bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of spatial transcriptomics with immunofluorescence staining reveals spatial heterogeneity and plasticity of astrocytes in experimental glioblastomas
Authors: Ghosh Mitrajit , Pilanc-Kudlek Paulina , Jacek Karol , Baluszek Szymon , Poleszak Katarzyna , Szadkowska Paulina , Gielniewski Bartłomiej , Miklaszewska Aleksandra Ellert , Kaminska Bozena 
Published: October 2024

AbstractAstrocytes comprise ∼50% of all brain cells and present distinct morphological, molecular and functional properties in different brain regions. In glioblastoma (GBM), an aggressive primary brain tumour, tumour-associated astrocytes (TAAs) become activated and exhibit different transcriptomic profiles, morphology and functions supporting disease progression. Heterogeneity and specific roles of TAAs within various regions of tumours are poorly known. Advancements of single-cell and spatial transcriptomics allow to profile tumours at unprecedented resolution revealing cell phenotypes, hidden functionalities and spatial architecture in disease-specific context.We combined spatial transcriptomics and multiple immunofluorescent staining to visualize TAAs heterogeneity and location of various subpopulations in intracranial murine gliomas. Using distinct gene expression profiles, we identified subtypes of TAAs with distinct localization and inferred their specialized functionalities. Gene signatures associated with TAAs reflected their reprograming in the tumour microenvironment (TME), revealed their multiple roles and potential contributing factors shaping the local milieu. Using spatial correlation analysis of the spots, we inferred the interactome ofSlc1a2(encoding a glutamate transporter) with the other markers of TAAs based on segregated areas of the tumour. The designer RGD peptide blocking tumour-microglia communications, alters the spatial distribution of TAAs in experimental gliomas providing insights into potential mechanisms. Spatial transcriptomics combined with multiple staining unveils multiple functional phenotypes of TAAs and interactions within TME. It shows their distinct morphology and unveils different roles in various regions of the tumour. We demonstrate the glioma-induced heterogeneity of TAAs and their adaption to the pharmacologically-induced modification of the immunosuppressive TME.
Neuroanatomy of the Accessory Olfactory Bulb in the Fossorial Water Vole
Authors: Ruiz-Rubio Sara , Ortiz-Leal Irene , Torres Mateo V. , Elsayed Mostafa G. A. , Somoano Aitor , Sanchez-Quinteiro Pablo 
Published: October 2024

AbstractThe accessory olfactory bulb (AOB) plays a key role in processing chemical signals crucial for species-specific social and reproductive behaviors. While extensive research has focused on the vomeronasal system of laboratory rodents, less is known about wild species, particularly those that rely heavily on chemical communication. This study aims to characterize the morphological and neurochemical organization of the AOB in the fossorial water vole (Arvicola scherman), a subterranean rodent species from the family Cricetidae. We have employed histological techniques, including Nissl and hematoxylin staining, as well as immunohistochemical and lectin-histochemical markers, to assess the AOB structure. Our findings reveal that the AOB of the water vole exhibits a distinct laminar organization with prominent mitral cells in the mitral-plexiform layer, as well as dense labeling of periglomerular and short-axon cells in the glomerular layer. Lectin histochemistry further confirmed zonation patterns analogous to those seen in other rodent species. Immunohistochemical analysis demonstrated significant expression of PGP 9.5, suggesting its involvement in maintaining neuronal activity within the AOB. In contrast, the absence of SMI-32 labeling in the AOB, compared to its strong expression in the main olfactory bulb, highlights functional distinctions between these two olfactory subsystems. These structural and neurochemical characteristics suggest that the AOB of the fossorial water vole is adapted for enhanced processing of chemosensory signals, which may play a pivotal role in its subterranean lifestyle. Our results provide a foundation for future studies exploring the functional implications of these adaptations, including potential improvements in the integrated management of these vole populations.
Deciphering gene regulatory programs in mouse embryonic skin through single-cell multiomics analysis
Authors: Deng Qiuting , Cai Pengfei , Luo Yingjie , Zhang Zhongjin , Ma Wen , Huang Zijie , Chen Xiaoya , Hao Shijie , Ma Weiguang , Xu Jiangshan , Cheng Mengnan , Lin Xiumei , Zhou Ru , Duan Shanshan , Chen Junjie , Li Ronghai , Shi Xuyang , Liu Chang , Gao Peng , Li Jianting , Xie Jun , Liu Longqi , Yuan Yue , Liu Chuanyu 
Published: October 2024

