their mitochondria are highly localized in the basal lateral membrane where EEC vesicle secretion occurs. Furthermore, CV EECs, but not GF EECs, exhibit spontaneous low-amplitude calcium fluctuation. The mitochondrial-to-cytoplasm Ca2+ratio is significantly higher in CV EECs. When stimulating the CV zebrafish with nutrients like fatty acids, nutrient stimulants increase cytoplasmic Ca2+in a subset of EECs and promote a sustained mitochondrial Ca2+increase. However, the nutrient induced EEC mitochondrial activation is nearly abolished in GF zebrafish. Together, our study reveals that commensal microbiota are critical in supporting EEC mitochondrial function and maturation. Selectively manipulating gut microbial signals to alter EEC mitochondrial function will provide new opportunities to change gut-brain nutrient sensing efficiency and feeding behavior.
Systematic perturbations of SETD2, NSD1, NSD2, NSD3 and ASH1L reveals their distinct contributions to H3K36 methylation
Authors: Shipman Gerry A. , Padilla Reinnier , Horth Cynthia , Hu Bo , Bareke Eric , Vitorino Francisca N. , Gongora Joanna M. , Garcia Benjamin A. , Lu Chao , Majewski Jacek 
Published: September 2023

AbstractBackgroundMethylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development, disease, and cancer, how the molecular agents collectively shape the H3K36me landscape is unclear.ResultsWe use a mouse mesenchymal stem cell model to perturb the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and is predominantly deposited at intergenic regions by NSD1, and partly by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 deposits most H3K36me3, it also deposits H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting other H3K36 methyltransferases (K36MTs) prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks on active promoters and enhancers. Meanwhile, the activity of ASH1L is restricted to the regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor.ConclusionsWithin genes, SETD2 deposits both H3K36me2/3, while the other K36MTs are capable of depositing H3K36me1/2 independently of SETD2 activity. For the deposition of H3K36me1/2, we find a hierarchy of K36MT activities where NSD1>NSD2>NSD3>ASH1L. While NSD1 and NSD2 are responsible for most genome-wide propagation of H3K36me2, the activities of NSD3 and ASH1L are confined to active regulatory elements.
Bacteria Contribute Exopolysaccharides to an Algal-Bacterial Joint Extracellular Matrix
Authors: Lipsman Valeria , Shlakhter Olesia , Rocha Jorge , Segev Einat 
Published: September 2023

AbstractMarine ecosystems are influenced by phytoplankton aggregation, which affects processes like marine snow formation and harmful events such as marine mucilage outbreaks. Phytoplankton secrete exopolymers, creating an extracellular matrix (ECM) that promotes particle aggregation. This ECM attracts heterotrophic bacteria, providing a nutrient-rich and protective environment. In terrestrial environments, bacterial colonization near primary producers relies on attachment and the formation of multidimensional structures like biofilms. Bacteria were observed attaching and aggregating within algal-derived exopolymers, but it is unclear if bacteria produce an ECM that contributes to this colonization. This study, usingEmiliania huxleyialgae andPhaeobacter inhibensbacteria in an environmentally relevant model system, reveals a shared algal-bacterial ECM scaffold that promotes algal-bacterial aggregation. Algal exudates play a pivotal role in promoting bacterial colonization, stimulating bacterial exopolysaccharide (EPS) production, and facilitating a joint ECM formation. A bacterial biosynthetic pathway responsible for producing a succinoglycan-like compound contributing to bacterial ECM formation is identified. Genes from this pathway show increased expression in algal-rich environments. These findings highlight the underestimated role of bacteria in aggregate-mediated processes in marine environments, offering insights into algal-bacterial interactions and ECM formation, with implications for understanding and managing disturbances like marine mucilage events.
Vision plays a calibrating role in discriminating threat-related vocal emotions
Authors: Falagiarda Federica , Occelli Valeria , Collignon Olivier 
Published: September 2023

AbstractThe ability to reliably discriminate vocal expressions of emotion is crucial to engage in successful social interactions. This process is arguably more crucial for blind individuals, since they cannot extract social information from faces and bodies, and therefore chiefly rely on voices to infer the emotional state of their interlocutors. Blind have demonstrated superior abilities in several aspects of auditory perception, but research on their ability to discriminate vocal features is still scarce and has provided unclear results. Here, we used a gating psychophysical paradigm to test whether early blind people would differ from individually matched sighted controls at the recognition of emotional expressions. Surprisingly, blind people showed lower performance than controls in discriminating specific vocal emotions. We presented segments of non-linguistic emotional vocalizations of increasing duration (100 to 400ms), portraying five basic emotions (fear, happy, sad, disgust, angry), and we asked our participants for an explicit emotion categorization task. We then calculated sensitivity indices and confusion patterns of their performance. We observed better performance of the sighted group in the discrimination of angry and fearful expression, with no between-group differences for other emotions. This result supports the view that vision plays a calibrating role for specific threat-related emotions specifically.
Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains
Authors: Malik Nauman , Miah Mohi-Uddin , Galgani Alessandro , McAleese Kirsty , Walker Lauren , LeBeau Fiona E. , Attems Johannes , Outeiro Tiago F. , Thomas Alan , Koss David J. 
Published: September 2023

