bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence
Authors: Louros Nikolaos , Wilkinson Martin , Tsaka Grigoria , Ramakers Meine , Morelli Chiara , Garcia Teresa , Gallardo Rodrigo U. , D’Haeyer Sam , Goossens Vera , Audenaert Dominique , Thal Dietmar Rudolf , Ranson Neil A. , Radford Sheena E. , Rousseau Frederic , Schymkowitz Joost 
Published: October 2022

AbstractDifferent tauopathies are characterized by specific amyloid filament folds that are conserved between patients. Disease-specific tau filament folds probably reflect the specific pathological contexts leading to their formation including isoforms or post-translational modifications. Little is known, however, as to whether and how intrinsic conformational tendencies of the tau sequence itself contribute to its polymorphism. Using cryo-EM structure determination we find that a short amyloidogenic C-terminal peptide consisting of residues 350-362 of the tau repeat domain adopts the same polymorphic conformations in isolation as it does in the context of major disease-associated protofilament folds. Biophysical characterisation and molecular modelling show that the amyloid conformations adopted by this peptide constitute core structural motifs stabilizing distinct disease-associated tau filament folds. In accordance this segment also contributes to the efficient propagation of human AD tau seeds in tau reporter cells while it is irrelevant to heparin-induced recombinant seeds. Our findings suggest that tau 350-362 is key to the propagation of disease-associated tau polymorphs and that the conformational preferences of this segment predispose to the topological diversity observed in tau filament folds.
Regeneration of Starfish Radial Nerve Cord restores animal mobility and unveils a new coelomocyte population
Authors: Magalhães Filipe , Andrade Claúdia , Simões Beatriz , Brigham Fredi , Valente Ruben , Martinez Pedro , Rino José , Sugni Michela , Coelho Ana Varela 
Published: October 2022

ABSTRACTThe potential to regenerate a damaged body part is expressed to a different extent in animals. Echinoderms, in particular starfish, are known for their outstanding potential to regenerate cell, tissue, organ, and body parts. For instance, humans have restricted abilities to restore organ systems being dependent on limited sources of stem cells. In particular, the potential to regenerate the central nervous system is extremely limited, explaining the lack of natural mechanisms that could overcome the development of neurodegenerative diseases and the presence of traumatisms. Therefore, understanding the molecular and cellular mechanisms of regeneration in starfish could lead to the development of new therapeutic approaches in humans. In this study, we tackle the problem of starfish central nervous system regeneration by examining anatomical and behavioral traits, including external anatomic anomalies, the dynamics of coelomocytes populations and neuronal tissue architecture. We noticed that several anatomic anomalies were evident and detected that the injured arm could not be used anymore to lead the starfish movement. Those seem to be related to defense mechanisms and protection of the wound. In particular, histology showed that tissue patterns during regeneration resemble those described in holothurians and in starfish arm tip regeneration. Flow cytometry coupled with imaging flow cytometry unveiled a new coelomocyte population during the late phase of the regeneration process. Morphotypes of previously characterized coelomocytes populations were described based on IFC data. Further studies of this new coelomocyte population might provide insights on their involvement in radial nerve cord regeneration.
Single-cell transcriptomics reveals striking heterogeneity and functional organization of dendritic and monocytic cells in the bovine mesenteric lymph node
Authors: Barut G.T. , Kreuzer M.C. , Bruggmann R. , Summerfield A. , Talker S.C. 
Published: October 2022

ABSTRACTDendritic and monocytic cells co-operate to initiate and shape adaptive immune responses in secondary lymphoid tissue. The complexity of this system is poorly understood, also because of the high phenotypic and functional plasticity of monocytic cells. We have sequenced mononuclear phagocytes in mesenteric lymph nodes (LN) of three adult cows at the single-cell level, revealing ten dendritic-cell (DC) clusters and seven monocyte/macrophage clusters with clearly distinct transcriptomic profiles. Among DC, we defined LN-resident subsets and their progenitors, as well as subsets of highly activated migratory DC differing in transcript levels for T-cell attracting chemokines. Our analyses also revealed a potential differentiation path for cDC2, resulting in a cluster of inflammatory cDC2 with close transcriptional similarity to putative DC3 and monocyte-derived DC. Monocytes and macrophages displayed sub-clustering mainly driven by pro- or anti-inflammatory expression signatures, including a small cluster of cycling, presumably self-renewing, macrophages.With this transcriptomic snapshot of LN-derived mononuclear phagocytes, we reveal functional properties and differentiation trajectories in a “command center of immunity” that are likely to be conserved across species.
High-throughput deep tissue two-photon microscopy at kilohertz frame rates
Authors: Xiao Sheng , Giblin John T. , Boas David A. , Mertz Jerome 
Published: October 2022

