bluuebunny/crossref_metadata_2025_split huggingface dataset:
AI-driven Classification of Cancer-Associated Fibroblasts Using Morphodynamic and Motile Features
Authors: Kang Minwoo , Min Chanhong , Somayadineshraj D. , Shin Jennifer H. 
Published: February 2024

AbstractThe heterogeneous natures of cancer-associated fibroblasts (CAFs) play critical roles in cancer progression, with some promoting tumor growth while others inhibit it. To utilize CAFs as a target for cancer treatment, issues with subtypes of CAFs must be resolved such that specific pro-tumorigenic subtypes can be suppressed or reprogrammed into anti-tumorigenic ones. Currently, single-cell RNA sequencing (scRNA-Seq) is a prevalent strategy for classifying CAFs, primarily based on their biomolecular features.Alternatively, this study proposes assessing CAFs on a larger biophysical scale, focusing on cell morphological and motile features. Since these features are downstream effectors of differential gene expression combinations, they can serve as holistic descriptors for CAFs, offering a complementary strategy for classifying CAF subtypes. Here, we propose an artificial intelligence (AI) classification framework to comprehensively characterize CAF subtypes using morphodynamic and motile features. This framework extracts these features from label-free live-cell imaging data of CAFs employing advanced deep learning and machine learning algorithms.The results of this study highlight the ability of morphodynamic and motile features to complement biomolecular features in accurately reflecting CAF subtype characteristics. In essence, our AI-based classification framework not only provides valuable insights into CAF biology but also introduces a novel approach for comprehensively describing and targeting heterogeneous CAF subtypes based on biophysical features.
Extracellular electron transfer genes expressed by candidate flocking bacteria in cable bacteria sediment
Authors: Lustermans Jamie JM , Sereika Mantas , Burdorf Laurine DW , Albertsen Mads , Schramm Andreas , Marshall Ian PG 
Published: February 2024

AbstractCable bacteria, filamentous sulfide oxidizers that live in sediments, are at times associated with large flocks of swimming bacteria. It has been proposed that these flocks of bacteria transport electrons extracellularly to cable bacteria via an electron shuttle intermediate, but the identity and activity of these bacteria in freshwater sediment remains mostly uninvestigated. We coupled metagenomics and metatranscriptomics to 16S rRNA amplicon-based correlations with cable bacteria from two time series experiments up to 155 days. We identified bacteria expressing genes for extracellular electron transfer and motility, including synthesis genes for potential extracellular electron shuttles: phenazines and flavins. Of the 85 high quality MAGs (Metagenome Assembled Genomes >90% complete and <5% contaminated), 56 had genes encoding flagellar proteins, and of these 22 had genes encoding extracellular electron transport proteins. The candidate flockers constituted 21.4% of all MAGs and 42.1% of the proposed flocking bacteria expressed extracellular electron transfer genes. The proposed flockers belonged to a large variety of taxonomic groups: 18 genera spread across 9 phyla. Our data suggest that electric relationships in freshwater sediments between cable bacteria and other microbes likely help to generate and/or sustain cryptic element cycling and ‘deep oxygen breathing’, affecting more element cycles than sulfur, like metal– and in particular iron– and carbon cycles.
Red blood cell passage through deformable interendothelial slits in the spleen: Insights into splenic filtration and hemodynamics
Authors: Li Guansheng , Li He , Ndou Papa Alioune , Franco Mélanie , Qiang Yuhao , Li Xuejin , Buffet Pierre A. , Dao Ming , Karniadakis George Em 
Published: February 2024

