bluuebunny/crossref_metadata_2025_split huggingface dataset:
Balancing tumour proliferation and sustained cell cycle arrest through proteostasis remodelling drives immune niche compartmentalisation in breast cancer
Authors: Celik Cenk , Withnell Eloise , Pan Shi , Chu Tooki , Labbadia John , Secrier Maria 
Published: January 2025

AbstractUncontrolled proliferation is a hallmark of cancer, yet tumour cells can enter G0 arrest by halting the cell cycle reversibly (quiescence) or irreversibly (senescence) to survive under stress and in hostile tumour microenvironments (TME). G0 arrested cells contribute to drug tolerance, metastasis and recurrence, but their identification remains challenging due to their rarity and elusive regulatory pathways. Here, we quantify G0 arrest and proliferation decisions in single-cell and spatially profiled breast primary tumours to unveil adaptive responses driving immune compartmentalisation. We identify a genomically-constrained and prolonged G0 arrest state resembling that of dormant precursors of cancer progression. This state featured adaptive transcriptional reprogramming, including unfolded protein response stress, reduced mitochondrial translation and epithelial-mesenchymal plasticity enabled by semaphorin signalling. Spatial transcriptomics revealed G0 arrest pockets encapsulated byAPOE+ lipid-associated macrophages, myofibroblastic CAFs and immature perivascular cells, suggestive of an immunosuppressive niche contrasting with cytotoxic environments in proliferative hotspots and displaying distinct drug sensitivities. To facilitate future research, we provide a foundation model capturing G0 arrest and proliferation with 94% accuracy in single cell data, available athttps://github.com/secrierlab/G0-LM. Our findings provide new insights into the spatial organisation of cell cycle arrest in breast cancer, highlighting the role of G0 states in tumour heterogeneity and adaptation.
Learning a CoNCISE language for small-molecule binding
Authors: Erden Mert , Devkota Kapil , Varghese Lia , Cowen Lenore , Singh Rohit 
Published: January 2025

AbstractRapid advances in deep learning have improvedin silicomethods for drug-target interaction (DTI) prediction. However, current methods do not scale to the massive catalogs that list millions or billions of commercially-available small molecules. Here, we introduce CoNCISE, a method that accelerates drug-target interaction (DTI) prediction by 2-3 orders of magnitude while maintaining high accuracy. CoNCISE uses a novel vector-quantized codebook approach and a residual-learning based training of hierarchical codes. Strikingly, we find that much of binding-specificity information in the small molecule space can be compressed into just 15 bits of information per compound, characterizing all small molecules into 32,768 hierarchically-organized binding categories. Our DTI architecture, which combines these compact ligand representations with fixed-length protein embeddings in a cross-attention framework, achieves state-of-the-art prediction accuracy at unprecedented speed. We demonstrate CoNCISE’s practical utility by indexing 6.4 billion ligands in the Enamine dataset, enabling researchers to query vast chemical libraries against a protein target in seconds. A “CoNCISE + docking” pipeline screened Enamine to propose strong binders (predictedKD≈ 10-20µM) of three difficult-to-drug targets, each within two hours. CoNCISE’s advance could democratize access to largescale computational drug discovery, potentially enabling rapid identification of promising molecules for therapeutic targets and cellular perturbations.
The MAP kinase scaffold MORG1 shapes cell death in unresolved ER stress in Arabidopsis
Authors: Kim Joo Yong , Ko Dae Kwan , Brandizzi Federica 
Published: January 2025

AbstractGoverned by the unfolded protein response (UPR), the ability to counteract endoplasmic reticulum (ER) stress is critical for maintaining cellular homeostasis under adverse conditions. Unresolved ER stress leads to cell death through mechanisms that are yet not completely known. To identify key UPR effectors involved in unresolved ER stress, we performed an ethyl methanesulfonate (EMS) suppressor screen on the Arabidopsisbzip28/60mutant, which is impaired in activating cytoprotective UPR pathways. This screen identified MAP kinase organizer 1 (MORG1), a conserved MAP kinase scaffold protein, as a previously uncharacterized regulator of ER stress tolerance. Thecoffin1mutant, which carries a mutation inMORG1, exhibited enhanced resilience to ER stress by partially restoring UPR gene expression and promoting growth under stress conditions. Mechanistically, we found that MORG1 modulates MPK6-dependent phosphorylation of the stress-responsive transcription factor WRKY8. Loss ofWRKY8phenocopied thecoffin1mutant, highlighting WRKY8’s role as a key repressor in the UPR. Together, these findings reveal a MORG1–MPK6–WRKY8 signaling axis that fine-tunes UPR gene expression, providing new insights into ER stress regulation and strategies for improving stress tolerance in multicellular eukaryotes.
ACTIVITY IN HUMAN DORSAL RAPHE NUCLEUS SIGNALS CHANGES IN BEHAVIOURAL POLICY
Authors: Priestley Luke , Mahmoodi Ali , Reith William , Khalighinejad Nima , Rushworth Matthew 
Published: January 2025

