bluuebunny/crossref_metadata_2025_split huggingface dataset:
Absence of cardiolipin from the outer leaflet of a mitochondrial inner membrane mimic restricts Opa1-mediated fusion
Authors: Ge Yifan , Boopathy Sivakumar , Nguyen Tran H , Lugo Camila Makhlouta , Chao Luke H. 
Published: September 2021

AbstractCardiolipin is a tetra-acylated di-phosphatidylglycerol lipid enriched in the matrix-facing (inner) leaflet of the mitochondrial inner membrane. Cardiolipin plays an important role in regulating mitochondria function and dynamics. Yet, the mechanisms connecting cardiolipin distribution and mitochondrial protein function remain indirect. In our previous work, we established an in vitro system reconstituting mitochondrial inner membrane fusion mediated by Opa1. We found that the long form of Opa1 (l-Opa1) works together with the proteolytically processed short form (s-Opa1) to mediate fast and efficient membrane fusion. Here, we extend our reconstitution system to generate supported lipid bilayers with asymmetric cardiolipin distribution. Using this system, we find the presence of cardiolipin on the inter-membrane space-facing (outer) leaflet is important for membrane tethering and fusion. We discuss how the presence of cardiolipin in this leaflet may influence protein and membrane properties, and future applications for this approach.
Horizontal mitochondrial transfer from the microenvironment increases glioblastoma tumorigenicity
Authors: Watson Dionysios C. , Bayik Defne , Williford Sarah E. , Lauko Adam , Zhou Yadi , Deshpande Gauravi , Seder Juliana , Mears Jason A. , Cheng Feixiong , Hjelmeland Anita B. , Lathia Justin D. 
Published: September 2021

AbstractWhile dynamic microenvironmental interactions drive tumor growth and therapeutic resistance, the underlying direct cell-cell communication mechanisms remain poorly understood. We identified horizontal mitochondrial transfer as a mechanism that enhances tumorigenesis in glioblastoma. This transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth.One-Sentence SummaryMitochondrial transfer from astrocytes to glioblastoma alters metabolic profile and enhances the tumor-initiation capacity.
Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production
Authors: Kang Yoon-A , Paik Hyojung , Zhang Si Yi , Chen Jonathan , Warr Matthew R. , Fan Rong , Passegué Emmanuelle 
Published: September 2021

AbstractRecent lineage tracing analyses revealed multipotent progenitors (MPP) to be major functional contributors to steady-state hematopoiesis (1–6). However, we are still lacking a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in MPPs. Here, we found that myeloid-biased MPP3 (2, 3) are functionally and molecularly heterogeneous, with a distinct subset of myeloid-primed secretory cells with high endoplasmic reticulum (ER) volume and FcγR expression. We show that FcγR+/ERhigh MPP3 are a transitional population for rapid production of granulocyte/macrophage progenitors (GMP), which directly amplify myelopoiesis through inflammation-triggered secretion of cytokines in the local bone marrow (BM) microenvironment. Our results identify a novel regulatory function for a subset of secretory MPP3 that controls myeloid differentiation through lineage-priming and cytokine production, and act as a self-reinforcing amplification compartment in stress and disease conditions.One-Sentence SummaryA secretory subset of multipotent hematopoietic progenitors augment myelopoiesis in stress and diseases conditions.
Riemannian geometry of functional connectivity matrices for multi-site attention-deficit/hyperactivity disorder data harmonization
Authors: Simeon Guillem , Piella Gemma , Camara Oscar , Pareto Deborah 
Published: September 2021

ABSTRACTThe use of multi-site datasets in neuroimaging provides neuroscientists with more statistical power to perform their analyses. However, it has been shown that imaging-site introduces a variability in the data that cannot be attributed to biological sources. In this work, we show that functional connectivity matrices derived from resting-state multi-site data contain a significant imaging-site bias. To this aim, we exploited the fact that functional connectivity matrices belong to the manifold of symmetric positive-definite matrices, making possible to operate on them with Riemannian geometry. We hereby propose a geometry-aware harmonization approach, Rigid Log-Euclidean Translation, that accounts for this site bias. Moreover, we adapted other Riemannian-geometric methods designed for other domain adaptation tasks, and compared them to our proposal. Based on our results, Rigid Log-Euclidean Translation of multi-site functional connectivity matrices seems to be among the studied methods the most suitable one in a clinical setting. This represents an advance with respect to previous functional connectivity data harmonization approaches, which do not respect the geometric constraints imposed by the underlying structure of the manifold. In particular, when applying our proposed method on data from the ADHD-200 dataset, a multi-site dataset built for the study of attention-deficit/hyperactivity disorder, we obtained results that display a remarkable correlation with established pathophysiological findings and, therefore, represent a substantial improvement when compared to the non-harmonization analysis. Thus, we present evidence supporting that harmonization should be extended to other functional neuroimaging datasets, and provide a simple geometric method to address it.
Neural Excursions from Low-Dimensional Manifold Structure Explain Intersubject Variation in Human Motor Learning
Authors: Areshenkoff Corson N. , Gale Dan J. , Nashed Joseph Y. , Standage Dominic , Flanagan J Randall , Gallivan Jason P. 
Published: September 2021

