bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiscale modelling of neuronal dynamics in hippocampus CA1
Authors: Tesler Federico , Lorenzi Roberta Maria , Ponzi Adam , Castellato Claudia , Palesi Fulvia , Gandolfi Daniela , Gandini Wheeler Kingshott Claudia A.M. , Mapelli Jonathan , D’Angelo Egidio , Migliore Michele , Destexhe Alain 
Published: April 2024

AbstractThe development of biologically realistic models of brain microcircuits and regions is currently a very relevant topic in computational neuroscience. From basic research to clinical applications, there is an increasing demand for accurate models that incorporate local cellular and network specificities, able to capture a broad range of dynamics and functions associated with given brain regions. One of the main challenges of these models is the passage between different scales, going from the microscale (cellular) to the meso (microcircuit) and macroscale (region or whole-brain level), while keeping at the same time a constraint on the demand of computational resources. One novel approach to this problem is the use of mean-field models of neuronal activity to build large-scale simulations. This provides an effective solution to the passage between scales with relatively low computational demands, which is achieved by a drastic reduction in the dimensionality of the system. In this paper we introduce a multiscale modelling framework for the hippocampal CA1, a region of the brain that plays a key role in functions such as learning, memory consolidation and navigation. Our modelling framework goes from the single cell level to the macroscale and makes use of a novel mean-field model of CA1, introduced in this paper, to bridge the gap between the micro and macro scales. To develop the mean-field model we make use of a recently introduced formalism based on a bottom-up approach that is easily applicable to different neuronal models and cell types. We test and validate the model by analyzing the response of the system to the main brain rhythms observed in the hippocampus and comparing our results with the ones of the corresponding spiking network model of CA1. In addition, we show an example of the implementation of our model to study a stimulus propagation at the macro-scale, and we compare the results obtained from our model with the corresponding spiking network model of the whole CA1 area.
Activity based proteome profiling of serum serine hydrolases: application in pediatric abusive head trauma
Authors: Maret Estelle , Wiskott Kim , Shipley Tobias , Gilardi Federica , Augsburger Marc , Thomas Aurelien , Fracasso Tony , Sajic Tatjana 
Published: April 2024

AbstractPurposeTraumatic brain injury (TBI), including pediatric abusive head trauma (AHT), is the leading cause of death and disability in children and young adults worldwide. The current understanding of trauma-induced molecular changes in the brain of human subjects with intracranial haemorrhage (ICH) remains inadequate and requires further investigation to improve the outcome and management of TBI in the clinic. Calcium-mediated damage at the site of brain injury has been shown to activate several catalytic enzymes.Experimental designSerine hydrolases (SHs) are major catalytic enzymes involved in the biochemical pathways of blood coagulation, systemic inflammation and neuronal signaling. Here we investigated activity-based protein profiling (ABPP) by measuring the activity status of SH enzymes in the serum of infants with severe ICH as a consequence of AHT or atraumatic infants who died of sudden infant death syndrome (SIDS).ResultsOur proof-of-principle study revealed significantly reduced physiological activity of dozens of metabolic SHs in the serum of infants with severe AHT compared to the SIDS group, with some of the enzymes being related to neurodevelopment and basic brain metabolism.Conclusions and clinical relevanceTo our knowledge, this is the first study to investigate the ABPP of the SHs enzyme family to detect changes in their physiological activity in blood serum in severe TBI. We used antemortem (AM) serum from infants under the age of 2 years who were victims of AHT with a severe form of ICH. The analytical approach used in the proof-of-principle study shows reduced activities of serum serine lipases in AHT cases and could be further investigated in mild forms of AHT, which currently show 30% of misdiagnosed cases in clinics.
Unraveling the phylogenetic signal of gene expression from single-cell RNA-seq data
Authors: Alves Joao M , Tomás Laura , Posada David 
Published: April 2024

