bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetically induced mouse model for colon-specific epithelial cell tumorigenesis driven by loss of K8 and Apc
Authors: Tayyab Mina , Minkkinen Mira M. E. , Stenvall Carl-Gustaf A. , Polari Lauri , Shah Yatrik M. , Toivola Diana M. 
Published: February 2025

AbstractLoss of keratin 8 (K8) has been shown to increase susceptibility towards colonocyte hyperproliferation and tumorigenesis. However, most colorectal cancer (CRC) mouse models require carcinogen, develop small intestinal tumors or have long latency period. The aim was to establish a genetic, colon-specific and more human like CRC model driven by loss of K8 and Apc. Colon epithelium specific targeting using the CDX2P-CreERT2mice was used to generate K8flox/flox; CDX2P-CreERT2and K8flox/flox; CDX2P-CreERT2; Apcflox/+mice. Body weight and stool consistency were monitored, and colon was analyzed for tumor burden and histopathology. Keratin expression, inflammation, and proliferation were assessed using immunoblotting and immunofluorescence analysis. This data was compared to K8 expression analysis in patients with CRC using UALCAN database. K8 downregulation in adult K8flox/flox; CDX2P-CreERT2mice triggers mild diarrhea and leads to loss of K8 and reduced partner keratin levels in a mosaic pattern in the colonic epithelium, while ileal K8 protein levels are unchanged. K8-negative colon areas display increased crypt loss and more MPO+ cells predominantly in the proximal colon. Increased colonocyte proliferation is observed as increased percentage of Ki67+ cells and lower IL-22BP protein levels throughout the colon. These mice with additional monoallelic Apc inactivation show increased colon tumor formation. In colon adenocarcinoma patients, K8 expression is decreased independent of disease type and stage, age or gender. New genetic and colon-specific mouse model with loss of K8 and Apc adequately resembles human CRC. This study also highlights a role of colonocyte K8 in maintaining colon epithelial integrity and protecting against colon tumorigenesis.
Hypoalbuminemia Increases Fibrin Clot Density and Impairs Fibrinolysis
Authors: Waller Amanda P. , Wolfgang Katelyn J. , Stevenson Zachary S. , Holle Lori A. , Wolberg Alisa S. , Kerlin Bryce A. 
Published: February 2025

ABSTRACTBackgroundHypoalbuminemia is a thrombotic disease risk biomarker. Albumin is a negative acute phase reactant and may thus be an indirect biomarker of thromboinflammation. However, nephrotic syndrome (resulting from non-inflammatory proteinuric glomerular disease) causes both hypoalbuminemia and elevated thrombotic risk. Hypofibrinolysis has been observed in nephrotic syndrome and published data suggest that albumin may directly enhance fibrinolysis. These observations suggest that albumin may directly influence thrombotic risk.ObjectiveTo test the hypothesis that hypoalbuminemia impairs fibrinolysis.MethodsHypoalbuminemic blood and plasma from nephrotic syndrome rat models and nephrotic patients were analyzed by thromboelastometry, clot lysis assays, fibrin clot turbidity, confocal microscopy, and immunoblotting. Some studies were conducted without vs. with albumin repletion. Plasma from an analbuminemic mutant rat model was used to confirm albumin-dependent observations.ResultsHypoalbuminemia was associated with hypofibrinolysis in nephrotic whole blood. Albumin levels were positively associated with fibrinolysis in both nephrotic rat and patient plasma. Hypoalbuminemia accelerated fibrin clot formation in nephrotic rat plasma. Dense fibrin clots are known to be resistant to fibrinolysis and fibrin clot network density was increased in hypoalbuminemic plasma clots from both nephrotic rats and patients. Clots formed from hypoalbuminemic plasma contained less albumin than controls, and repletion with recombinant albumin to healthy control levels corrected both fibrin network density and fibrinolysis in nephrotic and analbuminemic rat plasma.ConclusionThese data show that albumin directly increases fibrin network porosity and enhances fibrinolysis. Hypoalbuminemia may mechanistically contribute to nephrotic syndrome thrombotic complications and may similarly increase thrombotic risk in other hypoalbuminemic conditions.
Investigating the impact of carbamazepine on tomato plant metabolism using genome-scale metabolic modelling
Authors: Srinivasan Samyuktha , Raman Karthik , Srivastava Smita 
Published: February 2025

