bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capture of Human Neuromesodermal and Posterior Neural Tube Axial Stem Cells
Authors: Kelle Dolunay , Ugur Enes , Rusha Ejona , Shaposhnikov Dmitry , Livigni Alessandra , Horschitz Sandra , Davoudi Mahnaz , Blutke Andreas , Bushe Judith , Sterr Michael , Arkhipova Ksenia , Tak Benjamin , de Vries Ruben , Hochane Mazène , Spruijt Britte , Ali Aicha Haji , Lickert Heiko , Feuchtinger Annette , Koch Philipp , Mann Matthias , Leonhardt Heinrich , Wilson Valerie , Drukker Micha 
Published: March 2024

ABSTRACTThe spinal cord, nerves, and skeletal muscles arise from neuromesodermal progenitors (NMPs). We have developed a growth-factor screening strategy, utilizing ES and iPS cells, facilitating the indefinite self-renewal of two types of human axial stem cells (AxSCs), closely resembling mouse NMPs (NM-AxSCs) and posterior neural tube progenitors (N-AxSCs). Under specific regimens— Wnt/CHIR99021, FGF2, and TGF-β inhibitor SB431542 (CFS) and excluding FGF2 (CS), respectively—these AxSCs self-renew and sustain telomeres. Single cell transcriptomics and proteomics have revealed expression of posterior growth-zone and dorsoventral neural tube markers in NM-AxSCs, and correspondingly, differentiation to a wide spectrum of neural tube neurons and myocytes. N-AxSCs rapidly matured into dorsal sensory subsets and neural crest. Crucially, neither AxSC type produces teratomas, and analogous mouse NM-AxSCs integrated successfully into the neural tube and somites. Capturing of AxSCs from patient and GMP ES / iPS cells without transgenesis unveils ontogeny and promises modeling and therapy in neuropathies.
Distinct Gene Regulatory Dynamics Drive Skeletogenic Cell Fate Convergence During Vertebrate Embryogenesis
Authors: Wang Menghan , Di Pietro-Torres Ana , Feregrino Christian , Luxey Maëva , Moreau Chloé , Fischer Sabrina , Fages Antoine , Tschopp Patrick 
Published: March 2024

AbstractCell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being paramount to their evolutionary success. A prime example are the skeletogenic cells of vertebrates that form the basis of their developing endoskeletons. Depending on anatomical location, these cells originate from three different embryonic precursor lineages – the neural crest, the somites, and the lateral plate mesoderm – yet they converge developmentally towards similar cellular phenotypes. Furthermore, these lineages have gained ‘skeletogenic competency’ at distinct timepoints during vertebrate evolution, thus questioning to what extent different parts of the vertebrate skeleton rely on truly homologous cell types.Here, we investigate how lineage-specific molecular properties of the three precursor pools are integrated at the gene regulatory level, to allow for phenotypic convergence towards a skeletogenic cell fate. Using single-cell transcriptomics and chromatin accessibility profiling along the precursor-to-skeletogenic cell continuum, we examine the gene regulatory dynamics associated with this cell fate convergence. We find that distinct transcription factor profiles are inherited from the three precursor states, and that lineage-specific enhancer elements integrate these different inputs at thecis-regulatory level, to execute a core skeletogenic program.We propose a lineage-specific gene regulatory logic for skeletogenic convergence from three embryonic precursor pools. Early skeletal cells in different body parts thus share only a partial ‘deep homology’. This regulatory uncoupling may render them amenable to individualized selection, to help to define distinct morphologies and biomaterial properties in the different parts of the vertebrate skeleton.
Temporal prediction captures retinal spiking responses across animal species
Authors: Taylor Luke , Zenke Friedemann , King Andrew J. , Harper Nicol S. 
Published: March 2024

AbstractThe retina’s role in visual processing has been viewed as two extremes: an efficient compressor of incoming visual stimuli akin to a camera, or as a predictor of future stimuli. Addressing this dichotomy, we developed a biologically-detailed spiking retinal model trained on natural movies under metabolic-like constraints to either encode the present or to predict future scenes. Our findings reveal that when optimized for efficient prediction∼100 ms into the future, the model not only captures retina-like receptive fields and their mosaic-like organizations, but also exhibits complex retinal processes such as latency coding, motion anticipation, differential tuning, and stimulus-omission responses. Notably, the predictive model also more accurately predicts the way retinal ganglion cells respond across different animal species to natural images and movies. Our findings demonstrate that the retina is not merely a compressor of visual input, but rather is fundamentally organized to provide the brain with foresight into the visual world.
Cytosolic sodium accumulation is a common danger signal triggering endocytic dysfunction and NLRP3 inflammasome activation
Authors: Mangan Matthew S.J. , Akbal Anil , Rivara Sophie , Schröder Agnes , Horvath Gabor , Walch Philipp , Hegermann Jan , Kaiser Romina , Duthie Fraser , Selkrig Joel , Jantsch Jonathan , Gerhard Ralf , Wachten Dagmar , Latz Eicke 
Published: March 2024

