bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in microglia chromatin accessibility in aged female mice
Authors: Ansere Victor A. , Tooley Kyla B. , Srividya Kottapalli , Hoolehan Walker , Pham Kevin D. , Ocañas Sarah R. , Freeman Willard M. 
Published: January 2024

AbstractAged female microglia display a more inflammatory and disease-associated phenotype compared to age-matched males. Epigenetic mechanisms, such as chromatin accessibility, are key drivers of microglial plasticity and phenotypes necessary for development, priming, and immune activation. Therefore, alterations in chromatin accessibility patterns can potentially regulate the neuroimmune responses and phenotypes observed in female microglia with aging, but to date have not been assessed. In this study, hippocampal microglia chromatin accessibility in young (4-5 months) and old (23-24 months) female mice was interrogated by Assay for Transposable Accessible Chromatin using Sequencing (ATAC-Seq). Cx3cr1-cre/ERT2+: NuTRAP mice were used to tag microglia and enable INTACT (isolation of nuclei tagged in specific cell types) collection of microglia-specific nuclei. With aging, loci specific gains and losses in chromatin accessibility were observed. Notably, changes in chromatin accessibility were skewed, with aged female microglia having more regions gaining accessibility than loosing accessibility. These changes were under-represented in the proximal promoter region (≤1kb) of genes but were enriched in intergenic regions. Regions that gained accessibility were more concentrated around genes responsible for myeloid cell differentiation and the regulation of immune and inflammatory responses. In contrast, regions that became less accessible were closest to genes involved in neuronal and synaptic function. In addition, X Chromosome accessibility changes were less common compared to autosomal changes, which argues against increased X Chromosome escape from inactivation with aging in female microglia. Overall, our data demonstrate age-related chromatin accessibility changes in female microglia, which may be regulated within enhancers and distal regulatory elements, and that these changes have potential downstream implications for the inflammatory phenotype of microglia in aging female mice.
Genome-wide allele frequency changes reveal that dynamic metapopulations evolve differently
Authors: Angst Pascal , Haag Christoph R. , Ben-Ami Frida , Fields Peter D. , Ebert Dieter 
Published: January 2024

AbstractBackgroundTwo important characteristics of metapopulations are extinction– (re)colonization dynamics and gene flow between subpopulations. These processes can cause strong shifts in genome-wide allele frequencies that are generally not observed in “classical” (large, stable, panmictic) populations. Subpopulations founded by one or a few individuals, the so-called propagule model, are initially expected to show intermediate allele frequencies at polymorphic sites until natural selection and genetic drift drive allele frequencies toward a mutation-selection-drift equilibrium characterized by a negative exponential-like distribution of the site frequency spectrum (SFS).ResultsWe followed changes in SFS distribution in a natural metapopulation of the cyclically parthenogenetic pond-dwelling microcrustaceanDaphnia magnausing biannual pool-seq samples collected over a five-year period from 118 ponds occupied by subpopulations of known age. As expected under the propagule model, SFSs in newly founded subpopulations trended toward intermediate allele frequencies and shifted toward right skewed distributions as the populations aged. Immigration and subsequent hybrid vigor altered this dynamic.ConclusionsThe analysis of SFS dynamics is a powerful approach to understand evolution in metapopulations. It allowed us to disentangle evolutionary processes occurring in a natural metapopulation, where many subpopulations evolve in parallel. Thereby, stochastic processes like founder and immigration events lead to a pattern of subpopulation divergence, while genetic drift, leads to converging SFS distributions in the persisting subpopulations. The observed processes are well explained by the propagule model and highlight that metapopulations evolve differently from classical populations.
Multi-faceted roles of β-arrestins in G protein-coupled receptors endocytosis
Authors: Liu Junke , Xue Li , Ravier Magalie , Inoue Asuka , Drube Julia , Hoffmann Carsten , Trinquet Eric , Dupuis Elodie , Prézeau Laurent , Pin Jean-Philippe , Rondard Philippe 
Published: January 2024