AbstractBackgroundCell type-specific transcriptional heterogeneity in embryonic mouse skin is well-documented, but few studies have investigated the regulatory mechanisms.ResultsHere, we present high throughput single-cell chromatin accessibility and transcriptome sequencing (HT-scCAT-seq), a method that simultaneously profiles transcriptome and chromatin accessibility. We utilized HT-scCAT-seq to dissect the gene regulatory mechanism governing epidermal stratification, periderm terminal differentiation, and fibroblast specification.ConclusionsBy linking chromatin accessibility to gene expression, we identified candidatecis-regulatory elements (cCREs) and target genes crucial for dermal and epidermal development. We described cells with similar gene expression profiles that exhibit distinct chromatin accessibility statuses during periderm terminal differentiation. Finally, we characterized the underlying lineage-determining transcription factors (TFs), and demonstrated that ALX4 and RUNX2 were candidate TF regulators of the dermal papilla lineage development through in silico perturbation analysis.
Lipidomic Profiling Reveals Shared and Distinct Pathological Signatures in Sporadic Parkinson’s Disease and GBA Mutation Carriers: Implications for Disease Mechanisms
Authors: Muñoz Sonia Sanz , Marlet Frederik Ravnkilde , Bilgin Mesut , Dreier Jesper E , Bezard Erwan , Dehay Benjamin , Jaunmuktane Zane , Maeda Kenji , Galvagnion Céline 
Published: October 2024

AbstractParkinson’s Disease (PD) is a neurodegenerative disorder characterised by the deposition of protein inclusions, called Lewy Bodies (LBs), in neurons. LBs are heterogeneous structures whose main constituent is the protein alpha-synuclein (αS) and that are also composed of lipid molecules. Disruptions in the levels of specific lipids, including sphingolipids, fatty acids, and cholesterol, have been associated with PD, suggesting a role of lipids in the emergence and spreading of αS and PD pathology. Using a combination of shotgun lipidomics and biochemical analyses of PD amygdala homogenates, we have shown that long sporadic disease duration andGBArisk mutation are associated with a decrease in the protein and activity levels of glucocerebrosidase (GCase) activity and in cardiolipin levels and an increase in those of pathological αS, cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids (GPL). Long sporadic PD and GBA risk mutations also led to a shift from long unsaturated to short saturated GPL and from short to long sphingomyelin and ceramide. Moreover, the levels of lipid classes and species affected by long sPD andGBArisk mutations were found to correlate negatively with GCase activity and positively with pathological αS levels. We found thatGBAmutation with mild phenotype affects lipid levels in the same direction asGBArisk mutation and long sPD but to a lesser extent and thatGBAmutation carriers with severe phenotype led to changes in the opposite direction for the same lipids. Finally, the lipid analyses of LB- and small aggregates enriched fractions show that long sPD andGBArisk mutations led to the same changes in the levels and species distribution of GPL and SL than in homogenates but to a lesser extent. Together, these results suggest the need for patient stratification in clinical trials of therapeutic interventions in PD-GBA and that successful therapeutics against PD-GBA should be considered for sporadic PD.
The neuropeptide aCGRP impairs the chondrocyte response to mechanical load
Authors: Dietmar H.F. , Hecht N. , Diederichs S. 
Published: October 2024

