bluuebunny/crossref_metadata_2025_split huggingface dataset:
UnifiedGreatMod: A New Holistic Modeling Paradigm for Studying Biological Systems on a Complete and Harmonious Scale
Authors: Aucello Riccardo , Pernice Simone , Tortarolo Dora , Calogero Raffaele A. , Herrera-Rincon Celia , Ronchi Giulia , Geuna Stefano , Cordero Francesca , Lió Pietro , Beccuti Marco 
Published: September 2024

MotivationComputational models are crucial for addressing critical questions about systems evolution and deciphering system connections. The pivotal feature of making this concept recognisable from the biological and clinical community is the possibility of quickly inspecting the whole system, bearing in mind the different granularity levels of its components. This holistic view of system behaviour expands the evolution study by identifying the heterogeneous behaviours applicable, for example, to the cancer evolution study.ResultsTo address this aspect, we propose a new modelling paradigm, UnifiedGreatMod, which allows modellers to integrate fine-grained and coarse-grained biological information into a unique model. It allows for functional studies, in which the understanding of the system’s multi-level stable condition and the system’s fluctuating condition are combined to investigate the functional dependencies among the biological entities in the system under study. This is achieved thanks to the hybridisation of two analysis approaches that capture a system’s different granularity levels. The proposed paradigm was then implemented into the open-source, general modelling framework GreatMod, in which a graphical meta-formalism is exploited to simplify the model creation phase and R languages to define user-defined analysis workflows. The proposal’s effectiveness was demonstrated by mechanistically simulating the metabolic output ofEcherichia coliunder environmental nutrient perturbations and integrating a gene expression dataset. Additionally, the UnifiedGreatMod was used to examine the responses of luminal epithelial cells toClostridium difficileinfection.
Nucleus Pulposus Cell Network Modelling in the Intervertebral Disc
Authors: Tseranidou Sofia , Segarra-Queralt Maria , Chemorion Francis Kiptengwer , Le Maitre Christine , Piñero Janet , Noailly Jérôme 
Published: September 2024

AbstractIntervertebral disc degeneration (IDD) arises from an intricate imbalance between the anabolic and catabolic processes governing the extracellular matrix (ECM) within the disc. Biochemical processes are complex, redundant and feedback-looped, thus improved integration of knowledge is needed. To address this, a literature-based regulatory network model (RNM) for nucleus pulposus cells (NPC) is proposed, representing the normal state of the intervertebral disc (IVD) cells, in which proteins are represented by nodes that interact with each other through activation and/or inhibition edges. This model includes 32 different proteins and 150 edges by incorporating critical biochemical interactions in IVD regulation, testedin vivoorin vitroin human and animal NPC, alongside non-tissue-specific protein-protein interactions. We used the network to calculate the dynamic regulation of each node through a semi-quantitative method. The basal steady state successfully represented the activity of a normal NPC, and the model was assessed through the published literature, by replicating two independent experimental studies in human normal NPC. Pro-catabolic or pro-anabolic shifts of the network activated by nodal perturbations could be predicted. Sensitivity analysis underscored the significant influence of transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) on the regulation of structural proteins and degrading enzymes within the system. Given the ongoing challenge of elucidating the mechanisms that drive ECM degradation in IDD, this unique IVD RNM holds promise as a tool for exploring and predicting IDD progression, shedding light on IVD phenotypes and guiding experimental research efforts.
A Single-Cell Network Approach to Decode Metabolic Regulation in Gynecologic and Breast Cancers
Authors: Srivastava Akansha , Vinod P K 
Published: September 2024

