bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamate, GABA, and dense-core vesicle secretion regulate predatory feeding in the nematodePristionchus pacificus
Authors: Onodera Ageha , Zhang Andrew , Chihara Takahiro , Sommer Ralf J. , Okumura Misako 
Published: June 2024

AbstractNematodes are one of the most diverse groups of organisms, found in various environments, and exhibit various feeding behaviours.Pristionchus pacificusdisplays two types of feeding behaviours: predatory and bacterial feeding. Previously, we showed that the neurotransmitter serotonin plays important roles in regulating predatory feeding inP. pacificus.However, the role of other neurotransmitters in predatory feeding remains unclear. Using the CRISPR/Cas9 system, we generated mutants of the dense-core vesicle (DCV)-based neuropeptide secretion system and genes related to seven neurotransmitters. Predatory assays revealed that the vesicular glutamate transporterPpa-EAT-4, glutamic acid decarboxylasePpa-UNC-25 which is involved in GABA synthesis, and the calcium-dependent activator protein for DCV secretionPpa-UNC-31, play roles in predatory feeding behaviour. We assessed the pharyngeal movement necessary for predation as well as locomotion rate in these mutants. While thePpa-eat-4andPpa-unc-31mutants decreased predation movement, thePpa-unc-25mutant showed a reduction only in bacterial events compared to wild type animals. Additionally,Ppa-unc-25andPpa-unc-31decreased in motor movement, potentially reducing predation efficiency. Together, these results suggest that glutamate, GABA and DCV secretion modulate feeding behaviours inP. pacificus. Our mutant collection of neurotransmitter-related genes will be useful for future analysis of neurobiology and behavioural evolution.
Identification of Multi-landscape and Cell Interactions in the Tumor Microenvironment through High-Coverage Single-Cell Sequencing
Authors: Zhong Wenlong , Wang Ligang , Guo Tonglei , Zhao Lihua , Wu Daqin , Xie Fei , Wang Xiao , Li Xiuxin , Wang FangXiao , Gu Weiyue , Lin Tianxin , Chen Xu 
Published: June 2024

AbstractSingle-cell RNA sequencing (scRNA-seq) is a widely used method for classifying cell types and states and revealing disease mechanisms. However, most contemporary scRNA-seq platforms fail to explore the multi-landscape of RNA. Here, we designed a microfluidic chip combined oligo-dT primers and Random Bridging Co-labeling (RBCL) RNA sequencing to develop an innovative Chigene scRNA-seq technology that can identify gene expression, mutations, and RNA splicing landscapes at the single-cell level. The Chigene scRNA-seq platform demonstrated exceptional performance, with minimal doublet rates of 0.94% (Chigene V1) and 1.93% (Chigene V2). Both versions exhibit high sensitivity, with Chigene V2 achieving nearly 100% RNA coverage and detecting over 1800 genes per cell on average. Targeted capture of single-cell gene mutations enhances mutation detection sensitivity. Moreover, this Chigene V2 platform has been validated in clinical samples for its ability to detect mutations, gene fusions and alternative splicing. The reliability of the platform was further corroborated using known functional gene mutation (CDKN1A) and fusion (FGFR3-TACC). To validate this method’s potential for discovering novel gene mutations in clinical samples, our investigation revealed an intriguing cell subpopulation carrying an ARHGAP5 mutation in urothelial carcinoma. These cells exhibited high-frequency mRNA splicing and exhibited specific crosstalk with T cells, distinguishing them from the subpopulation with the ARHGAP5 wild-type phenotype. Overall, this method provides a robust scRNA-seq platform suitable for comprehensive analyses of clinical specimens at different genetic information levels, thereby offering significant potential in the discovery of novel genes and interactions at the single-cell level.
Post-encoding administration of oxytocin selectively enhances memory consolidation of male faces in females
Authors: Li Jiashen , Chen Zhengyue , Liu Wei 
Published: June 2024