ABSTRACTStrategies to image biological phenomena at millisecond time scales are generally technically challenging and suffer from compromises between imaging field-of-view, depth penetration and excitation efficiency in thick tissue. We present a simple and cost-effective solution that enables a conventional video-rate two-photon microscope (2PM) to perform 2D scanning at kilohertz frame rates, while preserving all the benefits of standard 2PM, which we demonstrate by imaging neurovascular dynamics in mouse brains.
Deep Learning Reveals How Cells Pull, Buckle, and Navigate Tissue-Like Environments
Authors: Padhi Abinash , Daw Arka , Sawhney Medha , Talukder Maahi M. , Agashe Atharva , Pour Mehran Mohammad Hossein , Jafari Mohammad , Genin Guy M. , Alisafaei Farid , Kale Sohan , Karpatne Anuj , Nain Amrinder S. 
Published: October 2022

AbstractCells move within tissues by pulling on and reshaping their fibrous surroundings. Measuring the associated forces has been a fundamental challenge in cell biology. Here, we develop deep-learning-enabled live-cell fiber-force microscopy (DLFM), which computes forces produced by living cells in real time as they interact with tissue-like fiber networks. DLFM combines basic phase microscopy with novel deep learning to simultaneously track cell movement and fiber deformation without disruptive fluorescent labels or chemical modifications. This allowed us to measure forces in real-time situations that were previously impossible to study, revealing an intricate mechanical landscape: cells generate ten-fold changes in force as they change shape during migration, create force-dipoles during cell-cell interactions, and dramatically alter their force patterns during stem cell differentiation. Through integrated experiments and mathematical modeling, we discovered that cells in fibrous environments form force-generating adhesions throughout their body, strikingly different from the edge-only adhesions seen in traditional petri dish experiments. Results clarify cytoskeletal pathways by which cells adapt force-generating machinery to navigate the fibrous architecture of tissues.
P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis
Authors: de Salles Érika Machado , Raeder Paulo Lisboa , Angeli Claudia , Santiago Verônica Feijoli , de Souza Cristiane Naffah , Ramalho Theresa , Câmara Niels Olsen Saraiva , Palmisano Giuseppe , Álvarez José Maria , D’Império Lima Maria Regina 
Published: October 2022

ABSTRACTThis study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes the differentiation of Th1 cells.In vivoanalysis was performed in thePlasmodium chabaudimodel of malaria in view of the great relevance of this infectious disease for human health, as well as the great availability of data concerning Th1/Tfh differentiation. We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+T cells. We also showin vitrothe phenotypic similarities of Th1-conditioned CD4+T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition,in vitroATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.
oskaracts with the transcription factor Creb to regulate long-term memory in crickets
Authors: Kulkarni Arpita , Ewen-Campen Ben , Terao Kanta , Matsumoto Yukihisa , Li Yaolong , Watanabe Takayuki , Kao Jonchee A. , Parhad Swapnil S. , Ylla Guillem , Mizunami Makoto , Extavour Cassandra G. 
Published: October 2022

AbstractNovel genes have the potential to drive the evolution of new biological mechanisms, or to integrate into pre-existing regulatory circuits and contribute to the regulation of older, conserved biological functions. One such gene, the novel insect-specific geneoskar, was first identified based on its role in establishing theDrosophila melanogastergerm line. We previously showed that this gene likely arose through an unusual domain transfer event involving bacterial endosymbionts, and played a somatic role before evolving its well-known germ line function. Here, we provide empirical support for this hypothesis in the form of evidence for a novel neural role foroskar. We show thatoskaris expressed in the adult neural stem cells of a hemimetabolous insect, the cricketGryllus bimaculatus. In these stem cells, called neuroblasts,oskaris required together with the ancient animal transcription factorCrebto regulate long-term (but not short-term) olfactory memory. We provide evidence thatoskarpositively regulatesCreb, which plays a conserved role in long-term memory across animals, and thatoskarin turn may be a direct target of Creb. Together with previous reports of a role foroskarin nervous system development and function in crickets and flies, our results are consistent with the hypothesis thatoskar’s original somatic role may have been in the insect nervous system. Moreover, its co-localization and functional cooperation with the conserved pluripotency genepiwiin the nervous system may have facilitatedoskar’s later co-option to the germ line in holometabolous insects.
Approximate Bayesian Computation applied to time series of population genetic data disentangles rapid genetic changes and demographic variations in a pathogen population
Authors: Saubin Méline , Tellier Aurélien , Stoeckel Solenn , Andrieux Axelle , Halkett Fabien 
Published: October 2022