AbstractCancer metabolism is characterized by significant heterogeneity, presenting challenges for treatment efficacy and patient outcomes. Understanding this heterogeneity and its regulatory mechanisms at single-cell resolution is crucial for developing personalized therapeutic strategies. In this study, we employed a single-cell network approach to characterize malignant heterogeneity in gynecologic and breast cancers, focusing on the transcriptional regulatory mechanisms driving metabolic alterations. By leveraging single-cell RNA sequencing (scRNA-seq) data, we assessed the metabolic pathway activities and inferred cancer-specific protein-protein interactomes (PPI) and gene regulatory networks (GRNs). We explored the crosstalk between these networks to identify key alterations in metabolic regulation. Clustering cells by metabolic pathways revealed tumor heterogeneity across cancers, highlighting variations in oxidative phosphorylation, glycolysis, cholesterol, fatty acid, hormone, amino acid, and redox metabolism. Our analysis identified metabolic modules associated with these pathways, along with their key transcriptional regulators. Notably, transcription factors related to ER stress, immune response, and cell proliferation, along with hypoxia-inducible factor and sterol regulatory element-binding proteins were found to drive metabolic reprogramming. These findings provide new insights into the complex interplay between metabolic rewiring and transcriptional regulation in gynecologic and breast cancers, offering potential avenues for targeted therapeutic strategies in precision oncology. Furthermore, this pipeline for dissecting coregulatory metabolic networks can be broadly applied to decipher metabolic regulation in any disease at single-cell resolution.
Phytochromes Enable Social Behavior in Marine Diatoms
Authors: Font-Muñoz Joan S. , Jaubert Marianne , Sourisseau Marc , Tuval Idan , Bailleul Benjamin , Duchêne Carole , Basterretxea Gotzon , Falciatore Angela 
Published: September 2024

AbstractThe phytochrome superfamily, a group of proteins that enable some organisms to detect changes in light intensity and quality, is widespread in terrestrial and marine microbes, fungi, algae, and plants. In terrestrial plants, these photosensory receptors monitor variations in the light environment by sensing red (R) and far-red (FR) regions of the spectrum and trigger important developmental, metabolic, and physiological responses. However, the role of these photosensors in marine microbes, living in environments where, due to absorption of water moleculesRandFRradiation does not penetrate beyond the upper few meters, remains controversial. Here, we investigate the role of phytochromes in light perception of the marine diatomPhaeodactylum tricornutumand their involvement in light-driven collective behavior. We perform experiments comparing the social conduct of wild-type and phytochrome knock-out strains to different light wavelengths. Our results show that cell movements become synchronized in a coordinated wobbling dance upon activation of their phytochromes by blue or far-red light, therefore, demonstrating the key role of phytochrome in light-mediated diatom collective behaviour. Furthermore, our experiments suggest that the observed phytochrome-mediated concerted dance implies a form of intercell communication, proposedly mediated by variable R/FR autofluorescence emission in the frequency range of diatom wobbling movements. Our findings provide new insights into communication pathways in aquatic microorganisms and emphasize the importance of social conduct in the sea at all ecological levels.
Natural killer cell function is regulated by TGF-β signaling in pregnancy and tumor progression
Authors: Yalin Adam , Wang Shuang-Yin , Landsberger Tomer , Gamliel Moriya , Elefant Naama , Kotzur Rebecca , Goldman-Wohl Debra , David Eyal , Molgora Martina , Bhattarai Bishan , Cella Marina , Meir-Salame Tomer , Gilad Ronit , Abdelkader Rana , Shveiky David , Yagel Simcha , Zuk Or , Colonna Marco , Mandelboim Ofer , Amit Ido 
Published: September 2024

AbstractThe immune compartment of the maternal-fetal interface must balance between supporting maternal-fetal interactions and maintaining maternal tolerance. Despite recent advances, the cellular and molecular regulators that drive maternal immune cell remodeling remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively characterized the immune compartment dynamics in the maternal-fetal interface of both human and mouse and charted the markers and functional pathways associated with these cells. Comparing immune signatures in decidua and tumors of human and mice, we identify conserved gene modules that are activated in natural killer (NK) cells of both compartments, including TFG-β signaling. Genetic ablation and antibody blockade of the TGF-β pathway in NK cells resulted in enhanced anti-tumor immunity.
Bimodal Specificity of TF-DNA Recognition in Embryonic Stem Cells
Authors: Povolotskii Michael , Yehezkehely Maor , Ram Oren , Lukatsky David B. 
Published: September 2024