AbstractOxytocin plays a critical role in modulating social cognition and enhancing human memory for faces. However, it remains unclear which stage of memory oxytocin affects to enhance face memory. Our study explored oxytocin’s potential to selectively enhance the consolidation of social memories, specifically human faces, and whether this effect varies between genders. In two preregistered, randomized, double-blind, placebo-controlled trials with heterosexual participants (total N=294, comprising 149 males and 145 females), we explored how oxytocin affects memory consolidation. We administered oxytocin immediately after encoding (i.e., Study1) and 30 minutes before retrieval in a parallel study (i.e., Study2). This design allowed us to confirm that oxytocin’s effects were indeed due to consolidation rather than retrieval. We found that administering oxytocin post-encoding, but not before-retrieval, significantly improved female participants’ ability to recognize male faces 24 hours later, with no similar enhancement observed in males recognizing opposite-gender faces. Together with our analyses of social placebo effects and approachability rating during encoding, we concluded that oxytocin enhanced consolidation of long-term social memories in humans. Our results not only advance the understanding of the neurobiological mechanisms underlying social memory consolidation but also highlight oxytocin as a pharmacological tool for selectively enhancing human memory consolidation.HighlightsOxytocin selectively enhances memory consolidation of human faces, with gender-specific effects.In females, oxytocin after encoding improves recognition of male faces after 24 hours.Oxytocin-induced enhancement of social memory is due to enhanced consolidation, not retrieval or encoding.Oxytocin shows potential for selectively modulating memory consolidation in humans.
Fibrotic Extracellular Matrix Preferentially Induces a Partial Epithelial-Mesenchymal Transition Phenotype in a 3-D Agent Based Model of Fibrosis
Authors: Kim Kristin P. , Lemmon Christopher A. 
Published: June 2024

AbstractOne of the main drivers of fibrotic diseases is epithelial-mesenchymal transition (EMT): a transdifferentiation process in which cells undergo a phenotypic change from an epithelial state to a pro-migratory state. The cytokine transforming growth factor-β1 (TGF-β1) has been previously shown to regulate EMT. TGF-β1 binds to fibronectin (FN) fibrils, which are the primary extracellular matrix (ECM) component in renal fibrosis. We have previously demonstrated experimentally that inhibition of FN fibrillogenesis and/or TGF-β1 tethering to FN inhibits EMT. However, these studies have only been conducted on 2-D cell monolayers, and the role of TGF-β1-FN tethering in 3-D cellular environments is not clear. As such, we sought to develop a 3-D computational model of epithelial spheroids that captures both EMT signaling dynamics and TGF-β1-FN tethering dynamics. We have incorporated the bi-stable EMT switch model developed by Tian et al. (2013) into a 3D multicellular model, capturing both temporal and spatial TGF-β1 signaling dynamics. We show that the addition of TGF-β1 affects cell proliferation, EMT progression, and cell migration. We then incorporate TGF-β1-FN fibril tethering by locally reducing the TGF-β1 diffusion coefficient as a function of EMT to simulate the reduced movement of TGF-β1 when tethered to FN fibrils during fibrosis. We show that incorporation of TGF-β1 tethering to FN fibrils promotes a partial EMT state, independent of exogenous TGF-β1 concentration, indicating a mechanism by which fibrotic ECM can promote a partial EMT state.Author summaryEpithelial-mesenchymal transition (EMT) is a key cellular process where epithelial cells transform and become mesenchymal. The EMT states are not binary, but instead exhibit a spectrum of partial states where epithelial cells express a combination of epithelial and mesenchymal markers, along with several markers distinct to the partial state. In diseases such as fibrosis and cancer, growing evidence supports the finding that diseased epithelial cells exist primarily in a partial EMT state. However, the mechanisms and signaling factors that drive this partial EMT state in fibrotic diseases is unclear. We use an agent-based model that looks at EMT progression in a population of cells embedded in an ECM environment with controllable fibrotic properties to provide a more systematic approach at studying spatial and temporal changes in the microenvironment that could drive EMT progression and maintain specific EMT phenotypes.
BulkRNABert: Cancer prognosis from bulk RNA-seq based language models
Authors: Gélard Maxence , Richard Guillaume , Pierrot Thomas , Cournède Paul-Henry 
Published: June 2024