AbstractA comprehensive mechanistic analysis of emerging pharmaceutical pollutants’ stress response in plants is needed to understand its chronic impact on food-chain contamination and agricultural productivity. To unravel this at systems-level, the current study employs insights from green-liver concept and establishes the utility of constraint-based modelling approach for elucidating perturbations in a plant’s metabolism due to pharmaceutical stress.In this study, the stress response of an emerging recalcitrant anticonvulsant pollutant, carbamazepine (CBZ), was simulated in tomato crop under phototrophic conditions. For this, an updated genome-scale metabolic model of tomato leaf (CBZ_iSL3433) was developed and augmented with CBZ transformation reactions based on the green-liver concept. The model was able to capture energy and co-factor competition-induced biomass reduction in presence of CBZ stress. Further, the study provides anin silicomechanistic proof for abiotic stress response induced by CBZ in tomato with altered flux states in nutrient assimilation, synthesis of key precursors of leaf biomass and secondary metabolites. Additionally, to extend the applicability of model, potential ameliorative effects of biostimulants such as proline, spermine, glycerol, and ethanol were investigated through model predictions. Through systematic computational analysis, 154 significantly altered reactions were identified in the presence of CBZ stress, of which 92 % of reactions were ameliorated with biostimulants. Amino acid biosynthesis was found to be the most significantly altered pathway under CBZ stress in the presence of biostimulants.Overall, the proposed framework can aid in screening and developing rational strategies to maintain agricultural yields amid rising plant stress due to such anthropogenic pollutants.
Experimental Kinetic Mechanism of P53 Condensation-Amyloid Aggregation
Authors: Borkosky Silvia S. , Peralta-Martinez Ramon , Armella-Sierra Alicia , Esperante Sebastián A. , Lizárraga Leonardo , García-Pardo Javier , Ventura Salvador , Sanchez Ignacio E. , de Prat-Gay Gonzalo 
Published: February 2025

ABSTRACTThe tumor suppressor p53 modulates the transcription of a variety of genes constituting a protective barrier against anomalous cellular proliferation. High frequency “hot-spot” mutations result in loss-of-function by the formation of amyloid-like aggregates that correlate with cancerous progression. We show that full-length p53 undergoes spontaneous homotypic condensation at sub-micromolar concentrations and in the absence of crowders, to yield dynamic coacervates that are stoichiometrically dissolved by DNA. These coacervates fuse and evolve into hydrogel-like clusters with strong thioflavin-T binding capacity, which further evolve into fibrillar species with a clearcut branching growth pattern. The amyloid-like coacervates can be rescued by the HPV master regulator E2 protein to yield large regular droplets. Furthermore, we kinetically dissected an overall condensation mechanism which consists of a nucleation-growth process by sequential addition of p53 tetramers, leading to discretely-sized and monodisperse early condensates followed by coalescence into bead-like coacervates that slowly evolve to the fibrillar species. Our results suggest strong similarities to condensation-to-amyloid transitions observed in neurological aggregopathies. Mechanistic insights uncover novel key early and intermediate stages of condensation that can be targeted for p53 rescuing drug discovery.SIGNIFICANT STATEMENTKnown as “the guardian of the genome”, the tumor suppressor protein p53 becomes activated by injuries to the DNA genome, and determines whether the cell must undergo self-destruction to avoid cancerous proliferation. P53 is in fact inactivated by mutations in over 50% of all cancers, and restoring its function is recognized as a therapeutic cancer target. A recent biochemical revolution in cell physiology and pathology are liquid entities known as biomolecular condensates. We show that p53 form condensates en route to pathological forms in a surprisingly similar manner to neurological amyloid diseases such as Alzheimeŕs and Parkinsońs. We uncover the sequence of steps in the reaction, exposing flanks for a novel drug development platform based on the condensates paradigm.
Modelling and simulation of the interactions between the cardiovascular system, VA ECMO and IABP: when is it an appropriate combination?
Authors: De Lazzari Beatrice , Capoccia Massimo , Badagliacca Roberto , Maybauer Marc O , De Lazzari Claudio 
Published: February 2025