AbstractTranscription factors (TFs) bind genomic DNA regulating gene expression and developmental programs in embryonic stem cells (ESCs). Even though comprehensive genome-wide molecular maps for TF-DNA binding are experimentally available for key pluripotency-associated TFs, the understanding of molecular design principles responsible for TF-DNA recognition remains incomplete. Here, we show that binding preferences of key pluripotency TFs, such as Pou5f1 (Oct4), Smad1, Otx2, Srf, and Nanog, exhibit bimodality in the local GC-content distribution. Sequence-dependent binding specificity of these TFs is distributed across three major contributions. First, local GC-content is dominant in high-GC-content regions. Second, recognition of specifick-mers is predominant in low-GC-content regions. Third, short tandem repeats (STRs) are highly predictive in both low- and high-GC-content regions. In sharp contrast, the binding preferences of c-Myc are exclusively dominated by local GC-content and STRs in high-GC-content genomic regions. We demonstrate that the transition in the TF-DNA binding landscape upon ESC differentiation is solely regulated by the concentration of c-Myc, which forms a bivalent c-Myc-Max heterotetramer upon promoter binding, competing with key pluripotency factors such as Smad1. Finally, a direct interaction between c-Myc and key pluripotency factors is not required to achieve this transition.Graphical abstract
TSTA: Thread and SIMD-Based Trapezoidal Pairwise/Multiple Sequence Alignment Method
Authors: Zong Peiyu , Deng Wenpeng , Liu Jian , Ruan Jue 
Published: September 2024

AbstractsThe rapid advancements in sequencing length necessitate the adoption of increasingly efficient sequence alignment algorithms. The Needleman-Wunsch method introduces the foundational dynamic programming (DP) matrix calculation for global alignment, which evaluates the overall alignment of sequences. However, this method is known to be highly time-consuming. The proposed TSTA algorithm leverages both vector-level and thread-level parallelism to accelerate pairwise and multiple sequence alignments.Availability & ImplementationSource code are available athttps://github.com/bxskdh/TSTA.
Quantitative analysis of non-histone lysine methylation sites and lysine demethylases in breast cancer cell lines
Authors: Berryhill Christine A. , Evans Taylor N. , Doud Emma H. , Smith-Kinnaman Whitney R. , Hanquier Jocelyne N. , Mosley Amber L. , Cornett Evan M. 
Published: September 2024

ABSTRACTGrowing evidence shows that lysine methylation is a widespread protein post-translational modification that regulates protein function on histone and non-histone proteins. Numerous studies have demonstrated that dysregulation of lysine methylation mediators contributes to cancer growth and chemotherapeutic resistance. While changes in histone methylation are well documented with extensive analytical techniques available, there is a lack of high-throughput methods to reproducibly quantify changes in the abundances of the mediators of lysine methylation and non-histone lysine methylation (Kme) simultaneously across multiple samples. Recent studies by our group and others have demonstrated that antibody enrichment is not required to detect lysine methylation, prompting us to investigate the use of Tandem Mass Tag (TMT) labeling for global Kme quantification sans antibody enrichment in four different breast cancer cell lines (MCF-7, MDA-MB-231, HCC1806, and MCF10A). To improve the quantification of KDMs, we incorporated a lysine demethylase (KDM) isobaric trigger channel, which enabled 96% of all KDMs to be quantified while simultaneously quantifying 326 Kme sites. Overall, 142 differentially abundant Kme sites and eight differentially abundant KDMs were identified between the four cell lines, revealing cell line-specific patterning.
Polymeric Lysosomal-Targeting Chimeras: Extracellular Targeted Protein Degradation Without Co-opting Lysosome-Targeting Receptors
Authors: Lu Ryan Hung-Hsun , Krishna Jithu , Alp Yasin , Thayumanavan S. 
Published: September 2024

