bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circadian rhythm shows potential for mRNA efficiency and self-organized division of labor in multinucleate cells
Authors: Zinn-Brooks Leif , Roper Marcus L. 
Published: February 2021

AbstractMultinucleate cells occur in every biosphere and across the kingdoms of life, including in the human body as muscle cells and bone-forming cells. Data from filamentous fungi suggest that, even when bathed in a common cytoplasm, nuclei are capable of autonomous behaviors, including division. How does this potential for autonomy affect the organization of cellular processes between nuclei? Here we analyze a simplified model of circadian rhythm, a form of cellular oscillator, in a mathematical model of the filamentous fungusNeurospora crassa.Our results highlight the role played by mRNA-protein phase separation to keep mRNAs close to the nuclei from which they originate, while allowing proteins to diffuse freely between nuclei. Our modeling shows that syncytism allows for extreme mRNA efficiency — we demonstrate assembly of a robust oscillator with transcription levels 104-fold less than in comparable uninucleate cells. We also show self-organized division of the labor of mRNA production, with one nucleus in a two-nucleus syncytium producing at least twice as many mRNAs as the other in 30% of cycles. This division can occur spontaneously, but division of labor can also be controlled by regulating the amount of cytoplasmic volume available to each nucleus. Taken together, our results show the intriguing richness and potential for emergent organization among nuclei in multinucleate cells. They also highlight the role of previously studied mechanisms of cellular organization, including nuclear space control and localization of mRNAs through RNA-protein phase separation, in regulating nuclear coordination.Author summaryCircadian rhythms are among the most researched cellular processes, but limited work has been done on how these rhythms are coordinated between nuclei in multinucleate cells. In this work, we analyze a mathematical model for circadian oscillations in a multinucleate cell, motivated by frequency mRNA and protein data from the filamentous fungusNeurospora crassa. Our results illuminate the importance of mRNA-protein phase separation, in which mRNAs are kept close to the nucleus in which they were transcribed, while proteins can diffuse freely across the cell. We demonstrate that this phase separation allows for a robust oscillator to be assembled with very low mRNA counts. We also investigate how the labor of transcribing mRNAs is divided between nuclei, both when nuclei are evenly spaced across the cell and when they are not. Division of this labor can be regulated by controlling the amount of cytoplasmic volume available to each nucleus. Our results show that there is potential for emergent organization and extreme mRNA efficiency in multinucleate cells.
SARS-CoV-2 ORF6 disturbs nucleocytoplasmic trafficking to advance the viral replication
Authors: Miyamoto Yoichi , Itoh Yumi , Suzuki Tatsuya , Tanaka Tomohisa , Sakai Yusuke , Koido Masaru , Hata Chiaki , Wang Cai-Xia , Otani Mayumi , Moriishi Kohji , Tachibana Taro , Kamatani Yoichiro , Yoneda Yoshihiro , Okamoto Toru , Oka Masahiro 
Published: February 2021

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the coronavirus disease 2019 pandemic. ORF6 is known to antagonize the interferon signaling by inhibiting the nuclear translocation of STAT1. Here we show that ORF6 acts as a virulence factor through two distinct strategies. First, ORF6 directly interacts with STAT1 in an IFN-independent manner to inhibit its nuclear translocation. Second, ORF6 directly binds to importin α1, which is a nuclear transport factor encoded byKPNA2, leading to a significant suppression of importin α1-mediated nuclear transport. Furthermore, we found thatKPNA2knockout enhances the viral replication, suggesting that importin α1 suppresses the viral propagation. Additionally, the analyses of gene expression data revealed that importin α1 levels decreased significantly in the lungs of older individuals. Taken together, SARS-CoV-2 ORF6 disrupts the nucleocytoplasmic trafficking to accelerate the viral replication, resulting in the disease progression, especially in older individuals.
Cleavage of Braun lipoprotein Lpp from the bacterial peptidoglycan by a paralog of L,D-transpeptidases, LdtF
Authors: Bahadur Raj , Chodisetti Pavan Kumar , Reddy Manjula 
Published: February 2021