AbstractThe spleen constantly clears altered red blood cells (RBCs) from the circulation, tuning the balance between RBC formation (erythropoiesis) and removal. The retention and elimination of RBCs occur predominantly in the open circulation of the spleen, where RBCs must cross submicron-wide inter-endothelial slits (IES). Several experimental and computational studies have illustrated the role of IES in filtrating the biomechanically and morphologically altered RBCs based on a rigid wall assumption. However, these studies also reported that when the size of IES is close to the lower end of clinically observed sizes (less than 0.5μm), an unphysiologically large pressure difference across the IES is required to drive the passage of normal RBCs, sparking debates on the feasibility of the rigid wall assumption. In this work, we perform a computational investigation based on dissipative particle dynamics (DPD) to explore the impact of the deformability of IES on the filtration function of the spleen. We simulate two deformable IES models, namely the passive model and the active model. In the passive model, we implement the worm-like string model to depict the IES’s deformation as it interacts with blood plasma and allows RBC to traverse. In contrast, the active model involved regulating the IES deformation based on the local pressure surrounding the slit. To demonstrate the validity of the deformable model, we simulate the filtration of RBCs with varied size and stiffness by IES under three scenarios: 1) a single RBC traversing a single slit; 2) a suspension of RBCs traversing an array of slits, mimickingin vitrospleen-on-a-chip experiments; 3) RBC suspension passing through the 3D spleen filtration unit known as ‘the splenon’. Our simulation results of RBC passing through a single slit show that the deformable IES model offers more accurate predictions of the critical cell surface area to volume ratio that dictate the removal of aged RBCs from circulation compared to prior rigid-wall models. Our biophysical models of the spleen-on-a-chip indicates a hierarchy of filtration function stringency: rigid model > passive model > active model, providing a possible explanation of why the spleen-on-a-chip could overestimate the filtration function of IES. We also illustrate that the biophysical model of ‘the splenon’ enables us to replicate theex vivoexperiments involving spleen filtration of malaria-infected RBCs. Taken together, our simulation findings indicate that the deformable IES model could serve as a mesoscopic representation of spleen filtration function closer to physiological reality, addressing questions beyond the scope of current experimental and computational models and enhancing our understanding of the fundamental flow dynamics and mechanical clearance processes within in the human spleen.
Avian influenza virus circulation and immunity in a wild urban duck population prior to and during a highly pathogenic H5N1 outbreak
Authors: Wight Jordan , Rahman Ishraq , Wallace Hannah L. , Cunningham Joshua T. , Roul Sheena , Robertson Gregory J. , Russell Rodney S. , Xu Wanhong , Zhmendak Dmytro , Alkie Tamiru N. , Berhane Yohannes , Hargan Kathryn E. , Lang Andrew S. 
Published: February 2024

AbstractHighly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses were first detected in St. John’s, Newfoundland, Canada in late 2021, with the virus rapidly spreading across the western hemisphere over the next year. To investigate the patterns of avian influenza virus (AIV) infection and immune responses subsequent to the arrival of H5N1, we sampled the wild urban duck population in St. John’s for a period of 16 months after the start of the outbreak and compared these findings to archived samples. Antibody seroprevalence was relatively stable before the outbreak (2011-2014) at 27.6% and 3.9% for anti-AIV (i.e., NP) and H5-specific antibodies, respectively. During the winter of 2022, AIV-NP and H5-specific antibody seroprevalence both reached 100%, signifying a population-wide infection event. As expected, population-level immunity waned over time, and we found that ducks were seropositive for anti- AIV-NP antibodies for around twice as long as for H5-specific antibodies. The population was H5 seronegative to the latter approximately six months after the initial H5N1 incursion. In late February 2023, H5N1 clade 2.3.4.4b viruses were again detected in the duck population as a result of a second incursion into Newfoundland from Eurasia, which resulted in a second population-wide infection event. We observed a clear relationship of increasing antibody levels with decreasing viral RNA loads that allowed for interpretation of the course of infection and immune response in infected individuals and applied these findings to two cases of resampled ducks to infer infection history. Our study highlights the significance of applying both AIV surveillance and seroprevalence monitoring to provide a better understanding of AIV dynamics in wild populations, which may be crucial following the arrival of 2.3.4.4b H5Nx subtypes to assess the threats they pose to both wild and domestic animals, and to humans.
Characterizing the skeletal muscle immune microenvironment for sarcopenia using transcriptome analysis and histological validation
Authors: Shen Linhui , Zong Yuan , Zhao Jiawen , Yang Yi , Li Lei , Li Ning , Gao Yiming , Xie Xianfei , Bao Qiyuan , Jiang Liting , Hu Weiguo 
Published: February 2024