AbstractExtracellular targeted protein degradation (eTPD) is an emerging modality to regulate protein levels without genomic interruption. Current strategies co-opt lysosome-targeting receptors (LTRs) that are ubiquitously present in most cells, offering a high success rate of eTPD across cell types and tissues. Opening up the binding complementarity requirement from LTRs to any overexpressed cell surface receptor offers to endow eTPD platforms with new cellular targeting capabilities. Here, we report polymeric lysosome-targeting chimeras (PolyTACs), a polymer-antibody conjugate based platform for the targeted degradation of membrane-bound and soluble proteins without the need for involving LTRs. Mechanistic investigations suggest a non-classical uptake pathway that is attributed to the membrane tension caused by the multivalent interaction between the PolyTACs and the overexpressed functionalities on the cell surface. The utility of PolyTACs in eTPD has been demonstrated with three therapeutically relevant membrane proteins. Additionally, the same design principle has also been leveraged to bind and drag soluble extracellular proteins into the lysosome. The design and fabrication simplicity, non-reliance on LTRs, and tissue-targeting capabilities open up new avenues for eTPD in many disease-specific applications.
Reversal of elevatedGli3in Autosomal Recessive Polycystic Kidney Disease does not alter cystogenesis
Authors: Russell Lauren G , Kolatsi-Joannou Maria , Wilson Laura , Chandler Jennifer C , Tejedor Nuria Perretta , Stagg Georgie , Price Karen L , Rowan Christopher J , Crompton Tessa , Rosenblum Norman D , Winyard Paul JD , Long David A 
Published: September 2024

AbstractPolycystic kidney diseases (PKD) are genetic disorders characterised by the formation of fluid-filled cysts, which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations inPKHD1,and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated the ciliary-located Hedgehog (Hh) pathway in ADPKD, with increased levels of Hh components in experimental ADPKD models, and reduced cystogenesis following pharmacological Hh inhibition. In contrast, the role of the Hh pathway in ARPKD is poorly understood. We hypothesised that Hh pathway activity would be elevated during ARPKD pathogenesis, and its modulation may inhibit cystogenesis, akin to prior findings in ADPKD. To test this, we utilisedCpkmice, a model which replicates the pathophysiology of ARPKD, and generated a human cellular ARPKD 3-dimensional cystogenesis model by mutatingPKHD1in human collecting duct cells through CRISPR-Cas9 technology. We found significantly elevated levels of the Hh transcriptional effectorGli3in theCpkmouse, a finding replicated in our human cellular ARPKD model. In theCpkmouse, we also observed an increase in total GLI3 and GLI3 repressor protein levels. However, reduction of increasedGli3levels via genetic deletion in theCpkmouse did not affect cyst formation. Similarly, loweringGLI3transcript to wildtype levels, did not influence cyst size in our human cellular ARPKD model. Collectively, these data show that elevated Gli3 does not modulate cyst progression in the context of ARPKD, highlighting the complexity of the Hh pathway in PKD.New and NoteworthyThe role of the Hedgehog pathway in autosomal recessive polycystic kidney disease (ARPKD) is poorly understood. Here, we describe elevated levels ofGli3,the Hedgehog transcriptional effector, in murine and human ARPKD models. However, reversal of the increase inGli3did not significantly affect cystogenesis in a human cell model of ARPKD or disease progression in a mouse model which replicates ARPKD pathophysiology. Collectively, our data indicates that Gli3 does not modulate ARPKD progression.
Pharmacological SOS1 inhibitor BI-3406 demonstratesin vivoanti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors
Authors: Baltanas Fernando C. , Kramer-Drauberg Maximilian , Garcia-Navas Rósula , Patrucco Enrico , Petrini Ettore , Arnhof Heribert , Juan Andrea Olarte-San , Rodríguez-Ramos Pablo , Borrajo Javier , Calzada Nuria , Castellano Esther , Mair Barbara , Kostyrko Kaja , Hofmann Marco H. , Ambrogio Chiara , Santos Eugenio 
Published: September 2024

ABSTRACTResistance to KRASmutinhibitors frequently arises, warranting further searches for anti-RAS cancer therapies. We evaluated the tolerability and efficacy of SOS1 pharmacological inhibition in comparison to genetic ablation in different KRAS-dependent tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. In BI-3406-treated KRASmutMEFs, we observed significantly reduced RAS-GTP levels and RAS downstream signaling, as well as decreased tumor burden and slower disease progression resulting from tumor-intrinsic and extrinsic therapeutic drug effects. In vivo analyses of KRASG12Dallografts in immunocompromised mice and KRASG12D-driven lung adenocarcinomas in immunocompetent mice showed that systemic BI-3406 treatment impaired tumor growth and downmodulated components of the tumor microenvironment comparably to the KRASG12Dinhibitor MRTX1133. Markedly stronger synergistic antitumor effects were observed upon concomitant BI-3406+MRTX113 treatment, confirming SOS1 as an actionable therapy target in RAS-dependent cancers.
IL15/IL15Rα complex induces an anti-tumor immune response following radiation therapy only in the absence of Tregs and fails to induce expansion of progenitor TCF1+ CD8 T cells
Authors: Piper Miles , Gadwa Jacob , Hodgson Chloe , Knitz Michael , Yee Elliott , Zhu Yuwen , Larson Keira Y. , Klein Christian , Amann Maria , Saviola Anthony , Karam Sana D 
Published: September 2024