AbstractRNA sequencing (RNA-seq) has become a key technology in precision medicine, especially for cancer prognosis. However, the high dimensionality of such data may restrict classic statistical methods, thus raising the need to learn dense representations from them. Transformers models have exhibited capacities in providing representations for long sequences and thus are well suited for transcriptomics data. In this paper, we develop a pre-trained transformer-based language model through self-supervised learning using bulk RNA-seq from both non-cancer and cancer tissues, following BERT’s masking method. By probing learned embeddings from the model or using parameter-efficient fine-tuning, we then build downstream models for cancer type classification and survival time prediction. Leveraging the TCGA dataset, we demonstrate the performance of our method,BulkRNABert, on both tasks, with significant improvement compared to state-of-the-art methods in the pan-cancer setting for classification and survival analysis. We also show the transfer-learning capabilities of the model in the survival analysis setting on unseen cohorts. Code available athttps://github.com/instadeepai/multiomics-open-research
The role of liprin-α1 phosphorylation in its liquid-liquid phase separation: regulation by PPP2R5D/PP2A holoenzyme
Authors: Mayer Abigail , Derua Rita , Spahn Elijah , Verbinnen Iris , Zhang Yang , Wadzinski Brian , Swingle Mark R. , Honkanen Richard , Janssens Veerle , Xia Houhui 
Published: June 2024

AbstractLiprin-α1 is a widely expressed scaffolding protein responsible for regulating cellular processes such as focal adhesion, cell motility, and synaptic transmission. Liprin-α1 interacts with many proteins including ELKS, GIT1, liprin-β, and LAR-family receptor tyrosine protein phosphatase. Through these protein-protein interactions, liprin-α1 assembles large higher-order molecular complexes; however, the regulation of this complex assembly/disassembly is unknown. Liquid-liquid phase separation (LLPS) is a process that concentrates proteins within cellular nano-domains to facilitate efficient spatiotemporal signaling in response to signaling cascades. While there is no report that liprin-α1 spontaneously undergoes LLPS, we found that GFP-liprin-α1 expressed in HEK293 cells occasionally forms droplet-like condensates. MS-based interactomics identified Protein Phosphatase 2A (PP2A)/B56δ (PPP2R5D) trimers as specific interaction partners of liprin-α1 through a canonical Short Linear Interaction Motif (SLiM) in its N-terminal dimerization domain. Mutation of this SLiM nearly abolished PP2A interaction, and resulted in significantly increased LLPS. GFP-liprin-α1 showed significantly increased droplet formation in HEK293 cells devoid of B56δ (PPP2R5D knockout), suggesting that PPP2R5D/PP2A holoenzyme inhibits liprin-α1 LLPS. Guided by reported liprin-α1 Ser/Thr phosphorylation sites, we found liprin-α1 phospho-mimetic mutant at serine 763 (S763E) is sufficient to drive its LLPS. Domain mapping studies of liprin-α1 indicated that the intrinsically disordered region, the N-terminal dimerization domain, and the SAM domains are all necessary for liprin-α1 LLPS. Finally, expression of p.E420K, a human PPP2R5D variant causing Houge-Janssens Syndrome type 1 (also known as Jordan’s Syndrome), significantly compromised suppression of liprin-α1 LLPS. Our work identified B56δ-PP2A holoenzyme as an inhibitor of liprin-α1 LLPS via regulation at multiple phosphorylation sites.
WITHDRAWN: Extracting Auditory Emotion in Noise: A distributed auxiliary auditory network supporting affect processing of non-predictably obscured vocalisations
Authors: Swanborough Huw , Frühholz Sascha 
Published: June 2024

Withdrawal StatementThe authors have withdrawn their manuscript owing to data encoding fault causing incorrect analysis. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Mitochondrial dysfunction: unraveling the elusive biology behind anti-TNF response during ulcerative colitis
Authors: Kioroglou Dimitrios , Peña-Cearra Ainize , Corraliza Ana M. , Seoane Iratxe , Castelo Janire , Panés Julian , Gómez-Irwin Laura , Rodríguez-Lago Iago , de Zarate Jone Ortiz , Fuertes Miguel , Martín-Ruiz Itziar , Gonzalez Monika , Aransay Ana Mª , Salas Azucena , Rodríguez Héctor , Anguita Juan , Abecia Leticia , Marigorta Urko M. 
Published: June 2024