AbstractThe dorsal raphe nucleus (DRN) is an important source of serotonin to the human forebrain, however there is little consensus about its behavioural function. We build on recent results from animal models to demonstrate that activity in human DRN represents changes between general behavioural policies. We use a novel behavioural task to show that human participants change their policy to pursue or reject reward opportunities as a function of the average value of opportunities in the environment. Activity in DRN – but no other neuromodulatory nucleus – signalled such policy changes. Patterns of multivariate activity in dorsal anterior cingulate cortex (dACC) and anterior insular cortex (AI), meanwhile, tracked the relative value of reward opportunities given the average value of the environment. We therefore suggest that DRN, dACC and AI form a circuit in which dACC/AI compute the relative value of reward opportunities given the current context, and DRN implements changes in behavioural policy based on context-specific values.
Integrating flowering and stress responses in Arabidopsis through KH-domain genes
Authors: Rodríguez-Cazorla Encarnación , Ripoll Juan-José , Candela Héctor , Aranda-Martínez Almudena , Zavala-González Ernesto , Martínez-Laborda Antonio , Vera Antonio 
Published: January 2025

SummaryPlant reproductive success largely relies on flowering under favorable conditions. However, stress factors have forced plants to acquire adaptive strategies to coordinate floral timing and stress responses through key genetic elements. RNA-binding proteins with K-homology (KH) domains are emerging as versatile regulators of an increasing number of plant developmental processes, including flowering and stress acclimation. InArabidopsis thaliana,FLKandHOS5encode multifaceted KH-domain proteins associated with transcription and cotranscriptional operations.FLKfacilitates floral transition by repressingFLC, the central flowering inhibitor, while both KH-genes have been involved in abiotic stress and defense against pathogens. Our genetic and molecular data identify HOS5 as a novel flowering regulator that, together with FLK, repressesFLC. Our transcriptomics results reveal that, in addition,FLKandHOS5cooperatively repress numerous stress-responsive genes. Consistent with this,flk hos5double mutant plants exhibit elevated levels of stress-induced gene activities and enhanced resistance to abiotic stress and pathogenic fungi. The coordinated repression ofFLCand stress-induced genes by FLK and HOS5 suggests that these KH proteins are part of a cotranscriptional regulatory hub key for orchestrating flowering time and environmental adaptation responses.
Seeing is Feeling: How Aphantasia Alters Emotional Engagement with Stories
Authors: Abdelrahman Noha , Melcher David , Ripollés Pablo 
Published: January 2025

AbstractVisual imagery is thought to act as an ‘emotional amplifier’, potentially contributing to narrative engagement. To examine this, we conducted two experiments in which participants were presented with emotionally charged audio and video story excerpts. Experiment 1 included 84 online participants from the general population, while Experiment 2 involved 25 individuals with aphantasia (the inability to generate mental images) and 25 controls. In both experiments we assessed narrative engagement behaviorally using the Narrative Engagement Questionnaire (NEQ), while for Experiment 2 we also measured physiological responses. We found a main effect of modality, with video stimuli scoring higher across all NEQ subscales in both experiments. Notably, in experiment 2, a significant group effect on emotional—but not cognitive—engagement emerged, with aphantasics reporting less emotional engagement than controls. Moreover, controls experienced higher heart rate during audio narratives, while aphantasics had a similar heart rate across both modalities. Our results suggest that the enhanced physiological response seen in non-aphantasics during audio narratives is driven by the mental effort required to generate imagery. Furthermore, this capacity for visual imagery appears to enhance emotional engagement with stories. This highlights mental imagery’s role in both subjective and physiological responses, emphasizing distinct cognitive processes during narrative engagement.
CD20+natural killer cells are polyfunctional, memory-like cells that are enriched in inflammatory disorders
Authors: Albayrak Özgür , Tiryaki Ergün , Akkaya Nazan , Burak Kızılırmak Ali , Doran Tansu , Gökmenoğlu Gökçe , Yüksel Muhammed , Ulukan Bürge , Üzülmez Mina , Baytekin Işıl , Soylu Kemal , Esendağlı Güneş , Meinl Ingrid , Köseoğlu Mesrure , Yüksel Burcu , Erus Suat , Arıkan Çiğdem , Vural Seçil , Zeybel Müjdat , Soysal Aysun , Meinl Edgar , Vural Atay 
Published: January 2025