SummaryDetecting and responding to noxious molecules internalized within the endolysosomal system, including bacterial toxins and particulate matter, is essential to prevent cellular intoxication and damage. Here, we demonstrate that the NLRP3 inflammasome detects perturbations of the endolysosomal system by large clostridial toxins, including toxin B fromClostridioides difficile, as well as monosodium urate and silica crystals in human macrophages. These molecules cause sodium efflux from the endolysosomal system into the cytosol, driving cytosolic sodium accumulation. The rapid increase in cytosolic sodium subsequently triggers cell swelling and inhibits endocytic trafficking to activate the NLRP3 inflammasome. Furthermore, we demonstrate that cytosolic sodium accumulation is a common trigger for NLRP3 activation by non-particulate stimuli, including nigericin and inhibition of the Na+/K+ATPase. Our findings reveal that accumulation of cytosolic sodium is the common denominator underlying activation of the NLRP3 inflammasome upon exposure to different danger signals.
Selective regulation of corticostriatal synapses by astrocytic phagocytosis
Authors: Kim Ji-young , Kim Hyeyeon , Chung Won-Suk , Park Hyungju 
Published: March 2024

AbstractIn the adult brain, neural circuit homeostasis depends on the constant turnover of synapses via astrocytic phagocytosis mechanisms. However, it remains unclear whether this process occurs in a circuit-specific manner. Here, we reveal that astrocytes target and reorganize excitatory synapses in the striatum. Using model mice lacking astrocytic phagocytosis receptors in the dorsal striatum, we found that astrocytes constantly remove corticostriatal synapses rather than thalamostriatal synapses. This preferential elimination suggests that astrocytes play a selective role in modulating corticostriatal plasticity and functions via phagocytosis mechanisms. Supporting this notion, corticostriatal long-term potentiation (LTP) and the early phase of motor sequence learning are dependent on astrocytic phagocytic receptors. Together, our findings demonstrate that astrocytes contribute to the connectivity and plasticity of the striatal circuit by preferentially engulfing a specific subset of excitatory synapses within brain regions innervated by multiple excitatory sources.
An adverse rearing environment alters maternal responsiveness to infant ultrasonic vocalizations
Authors: Rekapalli Alekhya K. , Roman Isabel C. , Brenhouse Heather C. , Cody Caitlyn R. 
Published: March 2024

AbstractRodent pups use a variety of ultrasonic vocalizations (USVs) to facilitate maternal care. Importantly, infant USV repertoires are dependent on both the age and early life experiences of the pups. We have shown that an adverse rearing environment modeled with the maternal separation (MS) paradigm alters caregiving behavior, but little is known about how pup USVs differentially elicit maternal attention. In the present study, maternal approach towards a vocalizing pup over a non-vocalizing pup was tested in a Y-maze apparatus at two developmental time points over the course of MS. At the postnatal day (P) 10, dams engaged in longer interaction times with the vocalizing pup compared to the non-vocalizing pup. This effect was modulated by rearing environment and the sex of the pup, with only MS dams spending more time with vocalizing male pups. As expected at P20, dams did not show a preference for either the vocalizing or non-vocalizing pups regardless of rearing environment, however, MS dams spent a greater amount of time in the center of the apparatus as compared to control dams, which can be interpreted as a measure of uncertainty and indecision. These effects are important considering the sex specific effects of MS exposure across all developmental stages. Our novel findings support the hypothesis that sex-specific pup-dam interactions may drive later life outcomes following adversity.
A Multiparametric Analysis Reveals Differential Behavior of Spheroid Cultures on Distinct Ultra-Low Attachment Plates Types
Authors: Vitacolonna Mario , Bruch Roman , Agaçi Ane , Nürnberg Elina , Cesetti Tiziana , Keller Florian , Padovani Francesco , Sauer Simeon , Schmoller Kurt M. , Reischl Markus , Hafner Mathias , Rudolf Rüdiger 
Published: March 2024