AbstractSarcopenia is a condition characterized by the age-related loss of skeletal muscle mass and function. The pathogenesis of the disease is influenced by chronic low-grade inflammation. However, the specific changes in the immune landscape changes of sarcopenic muscle are not yet fully understood. To gain insights into the immune cell composition and interactions, we combined single-nuclei RNA sequencing data, bulk RNA sequencing datasets, and comprehensive bioinformatic analyses on skeletal muscle samples from young, aged, and sarcopenic individuals. Histological staining was then performed on skeletal muscles to validate the distribution of immune cells in clinical samples. Overall, we analyzed the transcriptomes of 101,862 single nuclei, revealing a total of 10 major cell types and 6 subclusters of immune cell types within the human skeletal muscle tissues. Among the immune cells, macrophages constituted the largest immune fraction. A specific marker gene LYVE1 for skeletal muscle macrophages was further identified. Cellular subclasses included four distinct groups of resident macrophages, which play a different role in physiological or non-physiological conditions. Using bulk RNA sequencing data, we identified strong enrichment for a macrophage-rich inflammation in sarcopenia. Our findings demonstrate age-related changes in the composition and cross-talk of immune cells, which contribute to chronic inflammation. Furthermore, macrophages emerge as a potential therapeutic target, thus advancing our understanding of the pathogenesis of sarcopenia.
Arg18 substitutions reveal the capacity of the HIV-1 capsid protein for non-fullerene assembly
Authors: Schirra Randall T. , Santos Nayara F. B. dos , Ganser-Pornillos Barbie K. , Pornillos Owen 
Published: February 2024

AbstractIn the fullerene cone HIV-1 capsid, the central channels of the hexameric and pentameric capsomers each contain a ring of arginine (Arg18) residues that perform essential roles in capsid assembly and function. In both the hexamer and pentamer, the Arg18 rings coordinate inositol hexakisphosphate, an assembly and stability factor for the capsid. Previously, it was shown that amino-acid substitutions of Arg18 can promote pentamer incorporation into capsid-like particles (CLPs) that spontaneously assemble in vitro under high salt conditions. Here, we show that these Arg18 mutant CLPs contain a non-canonical pentamer conformation and distinct lattice characteristics that do not follow the fullerene geometry of retroviral capsids. The Arg18 mutant pentamers resemble the hexamer in intra-oligomeric contacts, and forms a unique tetramer-of-pentamers that allows for incorporation of an octahedral vertex with a cross-shaped opening in the hexagonal capsid lattice. Our findings highlight an unexpected degree of structural plasticity in HIV-1 capsid assembly.
PLK1-Mediated Phosphorylation Cascade Activates the Mis18 Complex to Ensure Centromere Inheritance
Authors: Parashara Pragya , Medina-Pritchard Bethan , Abad Maria Alba , Sotelo-Parrilla Paula , Thamkachy Reshma , Grundei David , Zou Juan , Das Vimal , Yan Zhaoyue , Kelly David A. , McHugh Toni , Rappsilber Juri , Jeyaprakash A. Arockia 
Published: February 2024