ABSTRACTMechanical loading can contribute to articular cartilage homeostasis due to its anabolic effects, for example the stimulation of glycosaminoglycan (GAG) synthesis. During degenerative joint diseases, such as osteoarthritis, the ability to respond adequately to mechanical stimulation may be compromised. The neuropeptide and pain mediator αCGRP has previously been associated with osteoarthritis and is typical for sensory nerve fibres, but chondrocytes also possess the receptors for αCGRP and have been shown to respond to treatment in vitro. Since it was reported that murine macrophages were more sensitive to αCGRP following stretching, we hypothesised that αCGRP may influence the response of chondrocytes to mechanical stimulation. Here, we employed our previously established model system using human articular chondrocytes to generate tissue-engineered cartilage to investigate the effect of the sensory neuropeptide αCGRP on the chondrocyte loading response. Following culture under chondrogenic conditions for 35 days, tissue-engineered cartilage was subjected to a three-hour episode of unconfined dynamic compression in the presence or absence of αCGRP. Addition of αCGRP did not exert obvious anti-chondrogenic effects, and typical mechano-response markers were not altered when mechanical loading was performed in the presence of αCGRP. GAG synthesis rates were stimulated by mechanical loading in the control group as expected, but this anabolic effect was prevented by the presence of αCGRP. Our results suggest that high levels of αCGRP may interfere with the mechano-adaptation of articular cartilage and this may have important implications for osteoarthritis pathology and therapy.
Thermoceptive predictions and prediction errors in the anterior insula
Authors: Toussaint Birte , Heinzle Jakob , Friedli Nicole , Zahnd Nicole Jessica , Federici Elena , Köchli Laura , Harrison Olivia Kate , Iglesias Sandra , Stephan Klaas Enno 
Published: October 2024

AbstractContemporary theories of interoception propose that the brain constructs a model of the body for predicting the states and allostatic needs of all organs, including the skin, and updates this model using prediction error signals. However, empirical tests of this proposal are scarce in humans. This computational neuroimaging study investigated the presence and location of thermoceptive predictions and prediction errors in the brain using probabilistic manipulations of skin temperature in a novel interoceptive learning paradigm. Using functional MRI in healthy volunteers, we found that a Bayesian model provided a better account of participants’ skin temperature predictions than a non-Bayesian model. Further, activity in a network including the anterior insula was associated with trial-wise predictions and precision-weighted prediction errors. Our findings provide further evidence that the anterior insula plays a key role in implementing the brain’s model of the body, and raise important questions about the structure of this model.
Simultaneous quantification of oxygen and glucose consumption during visual stimulation in the human cortex
Authors: Bose Antonia , Epp Samira Maria , Belenya Roman , Kurcyus Katarzyna , Dominguez Eric Ceballos , Ranft Andreas , Villa Eliana Salas , Bursche Moritz , Preibisch Christine , Castrillón Gabriel , Riedl Valentin 
Published: October 2024

AbstractThe brain relies on oxidized glucose as its primary fuel. Despite robust coupling of cerebral oxygen and glucose consumption during rest, the oxygen to glucose index (OGI) has been suggested to drop significantly during neuronal activation. However, empirical evidence regarding the extent of this uncoupling is scarce, mainly due to the inability of previous studies to measure CMRO2and CMRglcconcurrently during tasks. Therefore, in the present study, we integrated multiparametric quantitative BOLD (mqBOLD) with functional PET (fPET) to simultaneously quantify cerebral oxygen and glucose metabolism during visual stimulation and rest within a single session. Results show increases in both CMRO2and CMRglcin visual areas, concomitant with focal blood flow increases. Moreover, OGI values during rest were close to the theoretical value of 6, which is in line with previous literature. In response to visual stimulation, the OGI decreased by 6.6-21.6%, depending on the mask applied. For the first time, the present study demonstrates the feasibility of combining mqBOLD and fPET to study CMRO2and CMRglcsimultaneously. This setup has the potential to be applied to various experimental settings, providing valuable information about the extent of oxidative glucose metabolism in the human brain under different conditions in health and disease.
Dissecting the nutritional regulations of a whole amino acid transporter family from a complex genome species: A holistic approach turning weaknesses into strengths
Authors: Garrec Soizig Le , Pinel Karine , Heraud Cécile , Ganot Akintha , Veron Vincent , Morin Guillaume , Iorfida Ophélie , Cardona Emilie , Marandel Lucie , Devin Anne , Labonne Jacques , Averous Julien , Bruhat Alain , Seiliez Iban , Beaumatin Florian 
Published: October 2024