AbstractSingle-cell RNA sequencing (scRNA-seq) has transformed our understanding of phenotypic heterogeneity. Although the predominant focus of scRNA-seq analyses has been assessing gene expression changes, several approaches have been proposed in recent years to identify changes at the DNA level from scRNA-seq data. In this study, we evaluated the relative performance of six strategies for calling single-nucleotide variants from scRNA-seq data using 381 single-cell transcriptomes from five cancer patients. Specifically, we focused on the quality of the inferred genotypes and the resulting single-cell phylogenies. We found that scAllele, Monopogen, and Monovar consistently returned phylogenetically informative genotype calls, providing more precise signals of discrimination between tumor and normal cells within heterogeneous samples and among distinct subclonal lineages in longitudinal samples. In addition, we evaluated the evolution of gene expression along the cell phylogenies. While most transcriptomic variation was very plastic and did not correlate with the cell phylogeny, a group of genes associated with cell cycle processes showed a strong phylogenetic signal in one of the patients, underscoring a potential link between gene expression patterns and lineage-specific traits in the context of cancer progression. In summary, our study highlights the potential of scRNA-seq data for inferring cell phylogenies to decipher the evolutionary dynamics of cell populations.
Knowledge Graph-based Thought: a knowledge graph enhanced LLMs framework for pan-cancer question answering
Authors: Feng Yichun , Zhou Lu , Ma Chao , Zheng Yikai , He Ruikun , Li Yixue 
Published: April 2024

AbstractBackgroundIn recent years, Large Language Models (LLMs) have shown promise in various domains, notably in biomedical sciences. However, their real-world application is often limited by issues like erroneous outputs and hallucinatory responses.ResultsWe developed the Knowledge Graph-based Thought (KGT) framework, an innovative solution that integrates LLMs with Knowledge Graphs (KGs) to improve their initial responses by utilizing verifiable information from KGs, thus significantly reducing factual errors in reasoning. The KGT framework demonstrates strong adaptability and performs well across various open-source LLMs. Notably, KGT can facilitate the discovery of new uses for existing drugs through potential drug-cancer associations, and can assist in predicting resistance by analyzing relevant biomarkers and genetic mechanisms. To evaluate the Knowledge Graph Question Answering (KGQA) task within biomedicine, we utilize a pan-cancer knowledge graph to develop a pan-cancer question answering benchmark, named the Pan-cancer Question Answering (PcQA).ConclusionsThe KGT framework substantially improves the accuracy and utility of LLMs in the biomedical field. This study serves as a proof-of-concept, demonstrating its exceptional performance in biomedical question answering.Key PointsWe introduce a framework combining LLMs with KGs to improve factual accuracy in LLM reasoning.Our system is a flexible architecture that seamlessly integrates various LLMs.Utilizing a pan-cancer knowledge graph, we have proposed the first KGQA benchmark in the field of biomedicine.Case studies reveal our method enhanced LLMs in addressing biomedical challenges such as drug repositioning, resistance research, individualized treatment, and biomarker analysis.The method performs favorably in comparison to existing methods.
Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma
Authors: Staaf Johan , Ehinger Daniel , Brunnström Hans , Jönsson Mats , Rosengren Frida , Kotevska Marija , Karlsson Anna , Aine Mattias , Frezza Christian , Planck Maria , Arbajian Elsa 
Published: April 2024

ABSTRACTBackgroundSquamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides -tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant tumor cell metabolism has been identified as one of the hallmarks of carcinogenesis. The aim of the current study was to identify SqCC-specific metabolites and key gene regulators that could eventually be used as new anticancer targets.MethodsTranscriptional (n=156), proteomics (n=118), and mass spectrometry-based metabolomic data (n=73) were gathered for a cohort of resected early-stage lung cancers representing all major histological subgroups. SqCC-specific differentially expressed genes were integrated with proteogenomic and metabolic data using genome scale metabolic models (GEMs). Findings were validated in cohorts of tumors, normal specimens, and cancer cell lines. In situ protein expression of SLC6A8 was investigated in 213 tumors.ResultsDifferential gene expression analysis identified 280 SqCC-specific genes, of which 57 were connected to metabolites through GEMs. Metabolic profiling identified 7 SqCC-specific metabolites, of which increased creatine and decreased phosphocholine levels matched to SqCC-specific elevated expression ofSLC6A8and decreased expression ofCHKA,part of respective GEMs. Expression of both genes appeared tumor cell-associated, and in particular the elevated expression ofSLC6A8identified SqCC also in stage IV disease.ConclusionElevated creatine levels and the overexpression of its transporter protein SLC6A8 appear as a distinct metabolic feature of SqCC. Considering ongoing clinical trials focused on SLC6A8 inhibition in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.
Gill regeneration in the mayflyCloeonuncovers new molecular pathways in insect regeneration
Authors: Martin-Blanco Carlos A. , Navarro Pablo , Esteban-Collado José , Serras Florenci , Almudi Isabel , Casares Fernando 
Published: April 2024

