bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of genetic (co)variances during the worldwide invasion ofDrosophila suzukii
Authors: Fraimout Antoine , Chantepie Stéphane , Navarro Nicolas , Teplitsky Céline , Debat Vincent 
Published: January 2024

AbstractBiological invasions offer particularly convenient situations to study phenotypic evolution in natural populations. In particular, the comparison of derived, invasive populations with ancestral extant populations allows to investigate the relative impact of neutral demographic events, genetic constraints and selection on the evolution of phenotypes. In this paper, focusing on the worldwide invasion ofDrosophila suzukii(Matsumara, 1931), we investigate how phenotypic divergence among populations is constrained by the genetic correlations summarized in the genetic covariance matrixGand howGitself evolves throughout periods of drift and selection. Leveraging invasion history resolved by population genetics approaches, we compared wing shapeGmatrices among ancestral native and derived invasive populations, contrasting patterns of quantitative divergence among populations to neutral expectations. Our results show moderate yet significant quantitative genetic differentiation of wing shape amongD. suzukiipopulations and a relative stability in the structure ofG, presenting a roughly spherical shape but slightly different volumes. These characteristics likely reflect the demographic history of populations and suggest a low level of genetic constraint on adaptive evolution. The divergence among populations was greater than expected under a purely neutral model of evolution, compatible with an effect of selection on wing shape. Overall, our study suggests that selection, drift but not constraints affected the early stages of wing shape evolution duringD. suzukiiinvasion.
Rab10 regulates neuropeptide release by maintaining Ca2+homeostasis and protein synthesis
Authors: Dong Jian , Chen Miao , van Weering Jan R. T. , Li Ka Wan , Smit August B , Toonen Ruud F. , Verhage Matthijs 
Published: January 2024

AbstractDense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10’s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+dynamics and protein synthesis. Gene ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER/ribosomal proteins, including the Ca2+-pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+levels were depleted and Ca2+homeostasis was impaired in Rab10-depleted neurons. However, Ca2+entry using a Ca2+ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.
Hybrid cancer stem cells utilise vascular tracks for collective streaming invasion in a metastasis-on-a-chip device
Authors: Scemama Alice , Lunetto Sophia , Tailor Artysha , Di Cio Stefania , Ambler Leah , Coetzee Abigail , Cottom Hannah , Khurram Syed Ali , Gautrot Julien , Biddle Adrian 
Published: January 2024

AbstractCancer stem cells (CSCs) drive cancer metastatic dissemination. They do not do so in a vacuum, and the important influence of the tumour microenvironment (TME) on metastatic dissemination is becoming increasingly recognised. Therapeutic targeting of CSC-TME interactions may be a promising route to suppression of tumour metastasis. However, we must first understand how interactions with the TME influence CSC metastatic dissemination. To achieve this understanding, there is a need for experimental models that enable the analysis of dynamic interactions at single cell resolution within a complex environment. To this end, we utilise a metastasis-on-a-chip device to produce a 3Din vitromodel of CSC interaction with a developing microvasculature, that is amenable to precise imaging and real time studies at single cell resolution. We show that the invasive phenotype of oral squamous cell carcinoma (OSCC) cells is markedly altered when in proximity to a microvasculature, with a switch to a hybrid CSC phenotype that undergoes collective streaming invasion. Mechanistically, ECM compression by the developing vasculature creates an environment that is refractory to cancer invasion, whilst leaving abandoned vascular tracks that can be utilised by hybrid CSCs for collective streaming invasion. Human tissue studies identify streaming invasion in association with vascularised regions in OSCC specimens. These findings elucidate the influence of the vasculature on CSC metastatic dissemination in OSCC, and the role of hybrid CSC invasion plasticity in overcoming this TME constraint.
Mechanisms of Cholesterol Binding to LAT1
Authors: Hutchinson Keino , Schlessinger Avner 
Published: January 2024

