bluuebunny/crossref_metadata_2025_split huggingface dataset:
Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer
Authors: Wei Xujin , Liu Jie , Cheng Jia , Cai Wangyu , Xie Wen , Wang Kang , Lin Lingyun , Hou Jingjing , Cai Jianchun , Zhuo Huiqin 
Published: May 2024

AbstractGastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial.MethodsIn this study, we performed H3K27ac CUT&Tag sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, ChIP/RIP experiments, and in vivo functional assays.ResultsWe demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3’UTR ofHDAC3mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation.ConclusionsCollectively, our findings provide mechanistic insights into the role of the SPI1– ZFP36L1–HDAC3–PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.
Therapeutic potential of SOX9 dysruption in Combined Hepatocellular Carcinoma-Cholangiocarcinoma
Authors: Park Yoojeong , Hu Shikai , Kim Minwook , Oertel Michael , Singhi Aatur , Monga Satdarshan P. , Liu Silvia , Ko Sungjin 
Published: May 2024

ABSTRACTCombined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) represents a challenging subtype of primary liver cancer with limited treatment options and a poor prognosis. Recently, we and others have highlighted the context-dependent roles of the biliary-specific transcription factor SOX9 in the pathogenesis of liver cancers using variousCreapplications inSox9(flox/flox)strains, to achieve elimination for exon 2 and 3 of theSox9gene locus as a preventive manner. Here, we reveal the contrasting responses of developmentalSox9elimination usingAlb-Cre;Sox9(flox/flox)(Sox9LKO) versusCRISPR/Cas9-based tumor specific acuteSox9CKO in SB-HDTVI-basedAkt-YAP1andAkt-NRAScHCC-CCA formation.Sox9LKO specifically abrogates theAkt-YAP1CCA region while robustly stimulating the proliferation of remaining poorly differentiated HCC pertaining liver progenitor cell characteristics, whereasSox9CKO potently preventsAkt-YAP1andAkt-NRAScHCC-CCA development irrespective of fate of tumor cells compared to respective controls. Additionally, we find thatAkt-NRAS, but notAkt-YAP1, tumor formation is partially dependent on theSox9-Dnmt1cascade. Pathologically, SOX9 is indispensable forAkt-YAP1-mediated HC-to-BEC/CCA reprogramming but required for the maintenance of CCA nodules. Lastly, therapeutic elimination ofSox9using theOPN-CreERT2strain combined with an inducibleCRISPR/Cas9-basedSox9iKO significantly reducesAkt-YAP1cHCC-CCA tumor burden, similar toSox9CKO. Thus, we contrast the outcomes of acuteSox9deletion with developmentalSox9knockout models, emphasizing the importance of considering adaptation mechanisms in therapeutic strategies. This necessitates the careful consideration of genetic liver cancer studies using developmental Cre and somatic mutant lines, particularly for genes involved in hepatic commitment during development. Our findings suggest that SOX9 elimination may hold promise as a therapeutic approach for cHCC-CCA and underscore the need for further investigation to translate these preclinical insights into clinical applications.
Flexible males, proactive females: personality tests show increased boldness/exploration in colonists damping with time in males but not in females
Authors: Tchabovsky Andrey V. , Surkova Elena N. , Savinetskaya Ludmila E. , Khropov Ivan S. 
Published: May 2024