AbstractGram-negative bacterial cell envelope is made up of an outer membrane (OM), an inner membrane (IM) that surrounds the cytoplasm, and a periplasmic space between the two membranes containing peptidoglycan (PG or murein). PG is an elastic polymer that forms a mesh-like sacculus around the IM protecting cells from turgor and environmental stress conditions. In several bacteria includingE. coli, the OM is tethered to PG by an abundant OM lipoprotein, Lpp (or Braun lipoprotein) that functions to maintain the structural and functional integrity of the cell envelope. Since its discovery Lpp has been studied extensively and although L,D-transpeptidases, the enzymes that catalyse the formation of PG–Lpp linkages have been earlier identified, it is not known how these linkages are modulated. Here, using genetic and biochemical approaches, we show that LdtF (formerlyyafK), a newly-identified paralog of L,D-transpeptidases inE. coliis a murein hydrolytic enzyme that catalyses cleavage of Lpp from the PG sacculus. LdtF also exhibits glycine-specific carboxypeptidase activity on muropeptides containing a terminal glycine residue. LdtF is earlier presumed to be an L,D-transpeptidase; however, our results show that it is indeed an L,D-endopeptidase that hydrolyses the products generated by the L,D-transpeptidases. To summarize, this study describes the discovery of a murein endopeptidase with a hitherto unknown catalytic specificity that removes the PG–Lpp cross-links suggesting a role for LdtF in regulation of PG-OM linkages to maintain the structural integrity of the bacterial cell envelope.Significance statementBacterial cell walls contain a unique protective exoskeleton, peptidoglycan, which is a target of several clinically important antimicrobials. In Gram-negative bacteria, peptidoglycan is covered by an additional lipid layer, outer membrane that serves as permeability barrier against entry of toxic molecules. In some bacteria, an extremely abundant lipoprotein, Lpp staples outer membrane to peptidoglycan to maintain the structural integrity of the cell envelope. In this study, we identify a previously unknown peptidoglycan hydrolytic enzyme that cleaves Lpp from the peptidoglycan sacculus and show how the outer membrane-peptidoglycan linkages are modulated inEscherichia coli. Overall, this study helps in understanding the fundamental bacterial cell wall biology and in identification of alternate drug targets for development of new antimicrobials.
Evaluation of dsRNA delivery methods for targeting macrophage migration inhibitory factor MIF in RNAi-based aphid control
Authors: Liu Shaoshuai , Ladera-Carmona Maria Jose , Poranen Minna M. , van Bel Aart J.E. , Kogel Karl-Heinz , Imani Jafargholi 
Published: February 2021

AbstractMacrophage migration inhibitory factors (MIF) are multifunctional proteins regulating major processes in mammals, including activation of innate immune responses. In invertebrates, MIF proteins participate in the modulation of host immune responses when secreted by parasitic organisms, such as aphids. In this study, we assessed the possibility to useMIFgenes as targets for RNA interference (RNAi)-based control of the grain aphidSitobion avenae(Sa) on barley (Hordeum vulgare). When nymphs were fed on artificial diet containing double-stranded (ds)RNAs (SaMIF-dsRNAs) that target sequences of the threeMIFgenesSaMIF1, SaMIF2andSaMIF3, they showed higher mortality rates and these rates correlated with reducedMIFtranscript levels as compared to the aphids feeding on artificial diet containing a control dsRNA (GFP-dsRNA). Comparison of different feeding strategies showed that nymphs’ survival was not altered when they fed from barley seedlings sprayed withSaMIF-dsRNAs, suggesting they did not effectively take up dsRNA from the sieve tubes of these plants. Furthermore, aphids’ survival was also not affected when the nymphs fed on leaves supplied with dsRNA via basal cut ends of barley leaves. Consistent with this finding, the use of sieve-tube-specific YFP-labeled Arabidopsis reporter lines confirmed that fluorescent 21 nt dsRNACy3supplied via petioles co-localized with xylem structures, but not with phloem tissue. Our results suggest thatMIFgenes are a potential target for insect control and also imply that application of naked dsRNA to plants for aphid control is inefficient. More efforts should be put into the development of effective dsRNA formulations.
Cancer cell-specific MHCII expression as a determinant of the immune infiltrate organization and function in the non-small cell lung cancer tumor microenvironment
Authors: Johnson Amber M. , Boland Jennifer M. , Wrobel Julia , Klezcko Emily K. , Weisner-Evans Mary , Heasley Lynn , Clambey Eric T. , Nemenoff Raphael A. , Schenk Erin L. 
Published: February 2021