ABSTRACTThe human L-type amino acid transporter 1 (LAT1; SLC7A5), is an amino acid exchanger protein, primarily found in the blood-brain-barrier, placenta, and testis, where it plays a key role in amino acid homeostasis. Cholesterol is an essential lipid that has been highlighted to play a role in regulating the activity of membrane transporters such as LAT1, yet little is known about the molecular mechanisms driving this phenomenon. Here we perform a comprehensive computational analysis to investigate cholesterol’s role in LAT1 structure and function, focusing on four cholesterol binding sites (CHOL1-4) identified in a recent LAT1-apo inward-open conformation cryo-EM structure. We performed four independent molecular dynamics (MD) simulations of LAT1 bound to each cholesterol molecule, as well as molecular docking, free energy calculation by MM/GBSA, and other analysis tools, to investigate LAT1-cholesterol interactions. Our results indicate that CHOL3 provides the most stable binding interactions with LAT1, and CHOL3 and CHOL1 sites have the largest stabilizing effect on LAT1’s primary functional motifs (hash and bundle) and substrate binding site. Our analysis also uncovers an alternative cholesterol binding site to the originally assigned CHOL1. Our study improves the understanding of cholesterol’s modulatory effect on LAT1 and proposes candidate sites for discovery of future allosteric ligands with rational design.
A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs
Authors: Notartomaso Serena , Antenucci Nico , Mazzitelli Mariacristina , Rovira Xavier , Boccella Serena , Ricciardi Flavia , Liberatore Francesca , Gomez-Santacana Xavier , Imbriglio Tiziana , Cannella Milena , Zussy Charleine , Luongo Livio , Maione Sabatino , Goudet Cyril , Battaglia Giuseppe , Llebaria Amadeu , Nicoletti Ferdinando , Neugebauer Volker 
Published: January 2024

AbstractKnowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of BLA input, and decreased feedforward inhibition of amygdala output neurons by BLA. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.
The NRF2/ID2 Axis in Vascular Smooth Muscle Cells: Novel Insights into the Interplay between Vascular Calcification and Aging
Authors: Xu Mulin , Wei Xiuxian , Wang Jinli , Li Yi , Huang Yi , Cheng Anying , He Fan , Zhang Le , Zhang Cuntai , Liu Yu 
Published: January 2024

AbstractOBJECTIVEVascular calcification (VC) significantly contributes to cardiovascular morbidity and mortality and escalates with age. However, effective pharmaceutical interventions are lacking, and the molecular mechanisms linking aging to VC remain elusive. This study explores the role of nuclear factor erythroid 2-related factor 2 (NRF2) in VC, specifically focusing on the interplay between vascular senescence and oxidative stress (OS).APPROACH AND RESULTSUsing a chronological aging mouse model, we noted a significant decline in the expression and activity of Nrf2 in the aortas of aged mice, coinciding with increased medial VC. Administering NRF2 activators effectively reduced this calcification. In the vascular smooth muscle cell (VSMC)-specific Nrf2 knockout (Nrf2SMCKO) models, created using adenine and Vitamin D, there was an increase in calcium deposition within the aortic medial layer, alongside heightened VSMC senescence and OS. Furthermore, NRF2 knockout exacerbated VC in aortic rings and primary VSMCs in high-phosphate conditions, while Nrf2 overexpression in VSMCs inhibited calcium deposition by alleviating cell senescence and OS. RNAseq analysis of the aortas fromNrf2SMCKOand control mice highlighted a significant downstream regulator of Inhibitor of DNA Binding 2 (ID2). Our results show that reduced NRF2 levels lead to increased VSMC senescence, characterized by heightened p16 expression and diminished ID2 expression. Inhibiting ID2 negated NRF2’s protective effects against VSMC senescence and VC.CONCLUSIONThis study emphasizes the critical role of NRF2 dysfunction in the nexus of vascular senescence, OS, and VC. It proposes the NRF2-ID2 axis in VSMCs as a promising therapeutic target for reducing VC and mitigating age-related cardiovascular diseases.HighlightsDecline in NRF2 activity is linked to increased vascular calcification (VC) and aging.VSMC-specificNrf2knockout causes a remarkable exacerbation of arterial calcification.NRF2 alleviates VC by inhibiting oxidative stress and VSMC senescence.ID2 contributes to the protective role of NRF2 in VSMC senescence and VC.
Reconstructing cell histories in space with image-readable base editor recording
Authors: Chadly Duncan M , Frieda Kirsten L , Gui Chen , Klock Leslie , Tran Martin , Sui Margaret Y , Takei Yodai , Bouckaert Remco , Lois Carlos , Cai Long , Elowitz Michael B. 
Published: January 2024