ABSTRACTThe capacity to regenerate lost or damaged organs is widespread among animals, and yet, the species in which regeneration has been experimentally probed using molecular and functional assays is very small. This is also the case for insects, for which we still lack a complete picture of their regeneration mechanisms and the extent of conservation of these mechanisms. Here we contribute to filling this gap by investigating regeneration in the mayflyCloeon dipterum.Mayflies, or Ephemeroptera, appeared early in the evolution of insects. We focus on the abdominal gills ofCloeonnymphs, which are critical for osmoregulation and gas exchange. After amputation, gills re-grow faster than they do during normal development. Direct cell count and EdU proliferation assays indicate that growth acceleration involves an uniform increase in cell proliferation throughout the gill, rather than a localized growth zone. Transcriptomic analysis reveals an early enrichment in cell cycle-related genes, in agreement with fast proliferation. Several other gene classes are also enriched in regenerating gills, including protein neddylation and other proteostatic processes. We then showed that protein neddylation, the activin signaling pathway or the mRNA-binding protein Lin28, among other genes and processes, are required forDrosophilalarval/pupal wing regeneration, and that some of these genes may have a regeneration-specific function in the wing. Globally, our results contribute to elucidating regeneration mechanisms in mayflies and suggest a conservation of regeneration mechanisms across insects, as evidenced by the regenerative role of candidate genes identified inCloeonin the distantDrosophila.
Loss of developmentally derived Irf8+ macrophages promotes hyperinnervation and arrhythmia in the adult zebrafish heart
Authors: Paquette Shannon E. , Oduor Cliff I. , Gaulke Amy , Stefan Sabina , Bronk Peter , Dafonseca Vanny , Barulin Nikolai , Lee Cadence , Carley Rachel , Morrison Alan R. , Choi Bum-Rak , Bailey Jeffrey A. , Plavicki Jessica S. 
Published: April 2024

SUMMARYRecent developments in cardiac macrophage biology have broadened our understanding of the critical functions of macrophages in the heart. As a result, there is further interest in understanding the independent contributions of distinct subsets of macrophage to cardiac development and function. Here, we demonstrate that genetic loss of interferon regulatory factor 8 (Irf8)-positive embryonic-derived macrophages significantly disrupts cardiac conduction, chamber function, and innervation in adult zebrafish. At 4 months post-fertilization (mpf), homozygousirf8st96/st96mutants have significantly shortened atrial action potential duration and significant differential expression of genes involved in cardiac contraction. Functionalin vivoassessments via electro- and echocardiograms at 12 mpf reveal thatirf8mutants are arrhythmogenic and exhibit diastolic dysfunction and ventricular stiffening. To identify the molecular drivers of the functional disturbances inirf8null zebrafish, we perform single cell RNA sequencing and immunohistochemistry, which reveal increased leukocyte infiltration, epicardial activation, mesenchymal gene expression, and fibrosis.Irf8null hearts are also hyperinnervated and have aberrant axonal patterning, a phenotype not previously assessed in the context of cardiac macrophage loss. Gene ontology analysis supports a novel role for activated epicardial-derived cells (EPDCs) in promoting neurogenesis and neuronal remodelingin vivo. Together, these data uncover significant cardiac abnormalities following embryonic macrophage loss and expand our knowledge of critical macrophage functions in heart physiology and governing homeostatic heart health.
Neural and computational mechanisms of effort under the pressure of a deadline
Authors: Pisauro M. Andrea , Pollicino Daniele , Fisher Lucy , Apps Matthew A. J. 
Published: April 2024