AbstractAccurate chromosome segregation requires the attachment of spindle microtubules to centromeres, which are epigenetically defined by the enrichment of CENP-A nucleosomes. During DNA replication, existing CENP-A nucleosomes undergo dilution as they get redistributed among the two DNA strands. To preserve centromere identity, CENP-A levels must be restored in a cell-cycle controlled manner orchestrated by the Mis18 complex. Here we provide a comprehensive mechanistic basis for PLK1-mediated licensing of CENP-A loading. We demonstrate that PLK1 interacts with Mis18α and Mis18BP1 subunits of the Mis18 complex by recognising self-primed phosphorylations of Mis18α (S54) and Mis18BP1 (T78 and S93) through its Polo-box binding domain. Disrupting these PLK1 phosphorylations perturbed the centromere recruitment of HJURP and new CENP-A loading. Biochemical and functional analyses show that phosphorylation of Mis18α and subsequent PLK1 binding is required to activate the Mis18α/β complex for robust Mis18α/β-HJURP interaction. Thus, our study reveals key molecular events underpinning the licensing role of PLK1 in ensuring accurate centromere inheritance.One-Sentence SummaryPLK1 phosphorylation cascade licenses CENP-A loading by facilitating HJURP centromere recruitment via Mis18α/β activation.
Detecting phenotype-specific tumor microenvironment by merging bulk and single cell expression data to spatial transcriptomics
Authors: Zhu Wencan , Tang Hui , Zeng Tao 
Published: February 2024

AbstractIn addressing the limitations of current multimodal analysis methods that largely ignore phenotypic data, leading to a lack of biological interpretability at the phenotypic level, we developed the Single-Cell and Tissue Phenotype prediction (SCTP), a deep-learning-based multimodal fusion framework. SCTP can simultaneously detect phenotype-specific cells and characterize the tumor microenvironment of pathological tissue by integrating essential information from the bulk sample phenotype, the composition of individual cells, and the spatial distribution of cells. Upon evaluating SCTP’s efficiency and robustness against traditional analytical methods, we developed a specialized model, SCTP-CRC, tailored for colorectal cancer (CRC). This model integrates RNA-seq, scRNA-seq, and spatial transcriptomic data to offer a better understanding of CRC. SCTP-CRC has proven effective in accurately identifying tumor-associated cells and clusters and continuously defines boundary regions as well as the spatial organization of the entire tumor microenvironment. This enables a detailed depiction of cellular communication networks, capturing the dynamic shifts that occur during tumor progression. Furthermore, SCTP-CRC extends to the identification of abnormal sub-regions in the early state of CRC and uncovers potential early-warning signature genes such as MMP2, IGKC, and PIGR. These biomarkers are not only important in recognizing the onset of CRC but may also play a crucial role in differentiating between CRC-derived liver metastases and primary liver tumors. SCTP stands as a transformative framework, offering a deeper understanding of the tumor microenvironment through its ability to quantitatively characterize cancer’s fundamental traits and dissect the intricate molecular and cellular interactions at play. This comprehensive insight supports the early diagnosis and enables personalized treatment strategies, marking a significant stride toward improving patient outcomes and tailoring therapies to individual disease profiles.
A series of spontaneously blinking dyes for super-resolution microscopy
Authors: Holland Katie L. , Plutkis Sarah E. , Daugird Timothy A. , Sau Abhishek , Grimm Jonathan B. , English Brian P. , Zheng Qinsi , Dave Sandeep , Rahman Fariha , Xie Liangqi , Dong Peng , Tkachuk Ariana N. , Brown Timothy A. , Singer Robert H. , Liu Zhe , Galbraith Catherine G. , Musser Siegfried M. , Legant Wesley R. , Lavis Luke D. 
Published: February 2024

ABSTRACTSpontaneously blinking fluorophores permit the detection and localization of individual molecules without reducing buffers or caging groups, thus simplifying single-molecule localization microscopy (SMLM). The intrinsic blinking properties of such dyes are dictated by molecular structure and modulated by environment, which can limit utility. We report a series of tuned spontaneously blinking dyes with duty cycles that span two orders of magnitude, allowing facile SMLM in cells and dense biomolecular structures.
Resolvin D2/GPR18 signaling enhances monocytic myeloid-derived suppressor cell function to mitigate abdominal aortic aneurysm formation
Authors: Bellotti Paolo , Ladd Zachary , Leroy Victoria , Su Gang , Sharma Shiven , Hartman Joseph B. , Krebs Jonathan , Viscardi Chelsea , Maile Robert , Moldawer Lyle L. , Efron Phillip , Sharma Ashish K. , Upchurch Gilbert R. 
Published: February 2024

ABSTRACTAbdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized proresolving lipid mediators, via G-protein coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption and increased smooth muscle cell α-actin expression as well as increased TGF-β2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-β2 and IL-10 secretions that mitigated smooth muscle cell activation in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling via this intercellular crosstalk. Collectively, this study demonstrates RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, and activates GPR18-dependent signaling to enhance TGF-β2 and IL-10 secretion that contributes to resolution of aortic inflammation and remodeling during AAA formation.
Criticalcis-parameters influence STructure Assisted RNA Translation (START) initiation on non-AUG codons in eukaryotes
Authors: Tidu Antonin , Alghoul Fatima , Despons Laurence , Eriani Gilbert , Martin Franck 
Published: February 2024

ABSTRACTIn eukaryotes, translation initiation is a highly regulated process, which combinescis-regulatory sequences located on the messenger RNA along withtrans-acting factors like eukaryotic initiation factors (eIF). One critical step of translation initiation is the start codon recognition by the scanning 43S particle, which leads to ribosome assembly and protein synthesis. In this study, we investigated the involvement of secondary structures downstream the initiation codon in the so-called START (Structure-Assisted RNA translation) mechanism on AUG and non-AUG translation initiation. The results demonstrate that downstream secondary structures can efficiently promote non-AUG translation initiation provided that they are stable enough to stall a scanning 43S particle and that they are located at an optimal distance from this non-AUG codon to trigger and stabilize the codon-anticodon base-pairing in the P site. The required stability of the downstream structure for efficient translation initiation varies in distinct cell types. We extended this study to genome-wide analysis of theHomo sapiensalternative translation initiation sites and discovered 556 of them starting with an AUG and 506 starting with a non-AUG that contained a downstream RNA structure at an optimal distance and with a predicted stability of at least -15 kcal/mol. We validated the impact of these structures on translation initiation for several selected uORFs.
PTEN and the PTEN-like phosphatase CnrN have both distinct and overlapping roles in aDictyosteliumchemorepulsion pathway
Authors: Consalvo Kristen M. , Rijal Ramesh , Beruvides Steven L. , Mitchell Ryan , Beauchemin Karissa , Collins Danni , Scoggin Jack , Scott Jerome , Gomer Richard H. 
Published: February 2024

AbstractThe directed movement of eukaryotic cells is crucial for processes such as embryogenesis and immune cell trafficking. The enzyme Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] to phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2].Dictyostelium discoideumcells require both PTEN and the PTEN-like phosphatase CnrN to locally inhibit Ras activation to induce biased movement of cells away from the secreted chemorepellent protein AprA. Both PTEN and CnrN decrease basal levels of PI(3,4,5)P3and increase basal numbers of macropinosomes, and AprA prevents this increase. AprA requires both PTEN and CnrN to increase PI(4,5)P2levels, decrease PI(3,4,5)P3levels, inhibit proliferation, decrease myosin II phosphorylation, and increase filopod sizes. AprA causes PTEN, similar to CnrN, to localize to the side of the cell towards AprA in an AprA gradient. However, PTEN and CnrN also have distinct roles in some signaling pathways. PTEN, but not CnrN, decreases basal levels of PI(4,5)P2, AprA requires PTEN, but not CnrN, to induce cell roundness, and CnrN and PTEN have different effects on the number of filopods and pseudopods, and the sizes of filopods. Together, our results suggest that CnrN and PTEN play unique roles inD. discoideumsignaling pathways, and possibly dephosphorylate PI(3,4,5)P3in different membrane domains, to mediate chemorepulsion away from AprA.