AbstractInternalization plays a crucial role in regulating the density of cell surface receptors and has been demonstrated to regulate intracellular signaling. Dysregulation of this process has been implicated in various diseases. The vast majority of GPCRs were considered to adopt one way for internalization. We challenged this conventional view by showing that multiple pathways converge to regulate the internalization of a specific receptor, based on an unparalleled characterization of 60 GPCR internalization profiles, both in the absence and presence of individual β-arrestins (βarrs). Furthermore, we revealed the internalization mechanism of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR pivotal in promoting insulin secretion from pancreatic beta cells to maintain glucose homeostasis. GLP-1R can undergo agonist-induced internalization without βarrs, but can recruit and form stable complexes with βarrs. We found that GLP-1R recruits clathrin adaptor protein-2 for agonist-induced internalization in both βarr-dependent and -independent manners. These results provide a valuable resource for GPCR signaling and reveal the plasticity of different GPCRs to employ or not βarrs in the clathrin-mediated internalization.
Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behaviour
Authors: Faig Christian A. , Kim Gloria H. K. , Do Alison D. , Dworsky-Fried Zoë , Jackson Jesse , Taylor Anna M. W. 
Published: January 2024

AbstractThe anterior cingulate cortex (ACC) processes nociceptive information and pain unpleasantness. The claustrum is a subcortical region that provides robust feed-forward inhibition onto the ACC, suggesting this circuit could play a role in modulating pathological states such as pain. However, the function of this circuit in the context of acute and chronic inflammatory pain is unclear. Here, we show that claustrocingulate neurons exhibit a bimodal pattern of activation following acute pain but are suppressed during states of chronic inflammatory pain. Molecular lesion and chemogenetic suppression of claustrocingulate neurons increased acute nociception but interfered with pain learning. Activation of this pathway rescued mechanical allodynia associated with chronic pain. Together, these results suggest claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.
Gene therapy targeting sustained FGF23-ERK signaling alleviates kidney inflammation
Authors: Salas-Bastos Adrian , Bardet Claire , Kopper Klaudia , Jauze Louisa , Collaud Fanny , Francois Amandine , Chen Gaozhi , Mohammadi Moosa , Stockmann Christian , Sommer Lukas , Loffing Johannes , Ronzitti Giuseppe , Pathare Ganesh 
Published: January 2024

ABSTRACTFibroblast growth factor 23 (FGF23) levels are highly elevated in patients with chronic kidney disease (CKD); however, whether it serves merely as a biomarker or actively contributes to kidney inflammation remains unclear. Full-length FGF23 is cleaved into C-terminal FGF23 (cFGF23), which acts as a natural antagonist of FGF23 by inhibiting its binding to the FGF receptor (FGFR) and the co-receptor Klotho. Here, we show that chronically elevated FGF23 levels in a mouse model Hyp-Duk cause sustained-ERK signaling and an inflammatory and immune responses in the kidney. cFGF23, delivered via adeno-associated virus (AAV) gene therapy, successfully mitigated sustained-ERK signaling and kidney inflammation in Hyp-Duk mice. On the other hand, acute physiological FGF23 levelsin vitroelicited transient-ERK signaling with the expression of canonical early-ERK targets (EGR1, JUNB, FOSB). Consistent within vivofindings, prolonged pathological FGF23 treatmentin-vitrorevealed sustained-ERK signaling with upregulation of late-ERK targets (ETV4/5, SPRED1/2, SPRY2/4) and unique inflammatory and immune gene signatures. These effects were significantly mitigated by FGFR and ERK inhibitors, as well as by recombinant cFGF23 treatment. In summary, chronically high levels of FGF23 induce kidney inflammation through the FGFR-Klotho complex and sustained-ERK activation, which are successfully mitigated by cFGF23 gene therapy.KEY POINTSFibroblast growth factor 23 (FGF23) levels are highly elevated in patients with chronic kidney disease (CKD). FGF23 is also a potential biomarker for CKD and related cardiovascular disorders, although its role in disease progression remains unclear.Our study identifies that chronically elevated FGF23 levels induce sustained-ERK signalingin-vitroandin-vivo, leading to inflammation and immune signaling pathways in the kidney.These untoward effects of FGF23 were significantly suppressed by gene therapy using the C-terminal peptide of FGF23 (cFGF23), a natural FGF23 antagonist, warranting further investigation to confirm its clinical potential in CKD.
ER and SOCE Ca2+signals are not required for directed cell migration in human microglia
Authors: Granzotto Alberto , McQuade Amanda , Chadarevian Jean Paul , Davtyan Hayk , Sensi Stefano L. , Parker Ian , Blurton-Jones Mathew , Smith Ian 
Published: January 2024

