bluuebunny/crossref_metadata_2025_split huggingface dataset:
The mitochondrial multi-omic response to exercise training across tissues
Authors: Amar David , Gay Nicole R , Jimenez-Morales David , Jean Beltran Pierre M , Ramaker Megan E , Raja Archana Natarajan , Zhao Bingqing , Sun Yifei , Marwaha Shruti , Gaul David , Hershman Steven G , Xia Ashley , Lanza Ian , Fernandez Facundo M , Montgomery Stephen B. , Hevener Andrea L. , Ashley Euan A. , Walsh Martin J , Sparks Lauren M , Burant Charles F , Rector R Scott , Thyfault John , Wheeler Matthew T. , Goodpaster Bret H. , Coen Paul M. , Schenk Simon , Bodine Sue C , Lindholm Maléne E. ,   the MoTrPAC Study Group
Published: January 2023

AbstractMitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.
Micromotion derived fluid shear stress mediates peri-electrode gliosis through mechanosensitive ion channels
Authors: Trotier Alexandre , Bagnoli Enrico , Walski Tomasz , Evers Judith , Pugliese Eugenia , Lowry Madeleine , Kilcoyne Michelle , Fitzgerald Una , Biggs Manus 
Published: January 2023

AbstractClinical applications for neural implant technologies are steadily advancing. Yet, despite clinical successes, neuroelectrode-based therapies require invasive neurosurgery and can subject local soft-tissues to micro-motion induced mechanical shear, leading to the development of peri-implant scaring. This reactive glial tissue creates a physical barrier to electrical signal propagation, leading to loss of device function. Although peri-electrode gliosis is a well described contributor to neuroelectrode failure, the mechanistic basis behind the initiation and progression of glial scarring remains poorly understood.Here, we develop anin silicomodel of electrode-induced shear stress to evaluate the evolution of the peri-electrode fluid-filled void, encompassing a solid and viscoelastic liquid/solid interface. This model was subsequently used to inform anin vitroparallel-plate flow model of micromotion mediated peri-electrode fluid shear stress.Ventral mesencephalic E14 rat embryonicin vitrocultures exposed to physiologically relevant fluid shear exhibited upregulation of gliosis-associated proteins and the overexpression of two mechanosensitive ion channel receptors, PIEZO1 and TRPA1, confirmedin vivoin a neural probe induced rat glial scar model. Finally, it was shownin vitrothat chemical inhibition/activation of PIEZO1 could exacerbate or attenuate astrocyte reactivity as induced by fluid shear stress and that this was mitochondrial dependant.Together, our results suggests that mechanosensitive ion channels play a major role in the development of the neuroelectrode micromotion induced glial scar and that the modulation of PIEZO1 and TRPA1 through chemical agonist/antagonist may promote chronic electrode stabilityin vivo.Graphical abstractHighlightsPeri-electrode void progression is mediated by fluid flow shear stressOscillatory fluid flow shear stress replicates neuroelectrode glial scarring in vitroAstrocyte PIEZO1 and TRPA1 are upregulated at the peri-electrode region in response to electrode micromotionPIEZO1 pharmaceutical activation diminishes shear stress-induced gliosisPIEZO1 chemical inhibition exacerbates gliosis and reduces mitochondrial functions
Spatio-temporal remodeling of extracellular matrix orients epithelial sheet folding
Authors: Tsuboi Alice , Fujimoto Koichi , Kondo Takefumi 
Published: January 2023

AbstractBiological systems are inherently noisy; however, they produce highly stereotyped tissue morphology.Drosophilapupal wings show a highly stereotypic folding through uniform expansion and subsequent buckling of wing epithelium within a surrounding cuticle sac. The folding pattern produced by buckling is generally stochastic; it is thus unclear how buckling leads to stereotypic tissue folding of the wings. We found that the extracellular matrix (ECM) protein, Dumpy, guides the position and direction of buckling-induced folds. Dumpy anchors the wing epithelium to the overlying cuticle at specific tissue positions. Tissue-wide alterations of Dumpy deposition and degradation yielded different buckling patterns. In summary, we propose that spatio-temporal ECM remodeling shapes stereotyped tissue folding through dynamic interactions between the epithelium and its external structures.One-Sentence SummaryRemodeling of extracellular matrix protein, Dumpy, guides epithelial tissue folding duringDrosophilawing development.
Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils
Authors: Li Jiang , Ruggiero-Ruff Rebecca E. , He Yuxin , Qiu Xinru , Lainez Nancy M. , Villa Pedro A. , Godzik Adam , Coss Djurdjica , Nair Meera G. 
Published: January 2023

AbstractObesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity co-morbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high fat diet-induced obesity. Compared to male mice, RELMα levels were elevated in both control and high fat dietfed females and correlated with adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had pro-inflammatory macrophage accumulation and eosinophil loss, while both RELMα treatment and eosinophil transfer rescued this phenotype. Single cell RNA-sequencing of the adipose stromal vascular fraction was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.
Oxygen-induced chromophore degradation in the photoswitchable red fluorescent protein rsCherry
Authors: Bui Thi Yen Hang , De Zitter Elke , Moeyaert Benjamien , Pecqueur Ludovic , Srinivasu Bindu Y , Economou Anastassios , Fontecave Marc , Van Meervelt Luc , Dedecker Peter , Pedre Brandán 
Published: January 2023

AbstractReversibly switchable monomeric Cherry (rsCherry) is a photoswitchable variant of the red fluorescent protein mCherry. We report that this protein gradually and irreversibly loses its red fluorescence in the dark over a period of months at 4°C and a few days at 37°C. We also find that its ancestor, mCherry, undergoes a similar fluorescence loss but at a slower rate. X-ray crystallography and mass spectrometry reveal that this is caused by the cleavage of thep-hydroxyphenyl ring from the chromophore and the formation of two novel types of cyclic structures at the remaining chromophore moiety. Overall, our work sheds light on a new process occurring within fluorescent proteins, further adding to the chemical diversity and versatility of these molecules.
Automated staging of zebrafish embryos with deep learning
Authors: Jones Rebecca A. , Renshaw Matthew J. , Devenport Danelle , Barry David J. 
Published: January 2023

AbstractThe zebrafish (Danio rerio), is an important biomedical model organism used in many disciplines. The phenomenon of developmental delay in zebrafish embryos has been widely reported as part of a mutant or treatment-induced phenotype. However, the detection and quantification of these delays is often achieved through manual observation with reference to staging guides, which is both time-consuming and subjective. We recently reported a machine learning-based classifier, capable of quantifying the developmental delay between two populations of zebrafish embryos. Here, we build on that work by introducing a deep learning-based model (KimmelNet) that has been trained to predict the age (hours post fertilisation) of populations of zebrafish embryos. We show that when KimmelNet is tested on 2D brightfield images of zebrafish embryos, the predictions generated agree closely with those expected from established approaches to staging. Random sampling of the test data demonstrate that KimmelNet can be used to detect developmental delay between two populations with high confidence based on as few as 100 images of each population. Finally, we show that KimmelNet generalises to previously unseen data, with limited transfer learning improving this performance significantly. With the ability to analyse tens of thousands of standard brightfield microscopy images on a timescale of minutes, we envisage that KimmelNet will be a valuable resource for the developmental biology community. Furthermore, the approach we have used could easily be adapted to generate models for other organisms.
DMRT1is a testis determining gene in rabbits and is also essential for female fertility
Authors: Dujardin Emilie , André Marjolaine , Dewaele Aurélie , Mandon-Pépin Béatrice , Poulat Francis , Frambourg Anne , Thépot Dominique , Jouneau Luc , Jolivet Geneviève , Pailhoux Eric , Pannetier Maëlle 
Published: January 2023

AbstractDMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, whereSRYis the testis-determining gene, remains ambiguous. So far, DMRT1 loss of function has been described in two mammalian species and induces different phenotypes: disorders of sex development (46, XY DSD) in men and male infertility in mice. We thus abolished DMRT1 expression by CRISPR/Cas9 in a third species of mammal, the rabbit. First, we observed that gonads from XYDMRT1-/-rabbit fetuses differentiated like ovaries, highlighting that DMRT1 is involved in testis determination. In addition to SRY, DMRT1 is required in the supporting cells to increase the expression of theSOX9gene, which heads the testicular genetic cascade. Second, we highlighted another function of DMRT1 in the germline since XX and XYDMRT1-/-ovaries did not undergo meiosis and folliculogenesis. XXDMRT1-/-adult females were sterile, showing that DMRT1 is also crucial for female fertility. To conclude, these phenotypes indicate an evolutionary continuum between non-mammalian vertebrates such as birds and non-rodent mammals. Furthermore, our data support the potential involvement ofDMRT1mutations in different human pathologies, such as 46, XY DSD as well as male and female infertility.
Prion-like characteristics of Hepatitis E virus ORF3 protein are associated with virus release and pathogenesis
Authors: Wang Yajing , Tian Houlu , Shi Na , Wu Chunyan , Huang Yaowei , Yang Yongling , Ding Qiang , Zheng Xu , Zhao Qin , Tuite Mick F. , Chen Hongying , Nan Yuchen 
Published: January 2023

AbstractHepatitis E virus (HEV) is a common causative agent of acute hepatitis. Due to the shortage of efficient in vitro model, the viral assembly and release processes are still poorly understood. In this study, we found that ORF3, an HEV structural protein showed prion-like properties. The prion domain (PrD) of yeast prion Sup35 could be functionally replaced by HEV-ORF3 and its candidate PrD (cPrD). A single amino acid substitution in the cPrD reduced the aggregation propensity of ORF3 and blocked the function of ORF3 in enhancing the stability of microtubules in HEV-infected cells, thus blocking virion release from the infected cells and resulting in reduced HEV pathogenicity in Mongolian gerbils. These data suggest that HEV-ORF3 is a novel functional prion-like protein which assembles into a filamentous structure for virion release, supporting the hypothesis that the self-propagating properties of prion proteins are widely exploited as epigenetic information carriers in nature.
Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex
Authors: Leech Robert , De Wael Reinder Vos , Vasa Frantisek , Xu Ting , Benn R. Austin , Scholz Robert , Braga Rodrigo M. , Milham Michael , Royer Jessica , Bernhardt Boris , Jones Emily , Jefferies Elizabeth , Margulies Daniel , Smallwood Jonathan 
Published: January 2023

AbstractRecent theories of cortical organisation maintain that important features of brain function emerge through the spatial arrangement of regions of cortex. For example, areas of association cortex are located in regions of cortex furthest from sensory and motor cortex. Association cortex is also ‘interdigitated’ since adjacent regions can have relatively different patterns of functional connectivity. It is assumed that topographic properties such as distance between cortical regions constrain their functions. For example, large distances between association and sensory and motor systems may enable these areas of cortex to maintain differentiable neural patterns, while an interdigitated organisation may enable association cortex to contain many functional systems in a relatively compact space. We currently lack a formal understanding of how spatial organisation impacts brain function, limiting the ability to leverage cortical topography to facilitate better interpretations of a regions function. Here we use variograms, a quantification of spatial autocorrelation, to develop a cortex-wide profile of how functional similarity changes as a function of the distance between regions. We establish that function changes gradually within sensory and motor cortex as the distance between regions increases, while in association cortex function changes rapidly over shorter distances. Subsequent analysis suggests these differential classes of spatial dependency are related to variation in intracortical myelin between sensory motor and association cortex. Our study suggests primary and association cortex are differentiated by the degree to which function varies over space, emphasising the need to formally account for spatial properties when estimating a system’s contribution to cognition and behaviour.Significance statementThe spatial arrangements of regions in the human brain are hypothesised to underpin important features of a brain regions function. Currently, however, we lack a formal understanding of how topography shapes brain function, limiting our ability to leverage topographical perspectives to inform better theories of brain function. Here we use a formal mathematical approach to establish that in regions of association cortex function varies across the cortex more rapidly than in sensory and motor cortex, a phenomenon linked to levels of intracortical myelin. This result highlights how topographical features distinguish between cortical regions with different functional profiles and provides a formal account of how spatial differences support different features of brain function.
Transplantation-based screen uncovers inducers of muscle progenitor cell engraftment across vertebrate species
Authors: Tavakoli Sahar , Adatto Isaac , Kakhki Sara Ashrafi , Chan Victoria S , Fotowat Haleh , Gähwiler Eric , Manning Margot E , Messemer Kathleen A , Rangan Apoorva , Yang Song , Wagers Amy J , Zon Leonard I 
Published: January 2023