AbstractIntroductionIn patients with non-small cell lung cancer (NSCLC), the prognostic significance of the tumor microenvironment (TME) immune composition has been demonstrated using single or dual-marker staining on sequential tissue sections. While these studies show that relative abundance and localization of immune cells are important parameters, deeper analyses of the NSCLC TME are necessary to refine the potential application of these findings to clinical care. Currently, the complex spatial relationships between cells of the NSCLC TME and potential drivers contributing to its immunologic composition remain unknown.MethodsWe employed multispectral quantitative imaging on the lung adenocarcinoma TME in 153 patients with resected tumors. On a single slide per patient, we evaluated the TME with markers for CD3, CD8, CD14, CD19, major histocompatibility complex II (MHCII), cytokeratin, and DAPI. Image analysis including tissue segmentation, phenotyping, and spatial localization were performed.ResultsSpecimens where ≥5% of lung cancer cells expressed MHCII (MHCIIhiTME) demonstrated increased levels of CD4+and CD8+T cell and CD14+cell infiltration. In the MHCIIhiTME, the immune infiltrate was closer to cancer cells and expressed an activated phenotype. Morphologic image analysis revealed cancer cells in the MHCIIhiTME more frequently interfaced with CD4+and CD8+T cells. Patients with an MHCIIhiTME experienced improved overall survival (p=0.046).ConclusionsLung cancer cell-specific expression of MHCII associates with levels of immune cell infiltration, spatial localization, and activation status within the TME. This suggest cancer cell-specific expression of MHCII may represent a biomarker for the immune system’s recognition and activation against the tumor.
Repeated truncation of a modular antimicrobial peptide gene for neural context
Authors: Hanson M.A. , Lemaitre B. 
Published: February 2021

AbstractAntimicrobial peptides (AMPs) are host-encoded antibiotics that combat invading pathogens. These genes commonly encode multiple products as post-translationally cleaved polypeptides. Recent studies have highlighted roles for AMPs in neurological contexts suggesting functions for these defence molecules beyond infection. During our immune study characterizing the antimicrobial peptide geneBaramicin,we recovered multipleBaramicinparalogs inDrosophila melanogasterand other species, united by their N-terminal IM24 domain. Not all paralogs were immune-induced. Here, through careful dissection of theBaramicinfamily’s evolutionary history, we find that these non-immune paralogs result from repeated events of duplication and subsequent truncation of the coding sequence from an immune-inducible ancestor. These truncations leave only the IM24 domain as the prominent gene product. Surprisingly, using mutation and targeted gene silencing we demonstrate that two such genes are adapted for function in neural contexts inD. melanogaster.We also show enrichment in the head for independentBaramicingenes in other species. TheBaramicinevolutionary history reveals that the IM24Baramicindomain is not strictly useful in an immune context. We thus provide a case study for how an AMP-encoding gene might play dual roles in both immune and non-immune processes via its multiple peptide products. We reflect on these findings to highlight a blind spot in the way researchers approach AMP research in in vivo contexts.Significance statementAntimicrobial peptides are immune proteins recently implicated in neurological roles. To date little attention has been paid to the contributions of different gene products in this function. Here we show that an antimicrobial peptide gene encodes multiple products with either immune-specific or neurological roles.
Sex-specific glycosylation of secreted immunomodulatory proteins in the filarial nematodeBrugia malayi
Authors: Koussa Joseph , Vitrinel Burcu , Whitney Peter , Kasper Brian , Mahal Lara K. , Vogel Christine , lustigman Sara , Salehi-Ashtiani Kourosh , Ghedin Elodie 
Published: February 2021