AbstractThe central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca2+) signaling in the directed migration of induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca2+changes revealed that this phenomenon does not require Ca2+signals generated from the endoplasmic reticulum (ER) and store-operated Ca2+entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca2+-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca2+homeostasis.
CD62L-selected umbilical cord blood universal CAR T cells
Authors: Georgiadis Christos , Nickolay Lauren , Syed Farhatullah , Zhan Hong , Gkazi Soragia Athina , Etuk Annie , Abramowski-Mock Ulrike , Preece Roland , Cuber Piotr , Adams Stuart , Ottaviano Giorgio , Qasim Waseem 
Published: January 2024

AbstractUmbilical cord blood (UCB) T cells exhibit distinct naïve ontogenetic profiles and may be an attractive source of starting cells for the production of chimeric antigen receptor (CAR) T cells. Pre-selection of UCB-T cells on the basis of CD62L expression was investigated as part of a machine-based manufacturing process, incorporating lentiviral transduction, CRISPR-Cas9 editing, T-cell expansion and depletion of residual TCRαβ T cells. This provided stringent mitigation against the risk of graft versus host disease (GVHD), and was combined with simultaneous knockout of CD52 to enable persistence of edited T cells in combination with preparative lymphodepletion using Alemtuzumab. Under compliant manufacturing conditions, two cell banks were generated with high levels of CAR19 expression and minimal carriage of TCRαβ T cells. Sufficient cells were cryopreserved in dose-banded aliquots at the end of each campaign to treat dozens of potential recipients. Molecular characterisation captured vector integration sites and CRISPR editing signatures and functional studies, includingin vivopotency studies in humanised mice, confirmed anti-leukaemic activity comparable to peripheral blood-derived universal CAR19 T cells. Machine manufactured UCB derived T cells banks offer an alternative to autologous cell therapies and could help widen access to CAR T cells.
EasyGrid: a versatile platform for automated cryo-EM sample preparation and quality control
Authors: Gemin Olivier , Armijo Victor , Hons Michael , Bissardon Caroline , Linares Romain , Bowler Matthew W. , Wolff Georg , Kovalev Kirill , Babenko Anastasiia , Salo Veijo T. , Schneider Sarah , Rossi Christopher , Lecomte Léa , Deckers Thibault , Lauzier Kévin , Janocha Robert , Felisaz Franck , Sinoir Jérémy , Galej Wojciech , Mahamid Julia , Müller Christoph W. , Eustermann Sebastian , Mattei Simone , Cipriani Florent , Papp Gergely 
Published: January 2024

AbstractImaging biological macromolecules in their native state with single-particle cryo-electron microscopy (cryo-EM) orin situcryo-electron tomography (cryo-ET) requires optimized approaches for the preparation and vitrification of biological samples. Here, we describe EasyGrid, a versatile technology enabling systematic, tailored and advanced sample preparation for cellular and structural biology. This automated, standalone platform combines in-line plasma treatment, microfluidic dispensing, blot-less sample spreading, jet-based vitrification and on-the-fly grid quality control using light interferometry to streamline cryo-EM sample optimization. With EasyGrid, we optimized grid preparation for different purified macromolecular complexes and subsequently determined their structure with cryo-EM. We also demonstrated how the platform allows better vitrification of large, mammalian cells compared to standard plunge-freezing. Automated sample preparation with EasyGrid establishes an advanced, high-throughput platform for both single-particle cryo-EM and cellular cryo-ET sample preparation.
Dynamic connectivity profiles characteristic of conscious states are associated with enhanced conscious processing of external stimuli
Authors: Türker Başak , Manasova Dragana , Béranger Benoît , Naccache Lionel , Sergent Claire , Sitt Jacobo D. 
Published: January 2024