SummaryDeadlines fundamentally shape the motivation for effort. Research examining effort-based choices finds high effort is an avoided cost. However, this work overlooks the fact that effort can be valuable when it makes progress on long-term goals before deadlines. We test a new framework where motivation depends on deadline pressure (work remaining / time remaining). Across three studies we use computational modelling on novel tasks examining effort-based decisions when effort makes progress on goals with deadlines. In support of hypotheses, deadline pressure significantly impacts decision-making, shifting people from avoiding effort, to seeking and valuing it. Using ultra-high-field fMRI, we show that functionally connected putamen and midcingulate cortex (MCC) sub-regions process and update estimates of deadline pressure, with distinct anterior cingulate and putamen sub-regions processing the costs or added value of effort. We show the neurocomputational mechanisms for how deadline pressure shapes motivation, and that keep us ‘on track’ for our goals.
Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1
Authors: Isu Ugochi H. , Polasa Adithya , Moradi Mahmoud 
Published: April 2024

AbstractCannabinoid receptor 1 (CB1) is a G protein-coupled receptor (GPCR) that regulates critical physiological processes including pain, appetite, and cognition. Understanding the confor- mational dynamics of CB1 associated with transitions between inactive and active signaling states is imperative for developing targeted modulators. Using microsecond-level all-atom molecular dynamics (MD) simulations, we identified marked differences in the conformational ensembles of inactive and active CB1 inapo. The inactive state exhibited substantially in- creased structural heterogeneity and plasticity compared to the more rigidified active state in the absence of stabilizing ligands. Transmembrane helices TM3 and TM7 were identified as distinguishing factors modulating the state-dependent dynamics. TM7 displayed amplified fluctuations selectively in the inactive state simulations attributed to disruption of conserved electrostatic contacts anchoring it to surrounding helices in the active state. Additionally, we identified significant reorganizations in key salt bridge and hydrogen bond networks con- tributing to the CB1 activation/inactivation. For instance, D213-Y224 hydrogen bond and D184-K192 salt bridge showed marked rearrangements between the states. Collectively, these findings reveal the specialized role of TM7 in directing state-dependent CB1 dynamics through electrostatic switch mechanisms. By elucidating the intrinsic enhanced flexibility of inactive CB1, this study provides valuable insights into the conformational landscape enabling functional transitions. Our perspective advances understanding of CB1 activation mechanisms and offers opportunities for structure-based drug discovery targeting the state- specific conformational dynamics of this receptor.Graphic for manuscriptFor Table of Contents Only
A cross-species framework for investigating perceptual evidence accumulation
Authors: Chakravarty Sucheta , Delgado-Sallent Cristina , Kane Gary A. , Xia Hongjie , Do Quan H. , Senne Ryan A. , Scott Benjamin B. 
Published: April 2024

SummaryCross-species studies are important for a comprehensive understanding of brain functions. However, direct quantitative comparison of behaviors across species presents a significant challenge. To enable such comparisons in perceptual decision-making, we developed a synchronized evidence accumulation task for human and non-human animals, by aligning mechanics, stimuli, and training. The task was readily learned by rats, mice and humans, with each species exhibiting qualitatively similar performance. Quantitative model comparison revealed that all three species employed an evidence accumulation strategy, but differed in speed, accuracy, and key decision parameters. Human performance prioritized accuracy, whereas rodent performance was limited by internal time-pressure. Rats optimized reward rate, while mice appeared to switch between evidence accumulation and other strategies trial-to-trial. Together, these results reveal striking similarities and species-specific priorities in decision-making. Furthermore, the synchronized behavioral framework we present may facilitate future studies involving cross-species comparisons, such as evaluating the face validity of animal models of neuropsychiatric disorders.HighlightsDevelopment of an evidence accumulation task for rats and miceSynchronized video game allows direct comparisons with humansRat, mouse and human behavior are well fit by the same decision modelsModel parameters reveal species-specific priorities in accumulation strategy
Placental malaria is associated with a TLR–Endothelin-3–oxidative damage response in human placenta tissues
Authors: Chenge Samuel , Mbalitsi Melvin , Ngure Harrison , Obimbo Moses , Singoei Mercy , Kangogo Mourine , Kanoi Bernard N. , Gitaka Jesse , Kobia Francis M. 
Published: April 2024