AbstractThe extended persistence of filarial nematodes within a host suggests immunomodulatory mechanisms that allow the parasites to resist or evade the host immune response. There is increasing evidence for immunomodulatory glycans expressed by a diversity of parasitic worms. In this study, we integrate multiple layers of the host-parasite interface to investigate the glycome of a model filarial parasite,Brugia malayi. We report a significant overrepresentation of terminal GalNAc moieties in adult female worms coupled with an overall upregulation in O-glycosylation, T-antigen expression, and a bias for galactose containing glycans. Adult males preferentially displayed a bias for terminal GlcNAc containing glycans, and fucosylated epitopes. Subsequent proteomic analysis confirmed sex-biases in protein glycosylation and highlighted the sex-specific glycosylation of well characterized immunomodulators expressed and secreted byB. malayi. We identify sex-specific effectors at that interface and suggest approaches to selectively interfere with the parasitic life cycle and potentially control transmission.
merlinv4.0: an updated platform for the reconstruction of high-quality genome-scale metabolic models
Authors: Capela João , Lagoa Davide , Rodrigues Ruben , Cunha Emanuel , Cruz Fernando , Barbosa Ana , Bastos José , Lima Diogo , Ferreira Eugénio C. , Rocha Miguel , Dias Oscar 
Published: February 2021

ABSTRACTGenome-scale metabolic models have been recognised as useful tools for better understanding living organisms’ metabolism.merlin(https://www.merlin-sysbio.org/) is an open-source and user-friendly resource that hastens the models’ reconstruction process, conjugating manual and automatic procedures, while leveraging the user’s expertise with a curation-oriented graphical interface. An updated and redesigned version ofmerlinis herein presented. Since 2015, several features have been implemented inmerlin, along with deep changes in the software architecture, operational flow, and graphical interface. The current version (4.0) includes the implementation of novel algorithms and third-party tools for genome functional annotation, draft assembly, model refinement, and curation. Such updates increased the user base, resulting in multiple published works, including genome metabolic (re-)annotations and model reconstructions of multiple (lower and higher) eukaryotes and prokaryotes.merlinversion 4.0 is the only tool able to perform template based and non-template based draft reconstructions, while achieving competitive performance compared to state-of-the art tools both for well and less-studied organisms.
Cerebellar Dentate Connectivity Across Adulthood: A Large-Scale Resting State Functional Connectivity Investigation
Authors: Bernard Jessica A. , Ballard Hannah K. , Jackson T. Bryan 
Published: February 2021

AbstractCerebellar contributions to behavior in advanced age are of interest and importance, given its role in motor and cognitive performance. There are differences and declines in cerebellar structure in advanced age and cerebellar resting state connectivity is lower. However, the work on this area to date has focused on the cerebellar cortex. The deep cerebellar nuclei provide the primary cerebellar inputs and outputs to the cortex, as well as the spinal and vestibular systems. Dentate networks can be dissociated such that the dorsal region is associated with the motor cortex, while the ventral aspect is associated with the prefrontal cortex. However, whether dentato-thalamo-cortical networks differ across adulthood remains unknown. Here, using a large adult sample (n=590) from the Cambridge Center for Ageing and Neuroscience, we investigated dentate connectivity across adulthood. We replicated past work showing dissociable resting state networks in the dorsal and ventral aspects of the dentate. In both seeds, we demonstrated that connectivity is lower with advanced age, indicating that connectivity differences extend beyond the cerebellar cortex. Finally, we demonstrated sex differences in dentate connectivity. This expands our understanding of cerebellar circuitry in advanced age and underscores the potential importance of this structure in age-related performance differences.
Investigation of the temporal and spatial dynamics of muscular action potentials through optically pumped magnetometers
Authors: Broser Philip J. , Marquetand Justus , Middelmann Thomas , Sometti Davide , Braun Christoph 
Published: February 2021