ABSTRACTOne of the goals of the neuroscience of consciousness is to identify neural markers capable of distinguishing brain dynamics in awake, healthy individuals from unconscious conditions. This problem also has a clinical diagnostic interest in disorders of consciousness. Recent research has shown that brain connectivity patterns characterized by long-range interactions and anticorrelations are associated with conscious states and diminish with loss of consciousness in human and non-human primates. However, the precise contribution of these patterns to conscious processing and subjective experience formation remains unclear. In this study, we investigated the functional role of these brain patterns in shaping conscious content by examining their influence on participants’ ability to process external information during wakefulness. Participants underwent fMRI recordings during an auditory detection task. Phase coherence-based functional connectivity and k-means clustering confirmed that the ongoing dynamics were underpinned by brain patterns consistent with those identified in previous research, including the “high pattern” characteristic of conscious states. We found that the detection of auditory stimuli at threshold was specifically improved when the connectivity pattern at the time of presentation corresponded to this high-pattern. In return, the occurrence of the high-pattern increased after detection, indicating that participants were more likely to transition to a high-pattern following stimulus detection. Our findings suggest that ongoing brain dynamics and conscious perception mutually influence each other and that certain brain configurations are more favorable for conscious processing of external stimuli. In the future, targeting these moments of favorable patterns in patients with disorders of consciousness may help us identify windows of greater receptivity to the external world, paving the way for developing individualized patient care protocols.
A Subcortical Model for Auditory Forward Masking with Efferent Control of Cochlear Gain
Authors: Maxwell Braden N. , Farhadi Afagh , Brennan Marc A. , Svec Adam , Carney Laurel H. 
Published: January 2024

AbstractPrevious physiological and psychophysical studies have explored whether feedback to the cochlea from the efferent system influences forward masking. The present work proposes that the limited growth-of-masking (GOM) observed in auditory-nerve (AN) fibers may have been misunderstood; namely, that this limitation may be due to the influence of anesthesia on the efferent system. Building on the premise that the unanesthetized AN may exhibit GOM similar to more central nuclei, the present computational modeling study demonstrates that feedback from the medial olivocochlear (MOC) efferents may account for GOM observed physiologically in onset-type neurons in both the cochlear nucleus and inferior colliculus (IC). Additionally, the computational model of MOC efferents used here generates a decrease in masking with longer masker-signal delays similar to that observed in IC physiology and in psychophysical studies. An advantage of this explanation over alternative physiological explanations (e.g., that forward masking requires inhibition from the superior paraolivary nucleus) is that this theory can explain forward masking observed in the brainstem, early in the ascending pathway. For explaining psychoacoustic results, one strength of this model is that it can account for the lack of elevation in thresholds observed when masker level is randomly varied from interval-to-interval, a result that is difficult to explain using the conventional temporal-window model of psychophysical forward masking. Future directions for evaluating the efferent mechanism as a contributing mechanism for psychoacoustical results are discussed.Significance StatementThe simulations presented here demonstrate that a recent computational model of the auditory subcortex including medial-olivocochlear efferents generates forward masking, an increase in detection threshold for a short probe tone following a preceding sound. This model explains results from physiological recordings and suggests potential connections to psychoacoustic experiments. The theory that efferent control of cochlear gain is a contributing mechanism for forward masking has several advantages. This theory can explain the strength of masking exhibited by cochlear nucleus neurons, a phenomenon not explained by current physiological theories in which the strength of forward-masking is not increased relative to the periphery until later in the ascending pathway. Additionally, this theory explains results for a psychoacoustic task with random variation in masker level, results not explained by the theory that persistent masker energy interferes with detection of the probe.
Retrieval of human aversive memories involves reactivation of gamma activity patterns in the hippocampus that originate in the amygdala during encoding
Authors: Costa Manuela , Pacheco Daniel , Gil-Nagel Antonio , Toledano Rafael , Imbach Lukas , Sarnthein Johannes , Strange Bryan A. 
Published: January 2024