AbstractSpheroids have become principal three-dimensional biological models to study cancer, developmental processes, and drug efficacy. For spheroid generation, ultra-low attachment plates are noteworthy due to their simplicity, compatibility with automation, and experimental and commercial accessibility. Nonetheless, it is unknown whether and to what degree the plate type impacts spheroid formation and biology. This study employed automated brightfield microscopy to systematically compare the size and eccentricity of spheroids formed in six different plate types using four distinct human cell lines, i.e., CCD-1137Sk fibroblasts, HaCaT keratinocytes, and MDA-MB-231 and HT-29 cancer cells. Results showed that all plate types exhibited similar sphe-roid-forming capabilities, and the gross patterns of growth or shrinkage during four days after seeding were comparable. Yet, size and eccentricity varied systematically among specific cell lines and plate types. A confocal wholemount analysis by a novel pipeline of AI-based 3D-image analysis procedures revealed changes in cell proliferation, cell number, nuclear volume, and keratino-cyte differentiation, which were accompanied by altered YAP1-signals. The findings show that the plate type may influence the outcome of experimental campaigns. It is advisable to scan different plate types for the optimal configuration for a specific investigation instead of using one standard plate for all kinds of applications.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age
Authors: Sarver Dylan C. , Saqib Muzna , Chen Fangluo , Wong G. William 
Published: March 2024

ABSTRACTOrgan function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: 1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; 2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; 3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; 4) age-effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and 5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
Butyrate and propionate are microbial danger signals that activate the NLRP3-inflammasome in human macrophages in the presence of TLR stimulation
Authors: Wang Wei , Dernst Alesya , Martin Bianca , Lorenzi Lucia , Cadefau Maria , Phulphagar Kshiti , Wagener Antonia , Budden Christina , Stair Neil , Wagner Theresa , Färber Harald , Jaensch Andreas , Stahl Rainer , Duthie Fraser , Schmidt Susanne V. , Coll Rebecca C. , Meissner Felix , Cuartero Sergi , Mangan Matthew S.J. , Latz Eicke 
Published: March 2024

AbstractShort chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through fermentation of dietary fibre. Although they are generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) have shown poor tolerance to fibre-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of toll-like receptor agonists. In contrast to their anti-inflammatory effects under steady state conditions, we observed that the SCFAs butyrate and propionate triggered the activation of the NLRP3 inflammasome when added in conjunction with TLR agonists. Mechanistically, butyrate and propionate activated NLRP3 by inhibiting HDACs 1-3 and 10, leading to an uneven distribution of histone hyperacetylation that resulted in alterations in the transcriptome. Specifically, there was a lack of hyperacetylation at the loci of theCFLARandIL10genes, two important inhibitors of NLRP3 inflammasome activation. The concurrent loss of transcription and protein expression of cFLIP and IL-10 enabled caspase-8-dependent NLRP3-inflammasome activation. SCFA-driven NLRP3 activation did not require potassium efflux and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially-derived, viability-dependent danger signals (vita-PAMPs) that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.SummaryUnder inflammatory conditions, SCFAs are bacterially-derived, viability-dependent danger signals that, through HDAC inhibition and epigenetic modification, prevent expression of the anti-cell death gene cFLIP to trigger activation of the NLRP3 inflammasome.
Two highly selected mutations in the tandemly duplicatedCYP6P4aandCYP6P4bdrive pyrethroid resistance inAnopheles funestus
Authors: Tatchou-Nebangwa Nelly M.T. , Mugenzi Leon M. J. , Muhammad Abdullahi , Nebangwa Derrick N. , Kouamo Mersimine F.M. , Tagne Carlos S. D. , Tekoh Theofelix A. , Tchouakui Magellan , Ghogomu Stephen M. , Ibrahim Sulaiman S. , Wondji Charles S. 
Published: March 2024

AbstractGaining a comprehensive understanding of the genetic mechanisms underlying insecticide resistance in malaria vectors is crucial for optimising the effectiveness of insecticide-based vector control methods and developing diagnostic tools for resistance management. Considering the heterogeneity of metabolic resistance in major malaria vectors, the implementation of tailored resistance management strategies is essential for successful vector control. In this study, we provide evidence demonstrating that two highly selected mutations in the tandemly duplicated cytochrome P450 genes namelyCYP6P4aandCYP6P4b, are driving pyrethroid insecticide resistance in the major malaria vectorAnopheles funestus,in West Africa. Through a continent-wide polymorphism survey, we observed heightened indications of directional selection in both genes between 2014 and 2021. By conductingin vitroinsecticide metabolism assays with recombinant enzymes expressed from both genes, we established that mutant alleles under selection exhibit higher metabolic efficiency compared to their wild-type counterparts. Furthermore, using the GAL4-UAS transgenic system, we demonstrated that transgenicDrosophila melanogasterflies overexpressing mutant alleles displayed an increased resistance to pyrethroids. These findings were in agreement within silicocharacterisation, which highlighted changes in enzyme active site architecture that enhance the affinity of mutant alleles for type I and II pyrethroids. Furthermore, we developed two DNA-based assays capable of detecting the CYP6P4a-M220I and CYP6P4b-D284E mutations, showing their current confinement to West Africa. Genotype/phenotype correlation analyses revealed that these markers are strongly associated with resistance to types I and II pyrethroids and combine to drastically reduce the efficacy of pyrethroid bednets. Overall, our study makes available two field-applicable insecticide resistance molecular markers that will help in the monitoring and better management of insecticide resistance in West Africa.TeaserTwo field-applicable diagnostic tools for detecting metabolic resistance inAnopheles funestusto enhance insecticide resistance management in West Africa.
The Interplay Between Multisensory Processing and Attention in Working Memory: Behavioral and Neural Indices of Audio-Visual Object Storage
Authors: Arslan Ceren , Schneider Daniel , Getzmann Stephan , Wascher Edmund , Klatt Laura-Isabelle 
Published: March 2024