AbstractAdaptation can occur at remarkably short timescales in natural populations, leading to drastic changes in phenotypes and genotype frequencies over a few generations only. The inference of demographic parameters can allow understanding how evolutionary forces interact and shape the genetic trajectories of populations during rapid adaptation. Here we propose a new Approximate Bayesian Computation (ABC) framework that couples a forward and individual-based model with temporal genetic data to disentangle genetic changes and demographic variations in a case of rapid adaptation. We test the accuracy of our inferential framework and evaluate the benefit of considering the full trajectory compared to few time samples. Theoretical investigations demonstrate high accuracy in both model and parameter estimations, even if a strong thinning is applied to time series data. Then, we apply our ABC inferential framework to empirical data describing the population genetics changes of the poplar rust pathogen following a major event of resistance overcoming. We successfully estimate key demographic and genetic parameters, including the proportion of resistant hosts deployed in the landscape and the level of standing genetic variation from which selection occurred. Inferred values are in accordance with our empirical knowledge of this biological system. This new inferential framework, which contrasts with coalescent-based ABC analyses, is promising for a better understanding of evolutionary trajectories of populations subjected to rapid adaptation.
Single-cell gene set enrichment analysis and transfer learning for functional annotation of scRNA-seq data
Authors: Pellecchia Simona , Viscido Gaetano , Franchini Melania , Gambardella Gennaro 
Published: October 2022

AbstractAlthough an essential step, the functional annotation of cells often proves particularly challenging in the analysis of single-cell transcriptional data. Several methods have been developed to accomplish this task. However, in most cases, these rely on techniques initially developed for bulk RNA sequencing or simply make use of marker genes identified from cell clustering followed by supervised annotation. To overcome these limitations and automatise the process, we have developed two novel methods, the single-cell gene set enrichment analysis (scGSEA) and the single cell mapper (scMAP). scGSEA combines latent data representations and gene set enrichment scores to detect coordinated gene activity at single-cell resolution. scMAP uses transfer learning techniques to repurpose and contextualise new cells into a reference cell atlas. Using both simulated and real datasets, we show that scGSEA effectively recapitulates recurrent patterns of pathways’ activity shared by cells from different experimental conditions. At the same time, we show that scMAP can reliably map and contextualise new single cell profiles on a breast cancer atlas we recently released. Both tools are provided in an effective and straightforward workflow providing a framework to determine cell function and significantly improve annotation and interpretation of scRNA-seq data.
Functional ultrasound imaging reveals an aberrant developmental trajectory of functional connectivity in a mouse model of the 15q13.3 copy number variant microdeletion
Authors: Grohs-Metz Gillian , Hengerer Bastian , Cruces Solis Hugo 
Published: October 2022

AbstractThe developmental nature of many neuropsychiatric disorders such as schizophrenia necessitates the detection of functional biomarkers during the prodromal phase of disease that can predict symptomatic conversion and outcomes. Structural chromosomal aberrations, such as copy number variants, confer high risk and penetrance of neuropsychiatric disorders. We used functional ultrasound imaging (fUS) to characterize the functional connectivity profile of the 15q13.3+/−copy number variant mouse model during major developmental milestones on post-natal day (p)35, 42, 60, and 90 in comparison to wild type littermates. We identified divergent trajectories for 15q13.3+/−mice and WT littermate controls where functional connectivity was reduced for both genotypes with age, but to a lesser extent for 15q13.3+/−mice. We were then able to isolate the distinct differences between genotypes to identify a large-scale network where 15q13.3+/−mice displayed global cortical hyperconnectivity and elevated intra-connectivity within the hippocampus and amygdala, in particular. In order to determine the stage of development where the connectivity trajectories bifurcated, we used machine learning to predict genotype. We found that the connectivity profile from p42, but not p35, predicted the genotype of individual mice at p90 with 82% accuracy. All together, these results suggest a crucial period of network maturation from early to late pubescence that is pivotal in the transition of healthy network connectivity into adulthood. This novel application of fUS longitudinally through development shows promise in improving the understanding of the disease biology of mouse models of psychiatric diseases.
Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma
Authors: Gil Jeovanis , Kim Yonghyo , Doma Viktória , Çakır Uğur , Kuras Magdalena , Betancourt Lazaro Hiram , Parada Indira Pla , Sanchez Aniel , Sugihara Yutaka , Appelqvist Roger , Oskolas Henriett , Lee Boram , de Siqueira Guedes Jéssica , Monnerat Gustavo , Alves Carneiro Gabriel Reis , Nogueira Fábio CS , Domont Gilberto B. , Malm Johan , Baldetorp Bo , Wieslander Elisabet , Balázs Németh István , Szász A. Marcell , Kwon Ho Jeong , Hong Runyu , Pawłowski Krzysztof , Rezeli Melinda , Tímár József , Fenyö David , Kárpáti Sarolta , Marko-Varga György 
Published: October 2022