AbstractEmotional memories require coordinated activity of the amygdala and hippocampus. Human intracranial recordings have shown that formation of aversive memories involves an amygdala theta-hippocampal gamma phase code. Yet, the mechanisms engaged during translation of aversive experiences into memories and subsequent retrieval remain unclear. Directly recording from human amygdala and hippocampus, here we show that hippocampal gamma activity increases for correctly remembered aversive scenes, while exerting unidirectional oscillatory influence within the theta/beta frequency range on the amygdala for previously seen aversive scenes. Crucially, patterns of amygdala high amplitude gamma activity at encoding are reactivated in the hippocampus, but not amygdala, during both aversive encoding and retrieval. Trial-specific hippocampal gamma patterns showing highest representational similarity with amygdala activity at encoding are replayed in the hippocampus during aversive retrieval. This reactivation process occurs against a background of gamma activity that is otherwise decorrelated between encoding and retrieval. Thus, retrieval of aversive memories is hippocampal-centered, with hippocampal activity patterns apparently entrained by the amygdala during encoding.
Diffusion-limited cytokine signaling in T cell populations
Authors: Brunner Patrick , Kiwitz Lukas , Li Lisa , Thurley Kevin 
Published: January 2024

AbstractEffective immune-cell responses depend on collective decision-making mediated by diffusible intercellular signaling proteins called cytokines. Here, we designed a spatio-temporal modeling framework and a precise finite-element simulation setup, to systematically investigate the origin and consequences of spatially inhomogeneous cytokine distributions in lymphoid tissues. We found that such inhomogeneities are critical for effective paracrine signaling, and they do not arise by diffusion and uptake alone, but rather depend on properties of the cell population such as an all-or-none behavior of cytokine secreting cells. Furthermore, we assessed the regulatory properties of negative and positive feedback in combination with diffusion-limited signaling dynamics, and we derived statistical quantities to characterize the spatio-temporal signaling landscape in the context of specific tissue architectures. Overall, our simulations highlight the complex spatiotemporal dynamics imposed by cell-cell signaling with diffusible ligands, which entails a large potential for fine-tuned biological control especially if combined with feedback mechanisms.
Altered physiological, affective, and functional connectivity responses to acute stress in patients with alcohol use disorder
Authors: Schwarze Yana , Voges Johanna , Schröder Alexander , Dreeßen Sven , Voß Oliver , Krach Sören , Paulus Frieder Michel , Junghanns Klaus , Rademacher Lena 
Published: January 2024

AbstractBackgroundThere is evidence that the processing of acute stress is altered in alcohol use disorder (AUD), but little is known about how this is manifested simultaneously across different stress parameters and which neural processes are involved. The present study examined physiological and affective responses to stress and functional connectivity in AUD.MethodsSalivary cortisol samples, pulse rate, and affect ratings were collected on two days from 34 individuals with moderate or severe AUD and 34 controls. On one day, stress was induced, and on the other day, a non-stressful control task was performed. Following the intervention, participants underwent fMRI to assess functional connectivity, focusing on cortical and subcortical seed regions previously reported to be involved in AUD and/or stress.ResultsFor pulse rate and cortisol, stress responses were blunted in AUD, whereas negative affect was increased. Furthermore, stress-related changes in pulse rate, cortisol, and affect were only correlated in healthy controls. Neuroimaging analyses revealed stress-related group differences in functional connectivity, involving the connectivity of striatal seeds with the posterior DMN, cerebellum and midcingulate cortex, and of the posterior DMN seed with the striatum and thalamus.ConclusionsThe results suggest a dissociation between subjective experienced distress and the physiological stress response in AUD as well as stress-related alterations in functional connectivity. These findings highlight the complex interplay between chronic alcohol use and acute stress regulation, offering valuable considerations for the development of therapeutic strategies.