ABSTRACTAimThis study aims to simultaneously record the magnetic and electric components of the propagating muscular action potential.MethodA single-subject study of the monosynaptic stretch reflex of the musculus rectus femoris was performed; the magnetic field generated by the muscular activity was recorded in all three spatial directions by five optically pumped magnetometers. In addition, the electric field was recorded by four invasive fine-wire needle electrodes. The magnetic and electric fields were compared, and modelling and simulations were performed to compare the magnetic field vectors with the underlying muscular anatomy of the rectus femoris muscle.ResultsThe magnetomyography (MMG) signal can reliably be recorded following the stimulation of the monosynaptic stretch reflex. The MMG signal shows several phases of activity inside the muscle, the first of which is the propagating muscular action potential. As predicted by the finite wire model, the magnetic field vectors of the propagating muscular action potential are generated by the current flowing longitudinal to the muscle fiber. Based on the magnetic field vectors, it was possible to reconstruct the pinnation angle in the muscle. The later magnetic components are linked to the activated contractile apparatus.InterpretationMMG allows to analyze the muscle physiology from the propagating muscular action potential to the initiation of the contractile apparatus. At the same time this methods reveal information about muscle fiber direction and extend. With the development of high-resolution magnetic cameras, it will be possible to image the function and structure of any skeletal muscle with high precision. This method could be used in clinical medicine but also in sports and training science.What this paper adds-A robust technique for triggering a muscular action potential that can be recorded by MMG and needle EMG simultaneously-The correlation of the MMG signal with the needle EMG signal-A method for detecting the direction of the propagating muscular action potential-A method for correlating the magnetic field vectors with the pinnation angle of the examined muscle
Recombination marks the evolutionary dynamics of a recently endogenized retrovirus
Authors: Yang Lei , Malhotra Raunaq , Chikhi Rayan , Elleder Daniel , Kaiser Theodora , Rong Jesse , Medvedev Paul , Poss Mary 
Published: February 2021

AbstractAll vertebrate genomes have been colonized by retroviruses along their evolutionary trajectory. While endogenous retroviruses (ERVs) can contribute important physiological functions to contemporary hosts, such benefits are attributed to long-term co-evolution of ERV and host because germline infections are rare and expansion is slow, because the host effectively silences them. The genomes of several outbred species including mule deer (Odocoileus hemionus) are currently being colonized by ERVs, which provides an opportunity to study ERV dynamics at a time when few are fixed. Because we have locus-specific data on the distribution of cervid endogenous retrovirus (CrERV) in populations of mule deer, in this study we determine the molecular evolutionary processes acting on CrERV at each locus in the context of phylogenetic origin, genome location, and population prevalence. A mule deer genome was de novo assembled from short and long insert mate pair reads and CrERV sequence generated at each locus. CrERV composition and diversity have recently measurably increased by horizontal acquisition of a new retrovirus lineage. This new lineage has further expanded CrERV burden and CrERV genomic diversity by activating and recombining with existing CrERV. Resulting inter-lineage recombinants endogenized and subsequently retrotransposed. CrERV loci are significantly closer to genes than expected if integration were random and gene proximity might explain the recent expansion by retrotransposition of one recombinant CrERV lineage. Thus, in mule deer, retroviral colonization is a dynamic period in the molecular evolution of CrERV that also provides a burst of genomic diversity to the host population.
Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals
Authors: Torres-Méndez Antonio , Pop Sinziana , Bonnal Sophie , Almudi Isabel , Avola Alida , Roberts Ruairí J V , Paolantoni Chiara , Alcaina Ana , Martín-Anduaga Ane , Haussmann Irmgard U , Morin Violeta , Casares Fernando , Soller Matthias , Kadener Sebastian , Roignant Jean-Yves , Prieto-Godino Lucia , Irimia Manuel 
Published: February 2021

SummaryNeurons draw on alternative splicing for their increased transcriptomic complexity throughout animal phylogeny. To delve into the mechanisms controlling the assembly and evolution of this regulatory layer, we characterized the neuronal microexon program inDrosophilaand compared it with that of mammals. We found that inDrosophila, this splicing program is restricted to neurons by the post-transcriptional processing of theenhancer of microexons(eMIC) domain inSrrm234by Elav and Fne. eMIC deficiency or misexpression leads to widespread neurological alterations largely emerging from impaired neuronal activity, as revealed by a combination of neuronal imaging experiments and cell-type-specific rescues. These defects are associated with the genome-wide skipping of short neural exons, which are strongly enriched in ion channels. Remarkably, we found no overlap of eMIC-regulated exons between flies and mice, illustrating how ancient post-transcriptional programs can evolve independently in different phyla to impact distinct cellular modules while maintaining cell-type specificity.