AbstractBackgroundRecent studies hint at mitochondrial genes influencing UC patient response to anti-TNF treatment. We evaluated this hypothesis by following a targeted strategy to identify gene expression that captures the relationship between mitochondrial dysregulation and response to treatment. Our objective was to initially examine this relationship in colon samples and subsequently assess whether the resulting signal persists in the bloodstream.MethodsWe analyzed the transcriptome of colon samples from an anti-TNF treated murine model characterized by impaired mitochondrial activity and treatment resistance. We then transferred the findings that linked mitochondrial dysfunction and compromised treatment response to an anti-TNF treated UC human cohort. We next matched differential expression in the blood using monocytes from peripheral blood of controls and IBD patients, and we evaluated a classification process at baseline with whole blood samples from UC patients.ResultsIn human colon samples, the derived gene-set from the murine model showed differential expression, primarily enriched metabolic pathways, and exhibited similar classification capacity as genes enriching inflammatory pathways. Moreover, the evaluation of the classification signal using blood samples from UC patients at baseline highlighted the involvement of mitochondrial homeostasis in treatment response.ConclusionOur results highlight the involvement of metabolic pathways and mitochondrial homeostasis in determining treatment response and their ability to provide promising classification signals with detection levels in both colon and bloodstream.
Mendelian randomization for multiple exposures and outcomes with Bayesian Directed Acyclic Graphs exploration and causal effects estimation
Authors: Zuber Verena , Cronjé Toinét , Cai Na , Gill Dipender , Bottolo Leonardo 
Published: June 2024

AbstractCurrent Mendelian randomization (MR) methods do not reflect complex relationships among multiple exposures and outcomes as is typical for real-life applications. We introduce MrDAG the first MR method to model dependency relations within the exposures, the outcomes, and between them to improve causal effects estimation. MrDAG combines three causal inference strategies in a unified manner. It uses genetic variation as instrumental variables to account for unmeasured confounders. It performs structure learning to detect and orientate the direction of the dependencies within exposures and outcomes. Finally, interventional calculus is employed to derive principled causal effect estimates. MrDAG was motivated to unravel how lifestyle and behavioural exposures impact mental health. It highlights education and smoking as key effective points of intervention given their down-stream effects on mental health. These insights would have been difficult to delineate without modelling the causal paths between multiple exposures and outcomes at once.
Dicarbonyl stress debilitates mesothelial defense against metastasizing ovarian cancer
Authors: Mishra Satyarthi , Vidhipriya Kottpalli , Gopikrishnan Anchita , Mishra Sudiksha , Prasanna CVS , Sen Prosenjit , Bhat Ramray 
Published: June 2024

AbstractChronic metabolic disorders and aging result in accumulation of active dicarbonyls that glycate biomolecules rendering them dysfunctional. Although metabolic aberrations are known to be epidemiologically associated with faster cancer progression, cell biological determinants of such associations remain elusive. The formation of micro-metastases in epithelial ovarian cancer involves its colonization of visceral peritonea through clearance of mesothelia that line the coelom. In this study, we observe that cocultures of immortalized human coelomic MeT-5A mesothelia with human ovarian cancer cells OVCAR-3 and SK-OV-3 show greater infiltration by the latter when exposed to increasing concentrations of the dicarbonyl methylglyoxal (MG). Treatment with increasing concentrations of MG caused death and senescence within human and murine serosal mesothelia. Cells showed higher levels of advanced glycation end products, dysregulated occludens junction protein ZO-1, and disrupted localization of cortical filamentous actin and its regulator ezrin, indicating poor inter-cell adhesion. Time lapse imaging also showed impaired migration for MG-treated single mesothelia and for their collective monolayers. Agent-based computer modeling of coculture dynamics predicted that a combined effect of confluence and migration allows inter-adherent mesothelia to contain the spread of colonizing cancer cells, which was confirmed through coculture time lapses of cancer colonization within higher and lower mesothelial densities. We found ovarian cancer cells showed higher levels of glyoxalase-1 (GLO-1) enzyme, which catabolizes MG, suggesting how they escaped its cytotoxic effects. Consistent with this, treatment of OVCAR-3 with MG concurrently with pharmacological inhibition of GLO-1 showed greater cell death. Our results suggest dicarbonyl stress helps colonizing cancer cells overcome the resistance of natural homoeostatic barriers and its inhibition may, in supplementation with chemotherapy, stem metastasis.
Variation in season length and development time is sufficient to drive the emergence and coexistence of social and solitary behavioral strategies
Authors: Ruttenberg Dee M. , Levin Simon A. , Wingreen Ned S. , Kocher Sarah D. 
Published: June 2024