AbstractKnowing the ancestral states and lineage relationships of individual cells could unravel the dynamic programs underlying development. Engineering cells to actively record information within their own genomic DNA could reveal these histories, but existing recording systems have limited information capacity or disrupt spatial context. Here, we introducebaseMEMOIR, which combines base editing, sequential hybridization imaging, and Bayesian inference to allow reconstruction of high-resolution cell lineage trees and cell state dynamics while preserving spatial organization. BaseMEMOIR stochastically and irreversibly edits engineered dinucleotides to one of three alternative image-readable states. By genomically integrating arrays of editable dinucleotides, we constructed an embryonic stem cell line with 792 bits of recordable, image-readable memory, a 50-fold increase over the state of the art. Simulations showed that this memory size was sufficient for accurate reconstruction of deep lineage trees. Experimentally, baseMEMOIR allowed precise reconstruction of lineage trees 6 or more generations deep in embryonic stem cell colonies. Further, it also allowed inference of ancestral cell states and their quantitative cell state transition rates, all from endpoint images. baseMEMOIR thus provides a scalable framework for reconstructing single cell histories in spatially organized multicellular systems.
Life stage impact on the human skin ecosystem: lipids and the microbial community
Authors: Pagac Martin P. , Davient Bala , Lam Hilbert Yuen In , Ravikrishnan Aarthi , Chua Wee Ling Esther , Muralidharan Sneha , Sridharan Aishwarya , Irudayaswamy Antony S. , Srinivas Ramasamy , Wearne Stephen , Mohamed Naim Ahmad Nazri , Ho Xin Pei Eliza , Ng H. Q. Amanda , Kwah Junmei Samantha , Png Eileen , Bendt Anne K. , Wenk Markus R. , Torta Federico , Nagarajan Niranjan , Common John , Seng Chong Yap , Tham Elizabeth Huiwen , Shek Lynette Pei-Chi , Loo Evelyn Xiu Ling , Chambers John , Yew Yik Weng , Loh Marie , Dawson Thomas L. 
Published: January 2024

AbstractWhile research into gut-microbe interactions is common and advanced, with multiple defined impacts on human health, studies exploring the significance of skin-microbe interactions remain underrepresented. Skin is the largest human organ, has a vast surface area, and is inhabited by a plethora of microorganisms which metabolise sebaceous lipids. Sebaceous free fatty acids are metabolized into bioactive lipid mediators with immune-modulatory properties by skin-resident microbes, includingMalassezia. Intriguingly, many of the same lipid mediators are also found on human skin, implying these compounds may have microbial or mixed microbial/human origin. To support this hypothesis, we isolated lipids and microbial DNA from the skin of prepubescent, adult, pre- and post-menopausal volunteers and performed correlational analyses using skin lipidomics and metagenomics to compare lipid mediator profiles and microbiome compositions on skin with either low or high sebaceous gland activity. We found that specific microbial taxonomies were positively and negatively correlated with skin lipid mediator species with high statistical significance. 2Din vitroco-cultures withMalasseziaand keratinocytes also directly linked the production of specific lipid mediators, detected on healthy human skin, to secretion of immuno-stimulatory cytokines. Together, these findings further support the hypothesis that microbial-derived skin lipid mediators influence healthy skin homeostasis and skin disease development and progression, thereby spotlighting the relevance of the skin microbiome’s footprint on human health.
Fast and lightweight cell atlas approximations across organs and organisms
Authors: Xu Ying , Ahn Joanna , Zanini Fabio 
Published: January 2024

AbstractOmic technologies at single-cell resolution are reshaping our understanding of cellular diversity. The generation of cell atlases that capture the cellular composition of an entire individual is progressing rapidly. However, the science of organising and extracting information from these atlases is still in its infancy and for many biomedical researchers atlas exploration remains challenging. Here, we leveraged extensive experience in single-cell data analytics to pinpoint three major accessibility barriers to cell atlases, related to (i) programming skill or language, (ii) scalability, and (iii) dissemination standards. To help researchers overcome these barriers, we developed cell atlas approximations, a computational approach enabling the analysis of cell atlases across organs and organisms without programming skills, rapidly, and at scale. The web interface athttps://atlasapprox.orgfacilitates the exploration of cell atlases in 19 species across the tree of life through a chatbot driven by frontend natural language processing. In parallel, application programming interfaces streamline data access for computational researchers and include specialised packages for Python, R, JavaScript, and Bash. Supported queries include marker gene identification, cross-organ comparisons, cell embeddings, gene sequences, searches for similar features, and bidirectional zoom between cell types and cell states. Most queries are answered in less than 1.5 seconds thanks to lossy data compression algorithms based on cell annotations and similarity graphs. Compared to traditional cell atlas analysis, this approach can reduce data size by more than 100 times and accelerate workflows by up to 100,000 times. Atlas approximations aim to make the exploration of cell atlases accessible to anyone in the world.
Tumor relapse-free survival prognosis related consistency between cancer tissue and adjacent normal tissue in drug repurposing for solid tumor via connectivity map
Authors: Hao Mingyue , Li Dandan , Qiao Yuanyuan , Xiong Ming , Li Jun , Ma Wei 
Published: January 2024