AbstractHumans vary greatly in their motor learning abilities, yet little is known about the neural mechanisms that underlie this variability. Recent neuroimaging and electrophysiological studies demonstrate that large-scale neural dynamics inhabit a low-dimensional subspace or manifold, and that learning is constrained by this intrinsic manifold architecture. Here we asked, using functional MRI, whether subject-level differences in neural excursion from manifold structure can explain differences in learning across participants. We had subjects perform a sensorimotor adaptation task in the MRI scanner on two consecutive days, allowing us to assess their learning performance across days, as well as continuously measure brain activity. We find that the overall neural excursion from manifold activity in both cognitive and sensorimotor brain networks is associated with differences in subjects’ patterns of learning and relearning across days. These findings suggest that off-manifold activity provides an index of the relative engagement of different neural systems during learning, and that intersubject differences in patterns of learning and relearning across days are related to reconfiguration processes in cognitive and sensorimotor networks during learning.
The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice
Authors: Zhang Han , Shevtsova Natalia A. , Deska-Gauthier Dylan , Mackay Colin , Dougherty Kimberly J. , Danner Simon M. , Zhang Ying , Rybak Ilya A. 
Published: September 2021

AbstractSpeed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. We have previously demonstrated that a subset of spinal V3 neurons contributes to stable locomotion by mediating mutual excitation between left and right lumbar rhythm generators (RGs). Here, we expanded our investigation to the V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used lateral-sequence walk. To understand the functional roles of V3 aLPNs, we adapted our previous model of spinal circuitry controlling quadrupedal locomotion (Danner et al., 2017), by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The updated model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left–right interactions within lumbar and cervical cords, promote left–right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.
The art of snacking: Innovative food extraction in a synanthropic species is associated with food exposure and food categorization
Authors: Dhananjaya Tejeshwar , Das Sayantan , Vyas Amal K. , Gahlot Prakhar , Singh Mewa 
Published: September 2021

ABSTRACTExtractive foraging is generally studied from the perspective of behavioral flexibility, cognitive ability, innovation and social learning. Despite its potential to elucidate synanthropic adaptation in species exploiting enclosed anthropogenic food, research on extractive foraging under urban conditions is limited. Since a large extent of anthropogenic food is packaged and contains highly processed food, processes of identification/extraction of food by nonhuman species become intriguing themes of research. We studied how processing status of embedded food determined extraction decisions across groups of a species differing in exposure and familiarity to the food. Further, we tested the generalizability of extraction methods. Experimenting with wild bonnet macaques (Macaca radiata), we found exposure- and form (native/shelled/peeled)-specific familiarity to peanuts, state (raw/boiled/roasted)-specific distinction in depeeling, and exposure- and state-specific differences in methods of depeeling. Group with the highest exposure to peanut differed in its propensity to use sophisticated extraction methods, e.g. depeeling by rubbing between palms (bimanual asymmetric action) and rubbing against horizontal substrata (unimanual action). The innovative methods were also extended to roasted peas and chickpeas by the urban group. Our study establishes a causal relationship between familiarity and processing status of food and shows the generalized extension of extraction methods based on food categorization.Summary StatementNonhuman species in cities face upheaval challenges of accessing enclosed and highly processed anthropogenic food. We studied the effects of minor processing of enclosed food on its extraction decisions.
Three new Cenomanian conifers from El Chango (Chiapas, Mexico) offer a snapshot of the geographic mosaic of the Mesozoic conifer decline
Authors: González-Ramírez Ixchel , Cevallos-Ferriz Sergio R.S. , Rothfels Carl J. 
Published: September 2021