AbstractWhile CD20 was initially characterized as a B cell-specific marker, its expression on memory T cells has expanded our understanding of this molecule’s distribution and function. Here, we identify a previously unrecognized CD20-expressing NK cell population and demonstrate its functional significance. CD56+CD20+ NK cells exhibit hallmarks of cellular activation, including elevated NKp46, CD69, and CD137 expression, enhanced proliferative capacity, and increased production of inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-10). Functional analyses revealed enhanced cytotoxicity against K562 targets, correlating with increased expression of cytolytic mediators including granzymes A, B, and K, perforin, FASL, and TRAIL. Single-cell transcriptional profiling demonstrated that MS4A1-expressing NK cells possess a distinct molecular signature characterized by elevated granzyme K expression and memory-like features. These cells preferentially localize to secondary lymphoid organs and accumulate in inflammatory tissues. Notably, CD56+CD20+ NK cells are enriched in multiple inflammatory conditions, including multiple sclerosis, autoimmune hepatitis, hepatitis B infection, hepatocellular carcinoma, and lung cancer. Treatment with rituximab depletes this population, suggesting potential therapeutic implications. Our findings establish CD20+ NK cells as a functionally distinct lymphocyte subset with enhanced effector capabilities and tissue-homing properties, providing new insights into immune regulation in inflammatory diseases.One Sentence SummaryOur study reveals expression of CD20 by NK cells, in relation with enhanced functionality, memory-like features, and inflammation.
Development of catecholaminergic neurons of Otp-lineage in the medial extended amygdala and other centers of the social behavior network
Authors: Morales Lorena , Desfilis Ester , Medina Loreta 
Published: January 2025

AbstractCatecholaminergic (CA) neurons of the medial extended amygdala, preoptic region and adjacent alar hypothalamus have been involved in different aspects of social behavior. Previous data suggested that at least some CA neurons of the medial extended amygdala could originate in a hypothalamic embryonic domain that expresses the transcription factor Otp. To investigate this, we used Otp-eGFP mice to analyze coexpression of GFP and tyrosine hydroxylase (TH) throughout ontogenesis by way of double immunofluorescence. Our results showed that some TH cells coexpress GFP in the medial extended amygdala preoptic region, and alar and basal hypothalamus. However, the presence of TH/GFP double-labeled cells in the extended amygdala is transient, as they are not seen in adults. Based on previous data, the Otp-related CA cells of the medial extended amygdala might derive from the telencephalon-opto-hypothalamic domain, and those of the central paraventricular and supraoptic hypothalamic nuclei likely derive from the supraopto-paraventricular hypothalamic core domain. Taken together, these data provide new evidence for several Otp-related CA subpopulations in centers of the social brain network. The results open interesting questions about the role of these catecholaminergic subpopulations during the development and in different aspects of social behavior.
Origin of subgenomes in the circumboreal allopolyploid carnivorous plantDrosera anglica(Droseraceae)
Authors: Mohn Rebekah A. , Yang Ya 
Published: January 2025