AbstractAmino acid transporters (AATs) are described as pivotal in maintaining circulating and cellular concentrations of AA via regulation of their expression in response to the cellular environment. Rainbow trout (RT), a complex genome species, is poorly described for AATs roles in controlling its predominant AA-based metabolism, despite representing a major challenge in the aquaculture nutrition field. Therefore, we identified the whole repertoire of AAT found in RT genome (>200), its expression in tissues and its nutritional regulationsin vitro. Results garnered revealed the existence of different clusters of AATs, notably due to promoters bearing ATF4-related AA response elements. Moreover, the modeling of each AAT-specific cluster activities disclosed mTOR-related signaling functions of Ile and Phe, yet unknown in RT. Thus, this novel approach herein described should help to better grasp AA homeostasis in most organisms and topics such as fish nutrition and evolution.
Identification of a specialized lipid barrier forDrosophilametamorphosis
Authors: Lampe Lena , Newell Clare L. , Wang Bing-Jun , Makki Rami , Alexandre Cyrille , Gilmore Ian S. , Zhao Li , Gould Alex P. 
Published: October 2024

ABSTRACTIn many terrestrial insects, the onset of metamorphosis marks a transition from humid to dry environments. Yet how metamorphosing insect pupae protect themselves against the threat of dehydration remains unclear. Here, we identify the chemical composition and biosynthetic origins of a lipid desiccation barrier specific to the pupal and sexually-immature adult stages ofDrosophila melanogaster. This barrier comprises unisex hyper-long hydrocarbons, 29-37 carbons in length, which are synthesized by larval oenocytes and stored in the larval fat body before being deployed on the pupal and young adult cuticles. We show that the fatty acid elongaseEloHLis required for the biosynthesis of hyper-long hydrocarbons that are essential for the barrier to water loss during metamorphosis. Across theDrosophilagenus, many species express unisex profiles of hyper-long hydrocarbons and, as young adults, transition to sex-specific shorter hydrocarbons with known pheromonal functions. The desert speciesD. mojavensis, however, retains hyper-long hydrocarbons during adulthood likely as an adaptation to an arid environment. Our study reveals how the cuticular lipid barrier is tuned to meet changing environmental pressures during insect development and evolution.
Amyloid beta precursor protein contributes to brain aging and learning decline in short-lived turquoise killifish (Nothobranchius furzeri)
Authors: de Bakker Dennis E.M. , Mihaljević Mihaela , Gharat Kunal , Richter Yasmin , Bagnoli Sara , van Bebber Frauke , Adam Lisa , Shamim-Schulze Farzana , Ohlenschläger Oliver , Bens Martin , Cirri Emilio , Antebi Adam , Matić Ivan , Schneider Anja , Schmid Bettina , Cellerino Alessandro , Kirstein Janine , Valenzano Dario Riccardo 
Published: October 2024

AbstractBrain aging is a pivotal risk factor for many neurodegenerative diseases, yet its molecular and cellular mechanisms remain elusive. The amyloid-beta precursor protein (APP) is among the most studied proteins linked to brain pathology; however, its role in non-pathological brain aging remains poorly characterized. Here, we investigate the natural impact of APP on normal brain aging using the short-lived turquoise killifish (Nothobranchius furzeri), which exhibits rapid and spontaneous age-related decline. We found that pyroglutamated amyloid beta —a neurotoxic Aβ variant—accumulates intra-neuronally in an age-dependent manner, co-localizing with a marker of cell death. We found that intraneuronal pyroglutamated amyloid beta is also present in old human brains, suggesting deep evolutionary conservation. To determine Aβ’s role in spontaneous brain aging, we generated an “amyloid precursor protein a” (appa) knock-out killifish line using CRISPR/Cas9. The knock-out ofapparescued age-dependent increase in cell death and inflammation, mitigated proteome-wide brain aging and improved the age-related decline in neuronal activity and learning capacity. Our findings show a key role for Aβ precursor protein in non-pathological brain aging, making it a suitable target for anti-aging interventions.
Syngeneic adipose-derived stromal cells modulate the immune response but have limited persistence within decellularized adipose tissue implants in C57BL/6 mice
Authors: Walker John T. , Cooper Tyler T. , Dunmore-Buyze Joy , Serack Fiona E. , Brooks Courtney , Grant Aaron , Drangova Maria , Lajoie Gilles , Dekaban Gregory A. , Flynn Lauren E. 
Published: October 2024