AbstractSeason length and its associated variables can influence the expression of social behaviors, including the occurrence of eusociality in insects. Eusociality can vary widely across environmental gradients, both within and between different species. Numerous theoretical models have been developed to examine the life history traits that underlie the emergence and maintenance of eusociality, yet the impact of seasonality on this process is largely uncharacterized. Here, we present a theoretical model that incorporates season length and offspring development time into a single, individual-focused model to examine how these factors can shape the costs and benefits of social living. We find that longer season lengths and faster brood development times are sufficient to favor the emergence and maintenance of a social strategy, while shorter seasons favor a solitary one. We also identify a range of season lengths where social and solitary strategies can coexist. Moreover, our theoretical predictions are well-matched to the natural history and behavior of two flexibly-eusocial bee species, suggesting our model can make realistic predictions about the evolution of different social strategies. Broadly, this work reveals the crucial role that environmental conditions can have in shaping social behavior and its evolution and underscores the need for further models that explicitly incorporate such variation to study evolutionary trajectories of eusociality.
Plasticity and evolution of metabolic division of labour within families
Authors: Bladon EK , Hakala SM , Kilner RM , LeBoeuf AC 
Published: June 2024

AbstractFluids produced by parents for dependent young, such as milk or regurgitate, carry molecules that assist offspring with growth, immunity and digestion, allowing the metabolic burden of development to be shared between parents and offspring. We tested whether this division of metabolic labour changes plastically and evolves when offspring are experimentally deprived of their parents’ metabolic assistance. In the burying beetleNicrophorus vespilloidesparents deposit oral fluids on their carrion nest during pre-hatching care, and facultatively transfer fluids to larvae through oral trophallaxis as post-hatching care. We analysed the oral fluid proteomes of replicate experimental populations that had been evolving for 50 generations with or without post-hatching care, and which were then allowed to raise larvae with or without post-hatching care for one experimental generation. We found that parents and larvae plastically and evolutionarily adjusted the proteins in their oral fluids when we prevented post-hatching care. When reared in the absence of post-hatching care, larvae that evolved without post-hatching care were also more capable of consuming carrion proteins than larvae that had evolved with post-hatching care, and had higher survival. Our results suggest that metabolic division of labour within families is plastically modulated, and that the extent of socially modulated plasticity can evolve rapidly when social conditions change.
Phasic alertness generates urgency and amplifies competition between evidence accumulators
Authors: Tromp Jeshua , Wurm Franz , Lucchi Federica , de Kleijn Roy , Nieuwenhuis Sander 
Published: June 2024

AbstractAlthough phasic alertness generally benefits cognitive performance, it often increases the interference caused by distracting information, resulting in impaired decision-making and cognitive control. However, it is unclear why phasic alertness has these negative effects. Here, we present a novel, biologically-informed account, according to which phasic alertness generates an evidence-independent urgency signal. This urgency signal shortens overall response times, but also amplifies competition between evidence accumulators, thus slowing down decision-making and impairing cognitive control. The key assumptions of this account are supported with pupil measurements and electrophysiological data from human decision-makers performing an arrow flanker task. We also show that a computational model of the flanker task that incorporates time-varying urgency can reproduce the behavioral effects of phasic alertness, but only when the evidence accumulators compete with each other through lateral inhibition. Our results reveal a close interplay between dynamic changes in urgency, cognitive control and evidence accumulation.