AbstractIndividuals colonizing new areas at expanding ranges encounter challenging and unfamiliar environments, suggesting that colonists should differ in behavioural traits from the residents of the source populations. The colonizer syndrome is supposed to be associated with boldness, exploration, activity, and low sociability. We assessed spatial and temporal variation in the colonizer syndrome in the expanding population of midday gerbils (Meriones meridianus). Male first colonists tended to be faster and bolder than residents, although the difference was not significant. Female first colonists were bolder, faster and more explorative than residents. These findings support boldness/exploration syndrome as a typical colonizer trait, which appears to be restricted to females in midday gerbils. Males and females also differed in the behavioural dynamics post-colony establishment. In males, boldness/exploration/sociability peaked in newly founded colonies, then sharply decreased in subsequent generations following decreasing environmental uncertainty in aging colonies. In females, increased boldness/exploration did not lower with time post-colonization, i.e. female colonists retained bold/explorative phenotype in subsequent generations despite facing a less challenging environment. Thus, female colonists, unlike males, carry a specialized behavioural colonizer phenotype corresponding to a proactive behavioural coping strategy. We link sex differences in behavioural traits of colonists to the sex-specific life-history strategies.
Coupled phylogenetic and functional enrichment in the tomato rhizosphere microbiome
Authors: Talavera-Marcos Silvia , Gallego Ramón , Chaboy Rubén , Rastrojo Alberto , de Cárcer Daniel Aguirre 
Published: May 2024

ABSTRACTPlant-microbe interactions occur mainly in the rhizosphere, a hot spot of microbial activity and diversity. Given that the outcome of such interactions can significantly impact plant productivity, we require a better understanding of the rhizosphere microbiome if knowledge-based microbiome modification strategies are to be successfully deployed in the future. Here, we aimed to gain a better understanding of the assembly process of the tomato rhizosphere microbiome and its potential composition-function relationships. Among other things, we studied community assembly through the lens of a conceptual framework for the phylogenetically constrained assembly of microbial communities, while assessing community function based on the predicted minimal metagenome of the microbial ecosystem. We observed a systematic enrichment in terms of phylogeny and predicted functional content in the rhizosphere and were able to delimit phylogenetic signal in the ecosystem with 12 functionally coherent phylogenetic groups present in all samples which together accounted for a large fraction of the total community. Our analyses indicated that these groups included a significantly larger content of the ecosystem’s minimal metagenome than expected by chance. Thus, our study suggests that community assembly followed coupled phylo-functional selection independent of host genetics, and we expect the same phenomenon to occur in other rhizosphere microbiomes. This knowledge provides a thrust in our understanding of how community composition-phylogeny-function relationships drive the assembly process of the rhizosphere microbiome and should help guide the design of synthetic rhizosphere microbiomes for both research and commercial purposes.
A simple active fluid model unites cytokinesis, cell crawling, and axonal outgrowth
Authors: Craig Erin M. , Oprea Francesca , Alam Sajid , Grodsky Ania , Miller Kyle E. 
Published: May 2024

ABSTRACTAxonal outgrowth, cell crawling, and cytokinesis utilize actomyosin, microtubule-based motors, cytoskeletal dynamics, and substrate adhesions to produce traction forces and bulk cellular motion. While it has long been appreciated that growth cones resemble crawling cells and that the mechanisms that drive cytokinesis help power cell crawling, they are typically viewed as unique processes. To better understand the relationship between these modes of motility, here, we developed a unified active fluid model of cytokinesis, amoeboid migration, mesenchymal migration, neuronal migration, and axonal outgrowth in terms of cytoskeletal flow, adhesions, viscosity, and force generation. Using numerical modeling, we fit subcellular velocity profiles of the motions of cytoskeletal structures and docked organelles from previously published studies to infer underlying patterns of force generation and adhesion. Our results indicate that, during cytokinesis, there is a primary converge zone at the cleavage furrow that drives flow towards it; adhesions are symmetric across the cell, and as a result, cells are stationary. In mesenchymal, amoeboid, and neuronal migration, the site of the converge zone shifts, and differences in adhesion between the front and back of the cell drive crawling. During neuronal migration and axonal outgrowth, the primary convergence zone lies within the growth cone, which drives actin retrograde flow in the P-domain and bulk anterograde flow of the axonal shaft. They differ in that during neuronal migration, the cell body is weakly attached to the substrate and thus moves forward at the same velocity as the axon. In contrast, during axonal outgrowth, the cell body strongly adheres to the substrate and remains stationary, resulting in a decrease in flow velocity away from the growth cone. The simplicity with which cytokinesis, cell crawling, and axonal outgrowth can be modeled by varying coefficients in a simple model suggests a deep connection between them.
The contribution of epigenetic variation to evolution in crows
Authors: Merondun Justin , Wolf Jochen B. W. 
Published: May 2024