AbstractAlthough real-life events are multisensory, how audio-visual objects are stored in working memory is an open question. At a perceptual level, evidence shows that both top-down and bottom-up attentional processes can play a role in multisensory interactions. To understand how attention and multisensory processes interact in working memory, we designed an audio-visual delayed match-to-sample task in which participants were presented with one or two audio-visual memory items, followed by an audio-visual probe. In three different blocks, participants were instructed to either (a) attend to the auditory features, (b) attend to the visual features, or (c) attend to both auditory and visual features. Participants were instructed to indicate whether the task-relevant features of the probe matched one of the task-relevant feature(s) or objects in working memory. Behavioral results showed interference from task-irrelevant features, suggesting bottom-up integration of audio-visual features and their automatic encoding into working memory, irrespective of their task relevance. Yet, ERP analyses revealed no evidence for active maintenance of these task-irrelevant features, while they clearly taxed greater attentional resources during recall. Notably, alpha oscillatory activity revealed that linking information between auditory and visual modalities required more attentional demands at retrieval. Overall, these results offer critical insights into how and at which processing stage multisensory interactions occur in working memory.Public Significance StatementCurrent working memory research is dominated by investigations of the visual domain. Yet, understanding how more complex representations, e.g., based on multisensory inputs, are formed, stored, and recalled is crucial to obtaining a more realistic understanding of working memory function. The present study shows that when confronted with audio-visual inputs at the same time and location, features from both modalities are combined into a working memory representation, irrespective of their task relevance. During maintenance, alpha oscillations serve to flexibly gate information flow in the cortex, allowing for the re-distribution of attentional resources between modalities depending on their task-relevance. Notably, when the task instructions explicitly involve the storage of audio-visual objects as a whole, recall requires more attentional resources.
The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma
Authors: Chen Ying-Jiun C. , Bhaskara Govinal Badiger , Lu Yue , Lin Kevin , Dent Sharon Y. R. 
Published: March 2024

AbstractDespite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of datasets in the Cancer Dependency Map Project revealed many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA-seq, ATAC-seq, and CUT&RUN results identified pathways directly regulated by ADA2B include MTORC1 signaling, MYC, E2F, and MM-specific MAF oncogenic programs. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.
Collective anti-predator escape manoeuvres through optimal attack and avoidance strategies
Authors: Bartashevich Palina , Herbert-Read James E. , Hansen Matthew J. , Dhellemmes Félicie , Domenici Paolo , Krause Jens , Romanczuk Pawel 
Published: March 2024

AbstractThe collective dynamics of self-organised systems emerge from the decision rules agents use to respond to each other and to external forces. This is evident in groups of animals under attack from predators, where understanding collective escape patterns requires evaluating the risks and rewards associated with particular social rules, prey escape behaviour, and predator attack strategies. Here, we find that the emergence of the ‘fountain effect’, a common collective pattern observed when animal groups evade predators, is the outcome of rules designed to maximise individual survival chances given predator hunting decisions. Using drone-based empirical observations of schooling sardine prey (Sardinops sagax caerulea) attacked by striped marlin (Kajikia audax), we first find the majority of attacks produce fountain effects, with the dynamics of these escapes dependent on the predator’s attack direction. Then, using a spatially-explicit agent-based model of predator-prey dynamics, we show that fountain manoeuvres can emerge from combining an optimal individual prey escape angle with social interactions. The escape rule appears to prioritise maximising the distance to the predator and creates conflict in the effectiveness of predators’ attacks and the prey’s avoidance, explaining the empirically observed predators’ attack strategies and the fountain evasions produced by prey. Overall, we identify the proximate and ultimate explanations for fountain effects and more generally highlight that the collective patterns of self-organised predatory-prey systems can be understood by considering both social escape rules and attack strategies.