AbstractPremise of study“El Chango” is a recently discovered quarry that contains extremely well preserved fossils. The Cenomanian age of the locality corresponds to a time when the global flora was transitioning from gymnosperm- to angiosperm-dominated, yet conifers predominate in this locality. These fossils thus provide a rare opportunity to understand the replacement of conifers by angiosperms as the dominant group of plants.MethodsWe collected material from El Chango in annual expeditions (2010 to 2014). We selected the three most abundant and best preserved conifer morphotypes and conducted a total-evidence (i.e.,, including molecular and morphological data) phylogenetic analysis of a sample of 72 extant conifer species plus the three fossils. We use these results to inform our taxonomic decisions.ResultsWe obtained four equally most-parsimonious trees (consistency index = 44.1%, retention index = 78.8%). Despite ambiguous relationships among some extant taxa, the three fossil conifers had the same phylogenetic position in all four most-parsimonious trees; we describe these species as new:Sequoiadendron helicalancifoliumsp. nov. (Cupressaceae), andMicrocachrys rhomboideasp. nov. andDacrydium bifoliosussp. nov (Podocarpaceae). The ecosystem is interpreted as a coastal humid mixed forest.ConclusionsOur findings contribute to the understanding of Cenomanian equatorial regions, and support the hypothesis of a geographically and ecologically structured “rise of angiosperms”, with conifers remaining dominant in brackish-water and angiosperms becoming dominant in freshwater-ecosystems. These fossils fill in gaps in the evolutionary history of lineages likeMicrocachrys, which we demonstrate occurred in the Northern hemisphere before becoming restricted to its current range (Tasmania).
Innate immunity pathways activate cell proliferation after penetrating traumatic brain injury in adult Drosophila
Authors: Marischuk Khailee , Crocker Kassi L. , Ahern-Djamali Shawn , Boekhoff-Falk Grace 
Published: September 2021

AbstractWe are utilizing an adult penetrating traumatic brain injury (PTBI) model in Drosophila to investigate regenerative mechanisms after damage to the central brain. We focused on cell proliferation as an early event in the regenerative process. To identify candidate pathways that may trigger cell proliferation following PTBI, we utilized RNA-Seq. We find that transcript levels for components of both Toll and Immune Deficiency (Imd) innate immunity pathways are rapidly and highly upregulated post-PTBI. We then tested mutants for the NF-κB transcription factors of the Toll and Imd pathways, Dorsal-related immunity factor (Dif) and Relish (Rel) respectively. We find that loss of either or both Dif and Rel results in loss of cell proliferation after injury. We then tested canonical downstream targets of Drosophila innate immune signaling, the antimicrobial peptides (AMPs), and find that they are not required for cell proliferation following PTBI. This suggests that there are alternative targets of Toll and Imd signaling that trigger cell division after injury. Furthermore, we find that while AMP levels are substantially elevated after PTBI, their levels revert to near baseline within 24 hours. Finally, we identify tissue-specific requirements for Dif and Rel. Taken together, these results indicate that the innate immunity pathways play an integral role in the regenerative response. Innate immunity previously has been implicated as both a potentiator and an inhibitor of regeneration. Our work suggests that modulation of innate immunity may be essential to prevent adverse outcomes. Thus, this work is likely to inform future experiments to dissect regenerative mechanisms in higher organisms.
Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease
Authors: D’Antonio Matteo , Arthur Timothy D. , Nguyen Jennifer P. , Matsui Hiroko , D’Antonio-Chronowska Agnieszka , Frazer Kelly A. 
Published: September 2021

AbstractThe causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leveraged spatiotemporal information on 966 RNA-seq cardiac samples and performed an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identified 2,578 eQTLs associated with a specific developmental stage-, tissue- and/or cell type. Colocalization between eQTL and GWAS signals of five cardiac traits identified variants with high posterior probabilities for being causal in 210 GWAS loci. Pulse pressure GWAS loci were enriched for colocalization with fetal- and smooth muscle- eQTLs; pulse rate with adult- and cardiac muscle- eQTLs; and atrial fibrillation with cardiac muscle- eQTLs. Fine mapping identified 79 credible sets with five or fewer SNPs, of which 15 were associated with spatiotemporal eQTLs. Our study shows that many cardiac GWAS variants impact traits and disease in a developmental stage-, tissue- and/or cell type-specific fashion.
The chromatin organization of a chlorarachniophyte nucleomorph genome
Authors: Marinov Georgi K. , Chen Xinyi , Wu Tong , He Chuan , Grossman Arthur R. , Kundaje Anshul , Greenleaf William J. 
Published: September 2021