AbstractTraditional drug discovery encounters challenges, including high costs, time-intensive processes, and inherent risks. Drug repurposing emerges as a compelling alternative strategy to identify new indications for investigational or approved drugs, circumventing these obstacles. Among the various drug repurposing methods, the Disease-specific Signature-based Connectivity Map (Cmap) approach is widely utilized. However, the commonly employed method for constructing disease-specific signatures, known as Differentially Expressed Genes (DEG), faces issues related to inconsistencies between dysregulated genes and the prognosis of genes in tumor tissue, as well as discrepancies in prognosis genes between tumor and normal tissues.In this study, we propose a novel approach, Prognosis Consistency Scoring (PCS), aimed at addressing these inconsistencies. PCS measures the consistency of gene prognosis between tumor and normal tissues by combining the Recurrence-Free Survival (RFS) prognosis power of genes in both contexts. Disease-specific signatures are then constructed based on PCS, and drug repurposing is performed using the Cmap and Lincs Unified Environment (CLUE). Validation of predicted drugs is conducted using data from DrugBank and ClinicalTrials databases.Our findings reveal that the aforementioned inconsistencies are pervasive. Compared to signatures based on DEGs, PCS-based signatures exhibit superior performance, identifying more drugs with higher prediction accuracy, as confirmed by DrugBank annotations. Notably, a significant proportion of predicted drugs without corresponding indications were subsequently validated in the ClinicalTrials database. Additionally, PCS-based signatures demonstrate elevated disease specificity and association with Drug Related Gene (DRG).
Threshold-Free Network-Oriented Statistics in Neuroscience
Authors: Hao Zexuan , Wang Pei , Xia Xiaoyu , Pan Yu , Dou Weibei 
Published: January 2024

AbstractNetwork neuroscience has emerged as an indispensable tool for studying brain structure and function. Currently, the network-based statistic (NBS) procedure is widely used for dealing with massive multiple testing/comparison problems in brain networks. However, the NBS requires choosing a hard cluster-forming threshold, lacking objective rules. A powerful and flexible statistical framework is urgently needed with growing interest in finer-grained network explorations across modalities and scales. Here, we introduce a permutation-based framework—”Threshold-Free Network-Oriented Statistics” (TFNOS). It integrates two “threshold-free” pathways: traversing all cluster-forming thresholds (TT) and using predefined clusters (PC). The TT procedure, building upon the threshold-free network-based statistics, requires setting additional parameters. The PC procedures comprise six variants given the degree of freedom in pooling data, null distribution construction, and controlled error rate. Using numerical simulations, we evaluated the performance of the TT procedure under 600 parameter combinations, then benchmarked TFNOS procedures and baselines across different topologies of effects, sample sizes, and effect sizes, and finally provided illustrative examples with real data. We offer recommended parameter values that allow the TT procedure to stably maintain leading power, while empirically controlling the false discovery rate (FDR) beyond only weakly controlling the familywise error rate (FWER). Notably, the relevant parameters commonly employed in the field appear overly liberal. Furthermore, for the PC procedures, FDR-controlling variants showed improved power compared to FWER-controlling variants, and some of them are simple but do not compromise power. The nonparametric PC procedures allow the selection of any test statistics considered appropriate. Overall, the TFNOS is a generalized framework for inference on edges/nodes of undirected/directed brain networks. We provide empirical and principled criteria for selecting appropriate procedures and may enhance the reproducibility and sensitivity of future brain research.
Live-cell imaging under centrifugation characterized the cellular force for nuclear centration in theCaenorhabditis elegansembryo
Authors: Goda Makoto , Shribak Michael , Ikeda Zenki , Okada Naobumi , Tani Tomomi , Goshima Gohta , Oldenbourg Rudolf , Kimura Akatsuki 
Published: January 2024

ABSTRACTOrganelles in cells are appropriately positioned, despite crowding in the cytoplasm. However, our understanding of the force required to move large organelles, such as the nucleus, inside the cytoplasm is limited, in part owing to a lack of accurate methods for measurement. We devised a novel method to apply forces to the nucleus of living, wild-typeCaenorhabditis elegansembryos to measure the force generated inside the cell. We utilized a centrifuge polarizing microscope (CPM) to apply centrifugal force and orientation-independent differential interference contrast (OI-DIC) microscopy to characterize the mass density of the nucleus and cytoplasm. The cellular forces moving the nucleus toward the cell center increased linearly at ∼14 pN/μm depending on the distance from the center. The frictional coefficient was ∼1,100 pN s/μm. The measured values were smaller than previously reported estimates for sea urchin embryos. The forces were consistent with the centrosome-organelle mutual pulling model for nuclear centration. Frictional coefficient was reduced when microtubules were shorter or detached from nuclei in mutant embryos, demonstrating the contribution of astral microtubules. Finally, the frictional coefficient was higher than a theoretical estimate, indicating the contribution of uncharacterized properties of the cytoplasm.