SummaryThe dynamics of more than 1900 mitochondrial proteins was explored through quantitative proteomics in 151 melanoma-related tissue samples of both surgical and autopsy origin. Dysregulation of mitochondrial pathways in primary tumors, metastases, and peritumoral tissues was correlated with age and survival of patients, as well as with tumor cell proliferation and the BRAF mutation status of the tumors. The outlined proteomic landscape confirmed the central role of a pathologically upregulated mitochondrial translation machinery and oxidative phosphorylation (OXPHOS) in the development, proliferation, and progression of melanomas. Our results from different melanoma cell lines confirmed our findings and we could document that treatments with selected OXPHOS inhibitors and antibiotics successfully impaired tumor cell proliferation. In addition, we provided proteomic evidence on the mechanism-of-action of the different treatments. These observations could contribute to the development of therapeutic approaches targeting the mitochondrial pathology in melanoma.TOC figureHighlightsMitochondrial proteome landscape outlined in 151 melanoma-related samplesMitochondrial Translation and OXPHOS impact disease severity and survivalBRAF V600E mutation correlates with upregulation of mitochondrial energy productionTargeting the mitochondrial OXPHOS and ribosomes impairs tumor cell proliferationTherapeutic opportunities complementary to the standard of care are proposedIn briefMitochondrial proteome profiling of melanomas reveals dysregulation in major metabolic pathways, suggesting a central role of the mitochondria within the development and progression of melanoma. Targeting mitochondrial pathways has the potential to impact the course of the disease, which provides opportunities for complementary drug interventions.
Spatiotemporal tissue maturation of thalamocortical pathways in the human fetal brain
Authors: Wilson Siân , Pietsch Maximilian , Cordero-Grande Lucilio , Christiaens Daan , Uus Alena , Karolis Vyacheslav , Kyriakopoulou Vanessa , Colford Kathleen , Price Anthony N. , Hutter Jana , Rutherford Mary A. , Hughes Emer J. , Counsell Serena J. , Tournier Jacques-Donald , Hajnal Joseph V , Edwards A. David , O’Muircheartaigh Jonathan , Arichi Tomoki 
Published: October 2022

AbstractThe development of connectivity between the thalamus and maturing cortex is a fundamental process in the second half of human gestation, establishing the neural circuits that are the basis for several important brain functions. In this study, we acquired high-resolutionin uterodiffusion MRI from 140 fetuses as part of the Developing Human Connectome Project, to examine the emergence of thalamocortical white matter over the second to third trimester. We delineate developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. We then quantify microstructural tissue components along the tracts in the fetal compartments that are critical substrates for white matter maturation, such as the subplate and intermediate zone. We identify patterns of change in the diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester, such as the disassembly of radial glial scaffolding and the lamination of the cortical plate. These maturational trajectories of MR signal in transient fetal compartments provide a normative reference to complement histological knowledge, facilitating future studies to establish how developmental disruptions in these regions contribute to pathophysiology.
Causes and consequences of linkage disequilibrium among transposable elements within eukaryotic genomes
Authors: Roze Denis 
Published: October 2022

ABSTRACTSex and recombination can affect the dynamics of transposable elements (TEs) in various ways: while sex is expected to help TEs to spread within populations, the deleterious effect of ectopic recombination among transposons represents a possible source of purifying selection limiting their number. Furthermore, recombination may also increase the efficiency of selection against TEs by reducing selective interference among loci. In order to better understand the effects of recombination and reproductive systems on TE dynamics, this article provides analytical expressions for the linkage disequilibrium (LD) among TEs in a classical model in which TE number is stabilized by synergistic purifying selection. The results show that positive LD is predicted in infinite populations despite negative epistasis, due to the effect of the transposition process. Positive LD may substantial inflate the variance in the number of elements per genome in the case of partially selfing or partially clonal populations. Finite population size tends to generate negative LD (Hill-Robertson effect), the relative importance of this effect increasing with the degree of linkage among loci. The model is then extended in order to explore how TEs may affect selection for recombination. While positive LD generated by transposition generally disfavors recombination, the Hill-Robertson effect may represent a non-negligible source of indirect selection for recombination when TEs are abundant. However, the direct fitness cost imposed by ectopic recombination among elements generally drives the population towards low-recombination regimes, at which TEs cannot be maintained at a stable equilibrium.