AbstractBackgroundThis work seeks to understand whether IL15-incorporating treatments improve response to radiotherapy and uncover mechanistic rationale for overcoming resistance to IL15 agonism using novel therapeutic combinations.Experimental DesignOrthotopic tumor models of PDAC were used to determine response to treatment. IL15-/- and Rag1-/- mouse models were employed to determine dependence on IL15 and CTLs, respectively. Flow cytometry was used to assess immune cell frequency and activation state. Phospho-proteomic analyses were used to characterize intracellular signaling pathways.ResultsWe show that the combination of radiation therapy (RT) and an IL15/IL15Ra fusion complex (denoted IL15c) fails to confer anti-tumor efficacy; however, a CD8-driven anti-tumor immune response is elicited with the concurrent administration of an aCD25 Treg-depleting antibody. Using IL15-/- and Rag1-/- mice, we demonstrate that response to RT + IL15c + aCD25 is dependent on both IL15 and CTLs. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT + PD1-IL2v, a novel immunocytokine with PD-1 and IL2Rβγ binding domains, CTL immunophenotyping and phospho-proteomic analysis of intracellular metabolites showed significant upregulation of activation and functionality in CD8 T cells treated with RT + PD1-IL2v. Finally, we show the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T cell generation in the absence of functional IL15 signaling.ConclusionsOur results are illustrative of a mechanism wherein unimpeded effector T cell activation through IL2Rβ signaling and Treg inhibition are necessary in mediating an anti-tumor immune response.
Loss ofSMARCB1evokes targetable epigenetic vulnerabilities in Epithelioid Sarcoma
Authors: Jin Jia Xiang , Fuchslocher Fabia , Carreno-Gonzalez Martha , Zahnow Felina , Ceranski A. Katharina , Will Rainer , Helm Dominic , Bestvater Felix , Banito Ana , Imle Roland , Ohmura Shunya , Cidre-Aranaz Florencia , Grünewald Thomas G. P. 
Published: September 2024

ABSTRACTDysfunction of epigenetic modulators, such as the SWI/SNF complex, is a wide-spread but relatively ill-defined feature of a broad spectrum of cancer entities. Among SWI/SNF-mutant entities,SMARCB1-deficient cancers, such as the highly aggressive Epithelioid Sarcoma (EpS), are characterized by this genetic event in an otherwise rather silent mutational landscape. This renders EpS an ideal model to study how epigenetic reprogramming by a single mutation can contribute to tumorigenesis.Hence, to characterize and compare the function of theSMARCB1-deficient, residual and the physiological SWI/SNF complex in cancer, we generated a panel ofSMARCB1re-expressing EpS cell lines and employed a functional multi-omics approach. Here, we show that SWI/SNF holds canonical characteristics of both tumor-suppressors and proto-oncogenes due to its multi-faceted role in the regulation of the epigenome. Our data indicates that the loss ofSMARCB1causes an overall loss of SWI/SNF chromatin affinity atcis-regulatory enhancer elements, inducing a preference for uncontrolled proliferation and cell cycle progression as opposed to development and differentiation. We further demonstrate that EpS cell lines depend on residual SWI/SNF action to maintain clonogenicity and proliferation. Consequently, EpS cell lines exhibit markedly increased sensitivity to pharmacological inhibition of the residual SWI/SNF when compared with SWI/SNF-proficient cancer entities.Collectively, our results from the EpS model shed new light on how a single mutation can rewire the pleiotropic effects of an epigenetic master regulator and provide inroads for therapeutic intervention.