ABSTRACTPremise of StudyThe parentage of a widespread member of the carnivorous sundew genusDrosera, the allopolyploidDrosera anglica,remains uncertain despite over 100 years of morphological, cytological, and, more recently, molecular study.MethodsUsing transcriptomic and genomic data from 12 speciesDroserasect.Droseraincluding fourD. anglicapopulations and a disjunct Idaho population ofD. intermedia, we assembled genes in HybPiper and phased sequences in HybPhaser. We estimated heterozygosity and generated flow cytometry data to assess ploidy levels. We estimated species relationships with phylogenetic and pairwise genetic distance methods. Additionally, we assembledrbcL and ITS reads to compare to previous data.Key ResultsSequences from phased subgenomes highly supportedD. anglicaas sister toD. rotundifoliaandD. linearis,differing from previous analyses based on chromosome pairing and Sanger sequencing with limited taxon sampling. Both ITS andrbcL sequences ofD. anglicawere the most similar toD. linearis.Drosera anglicais intermediate between both parents in leaf shape and microhabitat; however, acrossD.sect.Drosera, neither leaf shape nor biogeographic distribution were reliable indicators of phylogenetic relationships. Despite a range-wide sampling, we did not find evidence for multiple origins ofD. anglica. Additionally, we confirmed that the Idaho population previously identified asD. intermediaisD. anglica.ConclusionsDrosera anglicaarose from allopolyploidy betweenD. linearis(the chloroplast donor) andD. rotundifolia. Our study demonstrates the importance of taxon sampling and careful examining complex phylogenomic data, and presents an exemplar of analyzing allopolyploid relationships in plant lineages.
Strategies to improve selection compared to selection based on estimated breeding values
Authors: Pook Torsten , Hassanpour Azadeh , Niehoff Tobias A.M. , Calus Mario P.L. 
Published: January 2025

AbstractBackgroundSelection of individuals based on their estimated breeding values aims to maximize response to selection to the next generation in the additive model. However, when the aim is not only about short-term population-wide genetic gain but also the gain over multiple generations, an optimal strategy is not as clear-cut, as the maintenance of genetic diversity may become an important factor. This study provides an extended comparison of existing selection strategies in a unifying testing pipeline using the simulation software MoBPS.ResultsApplying a weighting factor on the estimated SNP effects based on the frequency of the beneficial allele resulted in an increase of the long-term genetic gain of 1.6% after 50 generations while reducing inbreeding rates by 16.2% compared to truncation selection based on estimated breeding values. However, this also resulted in short-term losses in genetic gain of 1.2% with the break-even point reached after 25 generations. In contrast, inclusion of the average kinship of an individual to top individuals of the population as an additional trait in the selection index with a weight of 17.5% resulted in no short-term losses and increased long-term genetic gains by 4.3% while reducing inbreeding by 15.8%, achieving very similar efficiency to the use of optimum genetic contribution selection. Combining multiple diversity management strategies, with weights for each strategy optimized using an evolutionary algorithm resulted in a breeding scheme with 5.1% increased genetic gain and 37.3% reduced inbreeding rates. The proposed strategy included the use of optimum genetic contribution, weighting of SNP effects based on allele frequency, average kinship as a trait in the selection index, avoiding matings between related individuals, and lowering the proportion of selected individuals.ConclusionsThe combination of selection strategies for the management of genetic diversity was shown to be far superior to the use of any singular method tested in this study. As an efficient use of methods for the management of genetic diversity and inbreeding does not necessarily lead to short-term losses in genetic gain and comes at no extra costs, it is critical for breeding companies to implement such strategies for long-term success.
Piezo1 activation increases the release of therapeutic extracellular vesicles after mechanical stimulation in bioreactors
Authors: Andrade André Cronemberger , Le Goas Oriane , Lemieux Shony , Grangier Alice , Nicolai Alice , Guerrera Chiara , Ribes Christopher , Suply Estelle , Volatron Jeanne , Gazeau Florence , Silva Amanda. K.A. 
Published: January 2025