AbstractThe amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques.
Enhancing plant photosynthesis through activating cells deficient in photosynthetic apparatus
Authors: Miao Fenfen , Zhao Yong-yao , Lyu Mingju , Shi Bihai , Liu Fusang , Zhu Xin-Guang 
Published: September 2023

AbstractMuch efforts have been devoted to identify options to improve plant photosynthetic capacity. Most of these engineering focuses more on enhancing photosynthetic capacity of the mesophyll cells. In this study, we specifically expressedCYTOKININRESPONSIVE GATA FACTOR 1 (CGA1)in the vascular bundle and bundle sheath cells (ProGLDPA: CGA1) which generally have low photosynthetic capacity. The introduction ofCGA1resulted in increased numbers and sizes of chloroplasts in both bundle sheath and vascular bundle, without noticeable difference in these properties in mesophylls. Additionally, compared with wild type (WT), transgenic lines showed enhanced development of mitochondria and peroxisomes. Leaf photosynthetic rates in these transgenic lines were higher than those in WT, especially under high light. Furthermore, the amount of RuBisCO, Vcmax, Jmax, and the number of starch granules were also significantly increased in the transgenic lines, which led to about 20% increase in biomass. Remarkably, the CO2compensation point ofProGLDPA: CGA1decreased compared with WT, resembling the characteristics of proto-Kranz during C4evolution. All these results indicated that enhancing photosynthetic properties of vascular bundle and bundle sheath cell is an effective approach to improve leaf photosynthesis, and highlighted that utilization of the cell lacking photosynthetic capacity is a promising way to improve plant photosynthesis for greater capacity.
Contact-FP: a dimerization-dependent fluorescent protein toolkit for visualizing membrane contact site dynamics
Authors: Miner Gregory E. , Smith Sidney Y. , Showalter Wendy K. , So Christina M. , Ragusa Joey V. , Powers Alex E. , Zanellati Maria Clara , Hsu Chih-Hsuan , Marchan Michelle F. , Cohen Sarah 
Published: September 2023

AbstractMembrane contact sites (MCSs) are sites of close apposition between two organelles used to exchange ions, lipids, and information. Cells respond to changing environmental or developmental conditions by modulating the number, extent, or duration of MCSs. Because of their small size and dynamic nature, tools to study the dynamics of MCSs in live cells have been limited. Dimerization-dependent fluorescent proteins (ddFPs) targeted to organelle membranes are an ideal tool for studying MCS dynamics because they reversibly interact to fluoresce specifically at the interface between two organelles. Here, we build on previous work using ddFPs as sensors to visualize the morphology and dynamics of MCSs. We engineered a suite of ddFPs called Contact-FP that targets ddFP monomers to lipid droplets (LDs), the endoplasmic reticulum (ER), mitochondria, peroxisomes, lysosomes, plasma membrane, caveolae, and the cytoplasm. We show that these probes correctly localize to their target organelles. Using LDs as a test case, we demonstrate that Contact-FP pairs specifically localize to the interface between two target organelles. Titration of LD-mitochondria ddFPs revealed that these sensors can be used at high concentrations to drive MCSs or can be titrated down to minimally perturb and visualize endogenous MCSs. We show that Contact-FP probes can be used to: (1) visualize LD-mitochondria MCS dynamics, (2) observe changes in LD-mitochondria MCS dynamics upon overexpression of PLIN5, a known LD-mitochondrial tether, and (3) visualize two MCSs that share one organelle simultaneously (e.g., LD-mitochondria and LD-ER MCSs). Contact-FP probes can be optimized to visualize MCSs between any pair of organelles represented in the toolkit.
Transcriptome analysis reveals temporally regulated genetic networks duringDrosophilaborder cell collective migration
Authors: Burghardt Emily , Rakijas Jessica , Tyagi Antariksh , Majumder Pralay , Olson Bradley J.S.C. , McDonald Jocelyn A. 
Published: September 2023