SummaryStem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited due to the deleterious effects of cell expansionin vitroand consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small molecule screening platform employing zebrafish and mouse, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to identify those that could increase myogenic engraftmentin vivoin zebrafish and mice. Two lipids, lysophosphatidic acid (LPA) and niflumic acid (NFA), are linked to activation of intracellular calcium ion flux, which showed conserved, dose-dependent and synergistic effects in promoting muscle engraftment across these vertebrate species.
Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Authors: Podolsky Michael J. , Kheyfets Benjamin , Pandey Monika , Beigh Afaq H. , Yang Christopher D. , Valenzuela Carlos Lizama , Datta Ritwik , Wolters Paul J. , McManus Michael T. , Qi Ling , Atabai Kamran 
Published: January 2023

AbstractAccumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, we executed unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discovered a previously unappreciated mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism is dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of SEL1L. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus cell-autonomous, rheostatic collagen clearance is a previously unidentified pathway of tissue homeostasis.
Sex-biased expression is associated with chromatin state inD. melanogasterandD. simulans
Authors: Nanni Adalena V. , Martinez Natalie , Graze Rita , Morse Alison , Newman Jeremy R. B. , Jain Vaibhav , Vlaho Srna , Signor Sarah , Nuzhdin Sergey V. , Renne Rolf , McIntyre Lauren M. 
Published: January 2023

AbstractWe propose a new model for the association of chromatin state and sex-bias in expression. We hypothesize enrichment of open chromatin in the sex where we see expression bias (OS) and closed chromatin in the opposite sex (CO). In this study ofD. melanogasterandD. simulanshead tissue, sex-bias in expression is associated with H3K4me3 (open mark) in males for male-biased genes and in females for female-biased genes in both species. Sex-bias in expression is also largely conserved in direction and magnitude between the two species on the X and autosomes. In male-biased orthologs, the sex-bias ratio is more divergent between species if both species have H3K27me2me3 marks in females compared to when either or neither species has H3K27me2me3 in females. H3K27me2me3 marks in females are associated with male-bias in expression on the autosomes in both species, but on the X only inD. melanogaster. In female-biased orthologs the relationship between the species for the sex-bias ratio is similar regardless of the H3K27me2me3 marks in males. Female-biased orthologs are more similar in the ratio of sex-bias than male-biased orthologs and there is an excess of male-bias in expression in orthologs that gain/lose sex-bias. There is an excess of male-bias in sex-limited expression in both species suggesting excess male-bias is due to rapid evolution between the species. The X chromosome has an enrichment in male-limited H3K4me3 in both species and an enrichment of sex-bias in expression compared to the autosomes.
Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin2G protein-coupled receptor
Authors: Babin Katie M. , Karim Jordan A. , Gordon Peyton H. , Lennon James , Dickson Alex , Pioszak Augen A. 
Published: January 2023

AbstractThe signaling peptides adrenomedullin 2/intermedin (AM2/IMD), adrenomedullin (AM), and CGRP have overlapping and distinct functions in the cardiovascular, lymphatic, and nervous systems by activating three shared receptors comprised of the class B GPCR CLR in complex with a RAMP1, −2, or −3 modulatory subunit. Here, we report that AM2/IMD, which is thought to be a non-selective agonist, is kinetically selective for CLR-RAMP3, known as the AM2R. AM2/IMD-AM2R elicited substantially longer duration cAMP signaling than the eight other peptide-receptor combinations due to AM2/IMD slow off-rate binding kinetics. The regions responsible for the slow off-rate were mapped to the AM2/IMD mid-region and the RAMP3 extracellular domain. MD simulations revealed how these bestow enhanced stability to the complex. Our results uncover AM2/IMD-AM2R as a cognate pair with unique temporal features, define the mechanism of kinetic selectivity, and explain how AM2/IMD and RAMP3 collaborate to shape the signaling output of a clinically important GPCR.