AbstractChromatin modifications provide a substrate for epigenetic variation with evolutionary potential. To quantify the contribution of this layer of variation to evolution we leveraged genome and methylome sequencing data from an incipient avian species: all-black carrion crows, grey-coated hooded crows and their hybrids. Combining controlled experimentation under common garden conditions and sampling of natural genetic variation across the hybrid zone we show that 5mC methylation variation was almost exclusively explained by genome properties and ontogenetic program of the organism. Evidence for an environmental contribution was minor, and all methylation variation of potential importance to speciation clustered in intergenic space within a genomic region of elevated genetic differentiation encoding the diagnostic color-contrast between taxa. We conclude that methylation variation may aid in phenotypic translation of genetic polymorphism, but provides little scope for an autonomous contribution to evolution in this system.
Consistency of resting-state correlations between fMRI networks and EEG band-power
Authors: Xavier Marta , Esteves Inês , Jorge João , Abreu Rodolfo , Giraud Anne-Lise , Sadaghiani Sepideh , Wirsich Jonathan , Figueiredo Patrícia 
Published: May 2024

AbstractSeveral simultaneous EEG-fMRI studies have aimed to identify the relationship between EEG band power and fMRI resting state networks (RSNs) to elucidate their neurobiological significance. Although common patterns have emerged, inconsistent results have also been reported. This study examines the consistency of these correlations across subjects and to understand how factors such as the hemodynamic response delay and the use of different EEG data spaces (source/scalp) influence them. Using three distinct EEG-fMRI datasets, acquired independently on 1.5T, 3T and 7T MRI scanners (comprising 42 subjects in total), we evaluate the generalizability of our findings across different acquisition conditions. We found consistent correlations between fMRI RSN and EEG band-power time-series across subjects in the three datasets studied, with systematic variations with RSN, EEG frequency-band, and HRF delay, but not with EEG space. Qualitatively, the majority of these correlations were similar across the three datasets, despite important differences in field strength, number of subjects and resting-state conditions. Our findings support consistent correlations across specific fMRI RSNs and EEG bands and highlight the importance of methodological considerations in interpreting them that may explain conflicting reports in existing literature.
Identification of a new cell cycle variant during multiciliated cell differentiation
Authors: Serizay Jacques , Damaa Michella Khoury , Boudjema Amélie-Rose , Balagué Rémi , Faucourt Marion , Delgehyr Nathalie , Noûs Camille , Zaragosi Laure-Emmanuelle , Barbry Pascal , Spassky Nathalie , Koszul Romain , Meunier Alice 
Published: May 2024

2AbstractA complex and conserved regulatory network drives the cell cycle. Individual components of this network are sometimes used in differentiated cells, i.e. to control organelle destruction in mammalian lens cells or light response in land plants. Some differentiated cells co-opt cell-cycle regulators more largely, to increase their ploidy using a cell cycle variant named endoreplication. Using single-cell RNA-seq profiling and functional assays in differentiating multiciliated cells, we identified a novel type of cell cycle variant that supports cytoplasmic organelle, rather than nuclear content amplification. This variant operates in post-mitotic, centriole-amplifying differentiating multiciliated cells and is characterized by (i) a circular trajectory of the transcriptome, (ii) sequential expression of more than 70% of the genes involved in S, G2 and M-like progression along this trajectory, and (iii) successive waves of cyclins. This cell cycle variant is tailored by the expression of the non-canonical cyclins O and A1 – which replace the transcriptionally silent cyclins E2 and A2 – and by the silencing of the APC/C inhibitor Emi1, two switches also detected in male meiosis, another variant of the canonical cell cycle where centriole and DNA replications are uncoupled. Re-expressing Cyclin E2, cyclin A2 or Emi1 is sufficient to induce partial replication and mitosis, suggesting that change in the regulation of expression of a few cell cycle key players drives a qualitative and quantitative tuning of Cdk activity, allowing the diversion of the cell cycle in the multiciliation variant. We also propose that this new cell cycle variant relies on the existence of a cytoplasmic – or centriolar – Cdk threshold, lower than the S-phase threshold, which affects only the cytoplasmic reorganization.One-Sentence SummaryMCC progenitors undergo a final, tailored iteration of the cell cycle during differentiation, to drive centriole amplification without DNA replication or mitosis.
The salivary virome during childhood dental caries
Authors: Tang Jonah , Baker Jonathon L. 
Published: May 2024