AbstractThe delivery of adipose-derived stromal cells (ASCs) on cell-instructive decellularized adipose tissue (DAT) scaffolds is a promising strategy for stimulating host-derived soft tissue regeneration. However, a better understanding of the mechanisms through which ASCs modulate regenerationin vivois needed to harness these cells more effectively. In this study, DAT scaffolds, both with and without seeded syngeneic DsRED+mouse ASCs, were implanted into immunocompetent C57BL/6 mice. Downstream analyses focused on assessing donor ASC persistence and phenotype, as well as the effects of ASC seeding on host macrophage polarization and the perfused host vascular network. Notably, most donor ASCs were cleared from the scaffolds by 2 weeks. Mass spectrometry-based proteomics indicated that the transplanted ASCs maintained their pre-implantation phenotype up to 1 weekin vivo, suggesting that the cells were not undergoing programmed cell death. A higher fraction of the infiltrating host macrophages expressed CD68 and Arginase-1 in the ASC-seeded implants up to 1-week post-implantation. Interestingly, a small population of phagocytic macrophages, identified by uptake of DsRED protein, was present in the DAT implants in the first 2 weeks and showed enhanced expression of CD68, Arginase-1, and CD163, along with reduced expression of iNOS. MicroCT angiography revealed a similar perfused vessel network in the seeded and unseeded groups at 4- and 8-weeks post-implantation. Overall, seeding with syngeneic ASCs modulated the host macrophage response to the DAT bioscaffolds at early timepoints, but did not impact long-term regenerative outcomes, potentially due to the rapid clearance of the donor cell population in this model.
Cellular signalling protrusions enable dynamic distant contacts in spinal cord neurogenesis
Authors: Hawley Joshua , Lea Robert , Biga Veronica , Papalopulu Nancy , Manning Cerys 
Published: October 2024

AbstractIn the developing mouse ventral spinal cord, HES5, a transcription factor downstream of Notch signalling, is expressed as evenly spaced clusters of high HES5-expressing neural progenitor cells along the dorsoventral axis. While Notch signalling requires direct membrane contact for its activation, we have previously shown mathematically that contact needs to extend beyond neighbouring cells for the HES5 pattern to emerge. However, the presence of cellular structures that could enable such long-distance signalling was unclear. Here, we report that cellular protrusions are present all along the apicobasal axis of individual neural progenitor cells. Through live imaging, we show that these protrusions dynamically extend and retract reaching lengths of up to ∼20μm, enough to extend membrane contact beyond adjacent cells. The Notch ligand DLL1 was found to colocalise with protrusions, further supporting the idea that Notch signalling can be transduced at a distance. The effect of protrusions on the HES5 pattern was tested by reducing the density of protrusions using the CDC42 inhibitor ML141, leading to a tendency to decrease the distance between high HES5 cell clusters. However, this tendency was not significant and leaves an open question about their role in the fine-grained organisation of neurogenesis.
Topic Modeling analysis of the Allen Human Brain Atlas
Authors: Pizzini Letizia , Valle Filippo , Osella Matteo , Caselle Michele 
Published: October 2024

ABSTRACTThe human brain is a complex interconnected structure controlling all elementary and high-level cognitive tasks. It is composed of many regions that exhibit specific distributions of cell types and distinct patterns of functional connections. This complexity is rooted in differential transcription. The constituent cell types of different brain regions express distinctive combinations of genes as they develop and mature, ultimately shaping their functional state in adulthood. How precisely the genetic information of anatomical structures is connected to their underlying biological functions remains an open question in modern neuroscience.A major challenge is the identification of “universal patterns”, which do not depend on the particular individual, but are instead basic structural properties shared by all brains. Despite the vast amount of gene expression data available at both the bulk and single-cell levels, this task remains challenging, mainly due to the lack of suitable data mining tools.In this paper, we propose an approach to address this issue based on a hierarchical version of Stochastic Block Modeling. Thanks to its specific choice of priors, the method is particularly effective in identifying these universal features. We use as a laboratory to test our algorithm a dataset obtained from six independent human brains from the Allen Human Brain Atlas. We show that the proposed method is indeed able to identify universal patterns much better than more traditional algorithms such as Latent Dirichlet Allocation or Weighted Correlation Network Analysis. The probabilistic association between genes and samples that we find well represents the known anatomical and functional brain organization. Moreover, leveraging the peculiar “fuzzy” structure of the gene sets obtained with our method, we identify examples of transcriptional and post-transcriptional pathways associated with specific brain regions, highlighting the potential of our approach.