AbstractVeno-arterial extracorporeal membrane oxygenation (VA ECMO) for the management of refractory cardiogenic shock (CS) has been widely used in recent years. Increased left ventricular (LV) afterload induced by retrograde flow remains a limiting factor, which is particularly evident during peripheral VA ECMO support. The concomitant use of the intra-aortic balloon pump (IABP) is an established strategy to achieve LV unloading during VA ECMO support. Nevertheless, there remains controversy about the combined use of IABP during central or peripheral VA ECMO in terms of beneficial effects and outcome. We developed a simulation setting to study left ventricular unloading with IABP during peripheral and central VA ECMO using CARDIOSIM©, an established software simulator of the cardiovascular system. The aim was to quantitatively evaluate potential differences between the two VA ECMO configurations and ascertain the true beneficial effects compared to VA ECMO alone.
sCIN: A Contrastive Learning Framework for Single-Cell Multi-omics Data Integration
Authors: Ebrahimi Amir , Siahpirani Alireza Fotuhi , Montazeri Hesam 
Published: February 2025

AbstractThe rapid advancement of single-cell omics technologies such as scRNA-seq and scATAC-seq has transformed our understanding of cellular heterogeneity and regulatory mechanisms. However, integrating these data types remains challenging due to distributional discrepancies and distinct feature spaces. To address this, we present a novel single-cell Contrastive INtegration framework (sCIN), that integrates different omics modalities into a shared low-dimensional latent space. sCIN uses modality-specific encoders and contrastive learning to generate latent representations for each modality, aligning cells across modalities and removing technology-specific biases. The framework was designed to rigorously prevent data leakage between training and testing, and was extensively evaluated on three real-world paired datasets including SHARE-seq, 10X PBMC (10k version), and CITE-seq. Paired datasets refer to multi-omics data generated using technologies capable of capturing different omics features from the same cell population. Results on paired datasets show that sCIN outperforms alternative models, including Con-AAE, Harmony, and MOFA across multiple metrics: Average Silhouette Width (ASW) for clustering quality, Recall@k, Cell type accuracy, and Median Rank for integration quality. Moreover, sCIN was evaluated on simulated unpaired datasets derived from paired data, demonstrating its ability to leverage available biological information for effective multimodal integration. In summary, sCIN reliably integrates omics modalities while preserving biological meaning in both paired and unpaired settings.
Filamented Light (FLight) Biofabrication of Mini-Tendon Models Show Tunable Matrix Confinement and Nuclear Morphology
Authors: Liu Hao , Scherpe Lynn , Hummer Linnea B. , Snedeker Jess Gerrit , Zenobi-Wong Marcy 
Published: February 2025

AbstractOne hallmark of healthy tendon tissue is the high confinement of tenocytes between tightly packed, highly aligned collagen fibers. During tendinopathy, this organization becomes dysregulated, leading to cells with round-shaped morphology and collagen fibers which exhibit crimping and misalignment. The elongated nuclei in healthy tendons are linked to matrix homeostasis through distinct mechanotransduction pathways, and it is believed that the loss of nuclear confinement could upregulate genes associated with abnormal matrix remodeling. Replicating the cell and nuclear morphology of healthy and diseased states of tendon, however, remains a significant challenge for engineeredin vitrotendon models. Here we report on a high throughput biofabrication of mini-tendons that mimick the tendon core compartment based on the Filamented Light (FLight) approach. Each mini-tendon, with a length of 4 mm, was composed of parallel hydrogel microfilaments (2-5 µm diameter) and microchannels (2-10 µm diameter) that confined the cells. We generated four distinct matrices with varying stiffness (7-40 kPa) and microchannel dimensions. After 14 days of culture, 29% of tenocytes in the softest matrix with the largest microchannel diameter were aligned, exhibiting an average nuclear aspect ratio (nAR) of 2.1. In contrast, 84% of tenocytes in the stiffest matrix with the smallest microchannel diameter were highly aligned, with a mean nAR of 3.4. When tenocytes were cultured on the FLight hydrogels (2D) as opposed to within the hydrogels (3D), the mean nAR was less than 1.9, indicating that nuclear morphology is significantly more confined in 3D environments. By tuning the stiffness and microarchitecture of the FLight matrix, we demonstrated that mechanical confinement can be modulated to exert control over the extent of nuclear confinement. This high-throughput, tunable platform offers a promising approach for studying the mechanobiology of healthy and diseased tendons and for eventual testing of drug compounds against tendinopathy.
Essential role of NLRC5 in cancer immune surveillance and cancer immunoediting
Authors: Shukla Akhil , Cayarga Anny Armas , Lucier Jean-François , Santharam Madanraj Appiya , Lévesque Dominique , Boisvert François-Michel , Ramanathan Sheela , Ilangumaran Subburaj 
Published: February 2025