AbstractWhile many studies have examined the bacterial taxa associated with dental caries, the most common chronic infectious disease globally, little is known about the caries-associated virome. In this study, the salivary viromes of 21 children with severe caries (>2 dentin lesions) and 23 children with healthy dentition were examined. 2,485 viral metagenome-assembled genomes (vMAGs) were identified, binned, and quantified from the metagenomic assemblies. These vMAGs were mostly phage, and represented 1,547 unique species-level vOTUs, 247 of which appear to be novel. The metagenomes were also queried for all 3,835 unique species-level vOTUs of DNA viruses with a human host on NCBI Virus, however all butHuman betaherpesvirus 7were at very low abundance in the saliva. The oral viromes of the children with caries exhibited significantly different beta diversity compared to the oral virome of the children with healthy dentition; several vOTUs predicted to infectPauljenseniaandNeisseriawere strongly correlated with health, and two vOTUs predicted to infect Saccharibacteria andPrevotella histicola, respectively, were correlated with caries. Co-occurrence analysis indicated that phage typically co-occurred with both their predicted hosts and with bacteria that were themselves associated with the same disease status. Overall, this study provided the sequences of 53 complete or nearly complete novel oral phages and illustrated the significance of the oral virome in the context of dental caries, which has been largely overlooked. This work represents an important step towards the identification and study of phage therapy candidates which treat or prevent caries pathogenesis.ImportanceDental caries is the most common chronic infectious disease, worldwide, and is caused by a dysbiosis of the oral microbiome featuring an increased abundance of acid-tolerant, acid-producing, and biofilm-forming bacteria. The oral microbiome also contains viruses; however, very little is known about the the caries-associated virome. In this study, the salivary virome of children with severe caries was compared to the salivary virome of children with healthy dentition. The metagenomes contained a total of 1,547 unique species-level vOTUs, 247 of which appeared to be novel. The viromes from the children with caries were significantly different than the viromes from the children with healthy teeth, and several health- and disease-associated vOTUs were identified. This study illustrated the importance of the oral virome in the context of dental caries, and serves as a step towards a better understanding of oral inter-kingdom interactions and identification of potential phage-based caries therapeutics.
Comprehensive network modeling approaches unravel dynamic enhancer-promoter interactions across neural differentiation
Authors: DeGroat William , Inoue Fumitaka , Ashuach Tal , Yosef Nir , Ahituv Nadav , Kreimer Anat 
Published: May 2024

AbstractBackgroundIncreasing evidence suggests that a substantial proportion of disease-associated mutations occur in enhancers, regions of non-coding DNA essential to gene regulation. Understanding the structures and mechanisms of regulatory programs this variation affects can shed light on the apparatuses of human diseases.ResultsWe collected epigenetic and gene expression datasets from seven early time points during neural differentiation. Focusing on this model system, we constructed networks of enhancer-promoter interactions, each at an individual stage of neural induction. These networks served as the base for a rich series of analyses, through which we demonstrated their temporal dynamics and enrichment for various disease-associated variants. We applied the Girvan-Newman clustering algorithm to these networks to reveal biologically relevant substructures of regulation. Additionally, we demonstrated methods to validate predicted enhancer-promoter interactions using transcription factor overexpression and massively parallel reporter assays.ConclusionsOur findings suggest a generalizable framework for exploring gene regulatory programs and their dynamics across developmental processes. This includes a comprehensive approach to studying the effects of disease-associated variation on transcriptional networks. The techniques applied to our networks have been published alongside our findings as a computational tool, E-P-INAnalyzer. Our procedure can be utilized across different cellular contexts and disorders.
Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C. 
Published: May 2024