AbstractNucleomoprhs are remnants of secondary endosymbiotic events between two eukaryote cells wherein the endosymbiont has retained its eukaryotic nucleus. Nucleomorphs have evolved at least twice independently, in chlorarachniophytes and cryptophytes, yet they have converged on a remarkably similar genomic architecture, characterized by the most extreme compression and miniaturization among all known eukaryotic genomes. Previous computational studies have suggested that nucleomorph chromatin likely exhibits a number of divergent features. In this work, we provide the first maps of open chromatin, active transcription, and three-dimensional organization for the nucleomorph genome of the chlorarachniophyte Bigelowiella natans. We find that the B. natans nucleomorph genome exists in a highly accessible state, akin to that of ribosomal DNA in some other eukaryotes, and that it is highly transcribed over its entire length, with few signs of polymerase pausing at transcription start sites (TSSs). At the same time, most nucleomorph TSSs show very strong nucleosome positioning. Chromosome conformation (Hi-C) maps reveal that nucleomorph chromosomes interact with one other at their telomeric regions, and show the relative contact frequencies between the multiple genomic compartments of distinct origin that B. natans cells contain.
Human IL-10-producing B cells have diverse states induced from multiple B cell subsets
Authors: Glass Marla C. , Glass David R. , Oliveria John Paul , Mbiribindi Berenice , Esquivel Carlos O. , Krams Sheri M. , Bendall Sean C. , Martinez Olivia M. 
Published: September 2021

AbstractRegulatory B cells (Bregs) can suppress immune responses through the secretion of IL-10 and other anti-inflammatory cytokines. This immunomodulatory capacity holds therapeutic potential, yet a definitional immunophenotype for enumeration and prospective isolation of B cells capable of IL-10 production remains elusive. We therefore applied mass cytometry to simultaneously quantify cytokine production and immunophenotype in human peripheral B cells across a range of stimulatory conditions and timepoints. While multiple B cell subsets produced IL-10, no phenotype uniquely identified IL-10+ B cells and a significant portion of IL-10+ B cells co-expressed the proinflammatory cytokines IL-6 and TNFα. Despite this heterogeneity, we found operationally tolerant liver transplant recipients had a unique enrichment of IL-10+, but not TNFα+ or IL-6+, B cells as compared to transplant recipients receiving immunosuppression. Thus, human IL-10-producing B cells constitute an induced, transient state arising from a diversity of B cell subsets that may contribute to maintenance of immune homeostasis.
The nutritional environment is sufficient to select coexisting biofilm and quorum-sensing mutants of Pseudomonas aeruginosa
Authors: Scribner Michelle R. , Stephens Amelia C. , Huong Justin L. , Richardson Anthony R. , Cooper Vaughn S. 
Published: September 2021

AbstractThe evolution of bacterial populations during infections can be influenced by various factors including available nutrients, the immune system, and competing microbes, rendering it difficult to identify the specific forces that select on evolved traits. The genomes of Pseudomonas aeruginosa isolated from the airway of patients with cystic fibrosis (CF), for example, have revealed commonly mutated genes, but which phenotypes led to their prevalence is often uncertain. Here, we focus on effects of nutritional components of the CF airway on genetic adaptations by P. aeruginosa grown in either well-mixed (planktonic) or biofilm-associated conditions. After only 80 generations of experimental evolution in a simple medium with glucose, lactate, and amino acids, all planktonic populations diversified into lineages with mutated genes common to CF infections: morA, encoding a regulator of biofilm formation, or lasR, encoding a quorum sensing regulator that modulates the expression of virulence factors. Although mutated quorum sensing is often thought to be selected in vivo due to altered virulence phenotypes or social cheating, isolates with lasR mutations demonstrated increased fitness when grown alone and outcompeted the ancestral PA14 strain. Nonsynonymous SNPs in morA increased fitness in a nutrient concentration-dependent manner during planktonic growth and surprisingly also increased biofilm production. Populations propagated in biofilm conditions also acquired mutations in loci associated with chronic infections, including lasR and cyclic-di-GMP regulators roeA and wspF. These findings demonstrate that nutrient conditions and biofilm selection are alone sufficient to select mutants with problematic clinical phenotypes including increased biofilm and altered quorum sensing.ImportancePseudomonas aeruginosa produces dangerous chronic infections that are known for their rapid diversification and recalcitrance to treatment. We performed evolution experiments to identify adaptations selected by two specific aspects of the CF respiratory environment: nutrient levels and surface attachment. Propagation of P. aeruginosa in nutrients present within the CF airway was alone sufficient to drive diversification into subpopulations with identical mutations in regulators of biofilm and quorum sensing to those arising during infection. Thus, the adaptation of opportunistic pathogens to nutrients found in the host may select mutants with phenotypes that complicate treatment and clearance of infection.