AbstractA key mechanism of immune escape from CD8+T cell-mediated tumor control occurs via downregulation of NLRC5, the IFNγ-induced transcriptional activator of MHC class-I. As NLRC5 deficiency does not abrogate CD8+T cell development, we investigated whether NLRC5-dependent antitumor immune mechanisms are required for immune surveillance. Development of 3-methylcholanthrene (MCA)-induced endogenous fibrosarcoma was studied inNlrc5-/-mice withNlrc5+/+andRag1-/-mice serving as controls.Nlrc5-/-andRag1-/-mice showed increased propensity to develop MCA-induced tumors with elevated growth rate compared toNlrc5+/+mice, and displayed significantly reduced survival. Tumors fromNlrc5+/+andNlrc5-/-mice, but not fromRag1-/-mice, contained necrotic areas and displayed T cell infiltration. Tumor cell lines established from MCA- induced tumors were evaluated for their sensitivity to immune-mediated growth control following implantation into immunocompetent C57BL/6 and immunodeficientRag1-/-hosts. Tumors formed byNlrc5+/+tumor cell lines progressed unhindered in C57BL/6 hosts that reflected their immunoedited status, whereas cell lines fromNlrc5-/-andRag1-/-tumors were efficiently controlled, indicating their non-immunoedited status. Proteomic analysis by mass spectrometry followed by pathway analysis revealed enrichment of granzyme-mediated cytolytic pathway inNlrc5+/+tumors that were absent inNlrc5-/-tumors, which showed enrichment of humoral and innate immune pathways. Overall, our findings show that NLRC5 is required for robust tumor immune surveillance and tumor immunoediting and that compensatory humoral and innate immune mechanisms activated by the loss of NLRC5 are insufficient for cancer immune surveillance and cancer immunoediting.
IAP antagonists potentiate TNFα-triggered apoptosis but selectively eliminate senescent tumor cells independently of TNFα
Authors: Ochiiwa Hiroaki , Wakasa Takeshi , Kataoka Yuki , Ando Koji , Oki Eiji , Maehara Yoshihiko , Iimori Makoto , Kitao Hiroyuki 
Published: February 2025

AbstractTherapy-induced senescence (TIS) is a state of cell division arrest induced by chemotherapy that blocks tumor growth. TIS tumor cells affect the tumor microenvironment through their senescence-associated secretory phenotype and independently acquire stemness, which makes them more aggressive and causes relapse once they regrow. To eradicate tumors by chemotherapy, long-lived TIS tumor cells must be efficiently eliminated. Here, we show that AZD5582 and AT406, which are potent antagonists of inhibitor of apoptosis proteins (IAP antagonists) that suppress the activities of cellular inhibitor of apoptosis protein 1 (cIAP1), cellular inhibitor of apoptosis protein 2 (cIAP2), and X-linked inhibitor of apoptosis protein (XIAP), selectively induced apoptosis mediated by caspase 8 and effector caspases in TIS tumor cells, which produced and secreted tumor necrosis factor α (TNFα). However, these IAP antagonists were still selectively cytotoxic to TIS tumor cells even when TNFα was absent (TNFα-knockout cells) or neutralized (by a neutralizing antibody), indicating they have TNFα-independent senolytic activity. Consistently, these IAP antagonists also sensitized tumor cells that had been induced to become senescent by nutlin-3a, which activates p53 but does not trigger TNFα production. Furthermore, TNFα sensitized tumor cells treated with these IAP antagonists irrespective of their senescence status. Collectively, these data indicate that IAP antagonists that inhibit cIAPs and XIAP not only potentiate TNFα-triggered apoptosis but also have TNFα-independent senolytic activity. We propose that IAP antagonists are good concomitant drugs of chemotherapy that induces TIS, not only as senolytic drugs but also as sensitizers of adjacent non-senescent tumor cells mediated by paracrine TNFα.
Optimizing crop varietal mixtures for viral disease management: A case study on cassava virus epidemics
Authors: Israël Tankam C. , Donnelly Ruairí , Gilligan Christopher A. 
Published: February 2025