AbstractTargeted radionuclide therapy is based on injections of cancer-specific molecules conjugated with radioactive nuclides. Despite the specificity of this treatment, it is not devoid of side-effects limiting its use and is especially harmful for rapidly proliferating organs well perfused by blood, like bone marrow. Optimization of radioconjugates administration accounting for toxicity constraints can increase treatment efficacy. Based on our experiments on disseminated multiple myeloma mouse model treated by225Ac-DOTA-daratumumab, we developed a mathematical model which investigation highlighted the following principles for optimization of targeted radionuclide therapy. 1) Nuclide to antibody ratio importance. The density of radioconjugates on cancer cells determines the density of radiation energy deposited in them. Low labeling ratio as well as accumulation of unlabeled antibodies and antibodies attached to decay products in the bloodstream can mitigate cancer radiation damage due to excessive occupation of specific receptors by antibodies devoid of radioactive nuclides. 2) Cancer binding capacity-based dosing. The rate of binding of drug to cancer cells depends on the total number of their specific receptors, which therefore can be estimated from the pharmacokinetic curve of diagnostic radioconjugates. Injection of doses significantly exceeding cancer binding capacity should be avoided since radioconjugates remaining in the bloodstream have negligible efficacy to toxicity ratio. 3) Particle range-guided multi-dosing. The use of short-range particle emitters and high-affinity antibodies allows for robust treatment optimization via initial saturation of cancer binding capacity, enabling redistribution of further injected radioconjugates and deposited dose towards still viable cells that continue expressing specific receptors.SignificanceMathematical modeling yields general principles for optimization of targeted radionuclide therapy in mouse models of multiple myeloma that can be extrapolated on another cancer models and on clinical setting.
Formation of vimentin biomolecular condensate-like structures under oxidative stress
Authors: Martínez-Cenalmor Paula , Martínez Alma E. , Moneo-Corcuera Diego , Jiménez Patricia González- , Pérez-Sala Dolores 
Published: May 2024

AbstractThe intermediate filament protein vimentin performs a key role in cytoskeletal interplay and dynamics, and in cellular responses to stress. The vimentin monomer possesses a central α-helical rod domain flanked by N- and C-terminal low complexity domains. Interactions between this type of domains play an important function in the formation of phase-separated biomolecular condensates, which in turn are critical for the organization of cellular components. Vimentin filaments undergo distinct and versatile reorganizations in response to diverse stimuli. Here we show that certain oxidants and electrophiles, including hydrogen peroxide and diamide, elicit the remodeling of vimentin filaments into small particles. Diamide in particular, induces a fast conversion of filaments into circular, motile dots, for which the presence of the single vimentin cysteine residue, C328, is critical. This effect is reversible, and filament reassembly can be noticed within minutes of removal of the oxidant. Diamide-elicited structures can recover fluorescence after photobleaching. Moreover, fusion of cells expressing differentially tagged vimentin allows the detection of dots positive for both tags, suggesting that vimentin dots can merge upon cell fusion. The aliphatic alcohol 1,6-hexanediol, known to alter interactions between low complexity domains, readily dissolves diamide-elicited vimentin dots at low concentrations, whereas at high concentrations it disrupts vimentin filaments. Taken together, these results indicate that vimentin oxidation can promote a fast and reversible filament remodeling into biomolecular condensate-like structures. Moreover, we hypothesize that this reorganization into droplet-like structures could play a protective role against irreversible damage by oxidative stress.