AbstractPlacental malaria, which is mainly caused by the sequestration ofPlasmodium falciparum- infected erythrocytes in the placenta, is an important driver of poor pregnancy outcomes, including fetal growth restriction, preterm birth, and stillbirth. However, the mechanisms underlying its adverse outcomes are unclear. Mouse models have shown that placental malaria triggers a proinflammatory response in the placenta, which is accompanied by a fetal Toll-like receptor (TLR)4-mediated innate immune response associated with improved fetal outcomes. Here, we used hematoxylin and eosin staining to identify placental malaria positive and negative samples in our biobank of placentas donated by women living in a malaria-endemic region of Kenya and assessed the impact of placental malaria on the expression of TLRs, Endothelins, and oxidative damage. RT-qPCR analysis revealed that placental malaria was associated with an upregulation of TLR4, TLR7, and Endothelin-3. Moreover, immunohistochemistry showed that placental malaria was associated with elevated expression levels of the oxidative DNA damage marker, 8- hydroxy-2’-deoxyguanosine, while RT-qPCR revealed that this was accompanied by an upregulation of p21, an inhibitor of cell cycle progression and marker of cellular response to DNA damage. These findings allude to a novel mechanism of placental malaria pathogenesis driven by a TLR–Endothelin-3–oxidative DNA damage signaling axis.
Nuclear size-regulated emergence of topological packing order on growing human lung alveolospheres
Authors: Tang Wenhui , Huang Jessie , Pegoraro Adrian F. , Zhang James H. , Tang Yiwen , Bi Dapeng , Kotton Darrell N. , Guo Ming 
Published: April 2024

AbstractWithin multicellular living systems, cells coordinate their positions with spatiotemporal accuracy to form various structures, setting the clock to control developmental processes and trigger maturation. These arrangements can be regulated by tissue topology, biochemical cues, as well as mechanical perturbations. However, the fundamental rules of how local cell packing order is regulated in forming three-dimensional (3D) multicellular architectures remain unclear. Furthermore, how cellular coordination evolves during developmental processes, and whether this cell patterning behavior is indicative of more complex biological functions, is largely unknown. Here, using human lung alveolospheres as a model system, by combining experiments and numerical simulations, we find that, surprisingly, cell packing behavior on alveolospheres resembles hard-disk packing but with increased randomness; the stiffer cell nuclei act as the ‘hard disks’ surrounded by deformable cell bodies. Interestingly, we observe the emergence of topological packing order during alveolosphere growth, as a result of increasing nucleus-to-cell size ratio. Specifically, we find more hexagon-concentrated cellular packing with increasing bond orientational order, indicating a topological gas-to-liquid transition. Additionally, by osmotically changing the compactness of cells on alveolospheres, we observe that the variations in packing order align with the change of nucleus-to-cell size ratio. Together, our findings reveal the underlying rules of cell coordination and topological phases during human lung alveolosphere growth. These static packing characteristics are consistent with cell dynamics, together suggesting that better cellular packing stabilizes local cell neighborhoods and may regulate more complex biological functions such as organ development and cellular maturation.
Biosynthesis of Arcyriaflavin F fromStreptomyces venezuelaeATCC 10712
Authors: Lai Hung-En , Tanner Lewis , Kennedy Agata , Chee Soo Mei , Freemont Paul S , Moore Simon J 
Published: April 2024

AbstractIndolocarbazoles are natural products with a broad spectrum of reported bioactivities. A distinct feature of indolocarbazole biosynthesis is the modification of the indole and maleimide rings by regioselective tailoring enzymes. Here, we study a new indolocarbazole variant, which is encoded by theacfXODCPgenes fromStreptomyces venezuelaeATCC 10712. First, we characterise this pathway by expressing theacfXODCPgenes inStreptomyces coelicolor, which led to the production of a C-5/C-5’-dihydroxylated indolocarbazole. We name this new product arcyriaflavin F. Second, we demonstrate the flavin-dependent monooxygenase AcfX catalyses the C-5/C-5’ dihydroxylation of the unsubstituted arcyriaflavin A into arcyriaflavin F. Interestingly, AcfX shares homology to EspX from erdasporine A biosynthesis, which instead catalyses a single C-6 indolocarbazole hydroxylation. In summary, we report a new indolocarbazole biosynthetic pathway and a regioselective C-5 indole ring tailoring enzyme AcfX.