AbstractEnhancing protocols and methods for producing therapeutic extracellular vesicles (EVs) in bioreactors is crucial to achieve scalable production while ensuring both quality and quantity. Studies have shown that mechanical stress can promote EV release, although the underlying mechanisms remain largely unclear. Here we investigated which mechanisms are responsible for the increase of EV production under shear stress. EVs were produced from adipose tissue-derived stromal cells (ASCs), also described as mesenchymal stromal cells (MSCs) that can support the regeneration of injured tissues via several paracrine factors. The cultures were treated with GsMTx4, an inhibitor which blocks the Piezo1 ion channels, or with YODA1, its agonist, to assess if mechanical or shear forces pathways are involved in enhancing the EV release. EVs were quantified and characterized after high shear (HS) stimulation compared with no shear stress stimulation (3D) and standard cultures methods (2D). These experiments showed that, after mechanical stimulation by shear stress, EV production increased in bioreactors and this effect was blocked by the inhibition of Piezo1 ion channels with GsMTx4 (88%) with no impact on cell viability. Consistently, the agonist YODA1 increased the EV production (149%). The implications of these findings are significant, especially for regenerative medicine and cellular therapies, where the efficient production of high-quality EVs is crucial. By understanding turbulence-induced shear stress and the natural mechanotransductive pathways within cells, it may be possible to optimize the production of therapeutic EVs, paving the way for more effective treatments in the future.
Competitive elimination of ZO-1/ZO-2-deficient cells regulates epithelial barrier homeostasis
Authors: Otani Tetsuhisa , Nguyen Thanh Phuong , Kinoshita Noriyuki , Fujimori Toshihiko , Furuse Mikio 
Published: January 2025

SummaryEpithelia cover the body and form a barrier to segregate the internal body from the external environment. Epithelial tissues contact the external environment and are exposed to various stresses that are potentially deleterious for the epithelial barrier1. However, how focal epithelial barrier defects are detected and repaired to maintain epithelial barrier homeostasis remains poorly understood. We co-culturedZO-1/ZO-2double-knockout (DKO) MDCK II cells, which lack tight junctions, with wild-type MDCK II cells, to understand how epithelial cells respond to focal epithelial barrier defects. When co-cultured with wild-type cells,ZO-1/ZO-2DKO cells were selectively eliminated by induction of apoptosis. The elimination depended on a purse-string-like contraction of supracellular actomyosin cables formed at the clone boundary, regulated by ROCK. Furthermore, Hippo signaling and adherens junctions in the surrounding wild-type cells were required to eliminateZO-1/ZO-2DKO cells. These results demonstrate that selective elimination of ZO-1/ZO-2-deficient cells by cell competition regulates epithelial barrier homeostasis.In briefOtani et al. reveal that epithelial barrier homeostasis is regulated by cell competition-mediated elimination of ZO-1/ZO-2-deficient cells. Supracellular actomyosin cables form at the clone boundary and constrict in a purse-string-like manner to eliminate the ‘loser’ cells. Mechanosensing in the winning cells is required to eliminate the ‘loser’ cells.HighlightsZO-1/ZO-2-deficient cells are eliminated by cell competitionActomyosin cables form in the winning cells at the clone boundaryA purse-string-like contraction of actomyosin cables compresses the losing cellsMechanosensing in the winning cells is important to eliminate the ‘loser’ cells
Identification of a BACH1 lung cancer signature: A novel tool for understanding BACH1 biology and identifying new inhibitors
Authors: Klenja-Skudrinja Donika , Walker David , Ali Kevin X. , Higgins Maureen , Patel Angana AH , Raj Dorota , Creelman Anna , McDowall Charlotte , Wenta Tomasz , Larsson Erik , Wiel Clotilde , Sayin Volkan I. , de la Vega Laureano 
Published: January 2025

AbstractThe transcription factor BACH1 is a transcriptional repressor with a central role in regulating oxidative stress and anti-inflammatory pathways, emerging as a promising therapeutic target for multiple conditions, including neoplastic malignancies, neurodegenerative disorders, ischemia-reperfusion injuries and sickle cell disease. In the field of cancer BACH1 has gained significant attention, with BACH1 overexpression correlating with poor prognosis and metastasis across various cancer types; however, despite this increasing relevance of BACH1, no universal pro-metastatic mechanism or transcriptional signature for BACH1 has been identified which is a major limitation for this growing field. To address this, we performed RNA-Seq coupled with ChIP-Seq in BACH1-proficient and BACH1-deficient lung cancer cells, identifying a set of common BACH1 directly regulated genes, which we thoroughly validated in a large panel of cancer cells. This novel lung cancer BACH1 transcriptional signature is highly sensitive and specific to BACH1 perturbations (both genetic and pharmacological) and does not respond to NRF2 modulation, underscoring its specificity. This signature not only represents a robust surrogate for BACH1 activity, but we also provide evidence of its potential value as a tool to i) identify novel BACH1 inhibitors, and ii) provide insights into BACH1’s pro-metastatic role.