AbstractBackgroundCollective cell migration underlies many essential processes, including sculpting organs during embryogenesis, wound healing in the adult, and metastasis of cancer cells. At mid-oogenesis,Drosophilaborder cells undergo collective migration. Border cells round up into a small group, detach from the epithelium, and migrate – at first rapidly through the surrounding tissue, then slower, with the cluster rotating several times before stopping at the oocyte. While specific genes that promote cell signaling, polarization of the cluster, formation of protrusions, and cell-cell adhesion are known to regulate border cell migration, there may be additional genes that promote these distinct dynamic phases of border cell migration. Therefore, we sought to identify genes whose expression patterns changed during border cell migration.ResultsWe performed RNA-sequencing on border cells isolated at pre-, mid-, and late-migration stages. We report that 1,729 transcripts, in nine co-expression gene clusters, are temporally and differentially expressed across the three migration stages. Gene ontology analyses and constructed protein-protein interaction networks identified genes expected to function in collective migration, such as regulators of the cytoskeleton, adhesion, and tissue morphogenesis, but also a notable enrichment of genes involved in immune signaling, ribosome biogenesis, and stress responses. Finally, we validated thein vivoexpression and function of a subset of identified genes in border cells.ConclusionsOverall, our results identified differentially and temporally expressed genetic networks that may facilitate the efficient development and migration of border cells. The genes identified here represent a wealth of new candidates to investigate the molecular nature of dynamic collective cell migrations in developing tissues.
The polarity protein Yurt associates with the plasma membrane via basic and hydrophobic motifs embedded in its FERM domain
Authors: Gamblin Clémence L. , Alende Charles , Corriveau François , Jetté Alexandra , Parent-Prévost Frédérique , Biehler Cornélia , Majeau Nathalie , Laurin Mélanie , Laprise Patrick 
Published: September 2023

AbstractThe subcellular distribution of the polarity protein Yrt is subjected to a spatio-temporal regulation inD. melanogasterembryonic epithelia. After cellularization, Yrt binds to the lateral membrane of ectodermal cells and maintains this localization throughout embryogenesis. During terminal differentiation of the epidermis, Yrt accumulates to septate junctions and is also recruited to the apical domain. While the mechanisms through which Yrt associates with septate junctions and the apical domain have been deciphered, how Yrt binds to the lateral membrane remains as an outstanding puzzle. Here, we show that the FERM domain of Yrt is necessary and sufficient for membrane localization. Our data also establish that the FERM domain of Yrt directly binds negatively charged phospholipids. Moreover, we demonstrate that positively charged amino acid motifs embedded within the FERM domain mediates Yrt membrane association. Finally, we provide evidence suggesting that Yrt membrane association is functionally important. Overall, our study highlights the molecular basis of how Yrt associates with the lateral membrane during the developmental time window where it is required for segregation of lateral and apical domains.Summary statementThis study reveals how Yurt associates with membrane lipids in epithelial cells, thereby further illuminating the mechanisms sustaining cell polarization and tissue morphogenesis.
Innovation-oriented supply chain integration for structural flexibility and strategic business performance
Authors: Asare Benjamin , Nuertey Dorcas , Poku Emmanuel 
Published: September 2023

PurposeInnovation has become extremely important, especially concerning manufacturing firms, as it is known to foster robust and healthy competition. The study aims to examine the effect of innovation orientation and supply chain integration on structural flexibility and strategic business performance.Design/methodology/approachUsing the quantitative approach, 315 questionnaires were distributed to manufacturing firms in three cities (Accra, Kumasi and Takoradi) in Ghana out of which 305 usable responses were retrieved. The partial least square structural equation modeling technique and the statistical package for social sciences software version 27 were used for the data analysis.FindingsThe findings showed that supply chain integration and innovation orientation have a strong beneficial association. A substantial favorable association between structural flexibility and supply chain integration was found in the study once more. What is more, the research revealed a strong positive relationship between supply chain integration and strategic business performance. Furthermore, the study found a strong relation between innovation orientation and strategic business performance.Originality/valueThe research paper adds to the body of knowledge by examining how supply chain integration affects the relationship between innovation orientation, structural flexibility and strategic business performance.
The global chameleons: the impact of early life international exposure on the career capital of adult third culture kids
Authors: Caselius Mireka , Suutari Vesa 
Published: September 2023

PurposeThe purpose of the present study is to explore the effects of early life international exposure on the career capital (CC) of adult third culture kids (ATCKs).Design/methodology/approachThe study adopts a qualitative research design based on 34 semi-structured interviews with ATCKs who have had international exposure in their childhood as members of an expatriate family.FindingsThe results show that a globally mobile childhood has extensive long-term impacts on ATCKs' CC in the areas of knowing-why, knowing-how and knowing-whom. Additionally, their early international experience also had several negative impacts across these aspects of CC.Originality/valueThis paper provides a novel understanding of the long-term impacts of early life international exposure on ATCKs' CC, and this paper is the first study to use the CC framework among an ATCK population.