AbstractCassava viral diseases, including Cassava Mosaic Disease (CMD) and Cassava Brown Streak Disease (CBSD), pose significant threats to global food security, particularly in sub-Saharan Africa. This study explores the potential of varietal mixtures as a sustainable disease management strategy by introducingCropMix, a novel web-based application. The application encodes a flexible insect-borne plant pathogen transmission model to predict and optimize yields under scenarios of varietal mixtures. For instance, we use the application to evaluate the ability of virus-resistant cassava varieties to protect more susceptible varieties against CMD and CBSD, and we also consider mixtures involving tolerant varieties and non-host crops. For CMD, the high transmission rates of cassava mosaic begomoviruses limits the efficacy of mixtures, with susceptible monocultures emerging as better than susceptible-resistant mixtures whatever the whitefly pressure. In contrast, for CBSD, varietal mixtures demonstrate substantial benefits, with resistant varieties shielding susceptible ones and mitigating severe yield losses under moderate or high insect pressure. Management strategies involving non-host crops and complementary control measures, such as roguing, can further enhance outcomes. The model’s simplicity and adaptability make it suitable for tailoring recommendations to diverse insect-borne crop viral diseases and agroecological contexts. The study emphasizes the need for integrating real-world data and participatory frameworks to refine and implement disease management strategies. We discuss the critical balance between agronomic potential and farmer acceptability, underscoring the importance of collaborative efforts to ensure sustainable cassava production.
Formyl-peptide receptor type 2 activation mitigates secondary organ damage in inflammatory arthritis
Authors: Margraf Andreas , Chen Jianmin , Christoforou Marilena , Claria-Ribas Pol , Schneider Ayda Henriques , Cecconello Chiara , Bu Weifeng , Imbert Paul RC , Wright Thomas D , Russo Stefan , Blacksell Isobel A , Koenis Duco S , Dalli Jesmond , Lupisella John A , Wurtz Nicholas R , Garcia Ricardo A , Cooper Dianne , Norling Lucy V , Perretti Mauro 
Published: February 2025

AbstractRheumatoid arthritis (RA) is associated with heart and lung dysfunction. Current therapies fail to attenuate such complications. Here, we identify formyl-peptide receptor type 2 (FPR2) as therapeutic target to treat heart and lung dysfunction associated with inflammatory arthritis. Arthritic mice on high levels of dietary homocysteine develop cardiac diastolic dysfunction and reduced lung compliance, mirroring two comorbidities in RA. Therapeutic administration of a small molecule FPR2 agonist (BMS986235) to hyper-homocysteine arthritic mice prevented diastolic dysfunction (monitored by echocardiography) and restored lung compliance. These tissue-specific effects were secondary to reduced neutrophil infiltration, modulation of fibroblast activation and phenotype (in the heart) and attenuation of monocyte and macrophage numbers (in the lung). A dual FPR1/2 agonist (compound 43) failed to prevent the reduction in lung compliance of arthritic mice and promoted accumulation of inflammatory monocytes and pro-fibrotic macrophages in lung parenchyma. This cellular response lies downstream of FPR1-mediated potentiation of CCL2-dependent monocyte chemotaxis and activation. This finding supports therapeutic development of selective FPR2 agonists to mitigate two impactful comorbidities associated with inflammatory arthritides.
Metagenomicc Profiling of Drinking Water Microbiomes: Insights into Microbial Diversity and Antimicrobial Resistance
Authors: Kumar Vikas , Sharma Shradha , Tyagi Kaomud , Lenin Barathi , Ravindran Aarti , Raman Karthik , Tyagi Inderjeet 
Published: February 2025

AbstractMonitoring microbial components in drinking water is as essential as tracking its chemical composition. While traditional culture-based methods can offer valuable insights into the morphology, behavior, and phenotype of organisms, their scope is limited to culturable species. With the advent of high-throughput sequencing, we can now detect a wider range of microbes in any ecosystem, gaining deeper insights into their functional potential and metabolic capabilities more efficiently. In this study, we employed metagenomic analysis to gain a comprehensive understanding of the microbiome of drinking water supplied through public distribution systems in an Indian city. Our findings identified bacteria from the phyla Pseudomonadota, Planctomycetota, Bacteroidota, and Actinomycetota, consistent with previous drinking water microbiome studies. We observed that the composition and diversity of the microbial community were influenced by the temperature of the water samples. No significant correlation between microbial abundance and metal concentration in the sample was detected. Additionally, we assessed the distribution of antibiotic resistance genes (ARGs), finding widespread resistance to aminoglycosides, tetracyclines, and macrolides across samples. However, the risk associated with these ARGs was out of the scope of this study. Overall, this research provides a preliminary analysis of the drinking water microbiome, offering a foundation for future management strategies.