bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep6: Classification of Metatranscriptomic Sequences into Cellular Empires and Viral Realms Using Deep Learning Models
Authors: Finke Jan F. , Kellogg Colleen , Suttle Curtis A. 
Published: September 2022

AbstractMetatranscriptomic data is increasingly used to study viral diversity and activity; yet, identifying and taxonomically assigning viral sequences is still challenging. Deep6 is a deep-learning model that classifies metatranscriptomic sequences into six groups: prokaryotes, eukaryotes, or one of the four viral realms. Deep6 is trained on reference coding sequences, but classification of query sequences is done reference-independent and alignment-free. The provided model is optimized for marine samples and can process sequences as short as 250 nucleotides. Average accuracies range from 0.87 to 0.97 depending on sequence length. Additionally, Deep6 includes scripts to easily encode and train custom models for other environments.
Regenerative MRL/MpJ Tendon Cells Exhibit Sex Differences in Morphology, Proliferation, Mechanosensitivity, and Cell-Matrix Remodeling
Authors: Marvin Jason C. , Brakewood Molly E. , Poon Mong Lung Steve , Andarawis-Puri Nelly 
Published: September 2022

AbstractClinical and animal studies have reported the influence of sex on the incidence and progression of tendinopathy, which results in disparate structural and biomechanical outcomes. However, there remains a paucity in our understanding of the sex-specific biological mechanisms underlying effective tendon healing. To overcome this hurdle, our group has investigated the impact of sex on tendon regeneration using the super-healer Murphy Roths Large (MRL/MpJ) mouse strain. Despite a shared scarless healing capacity, we have shown that MRL/MpJ patellar tendons exhibit sexually dimorphic regulation of gene expression for pathways involved in fibrosis, cell migration, and extracellular matrix (ECM) remodeling following an acute midsubstance injury. Moreover, we previously found decreased matrix metalloproteinase-2 (MMP-2) activity in female MRL/MpJ tendons after injury. Thus, we hypothesized that MRL/MpJ scarless tendon healing is mediated by sex-specific and temporally distinct orchestration of cell-ECM interactions. Accordingly, the present study comparatively evaluated MRL/MpJ tendon cells under two-dimensional (glass) and three-dimensional (nanofiber scaffolds) culture platforms to examine cell behavior under biochemical and biophysical cues associated with tendon homeostasis and healing. Female MRL/MpJ cells showed reduced 2D migration and spreading area accompanied with enhanced mechanosensing, 2D ECM alignment, and fibronectin-dependent cell proliferation. Interestingly, female MRL/MpJ cells cultured on 3D isotropic scaffolds showed diminished ECM deposition and alignment. Regardless of culture condition and sex, MRL/MpJ cells outperformed B6 cells and elicited a universal regenerative cellular phenotype. These results illustrate the utility of these in vitro systems for elucidating regenerative tendon cell biology, which will facilitate the long-term development of more equitable therapeutics.
Evolutionary crowdsourcing: alignment of fitness landscapes allows cross-species adaptation of a horizontally transferred gene
Authors: Kosterlitz Olivia , Grassi Nathan , Werner Bailey , McGee Ryan Seamus , Top Eva M. , Kerr Benjamin 
Published: September 2022

AbstractGenes that undergo horizontal gene transfer (HGT) evolve in different genomic backgrounds as they move between hosts, in contrast to genes that evolve under strict vertical inheritance. Despite the ubiquity of HGT in microbial communities, the effects of host-switching on gene evolution have been understudied. Here, we present a novel framework to examine the consequences of host-switching on gene evolution by probing the existence and form of host-dependent mutational effects. We started exploring the effects of HGT on gene evolution by focusing on an antibiotic resistance gene (encoding a beta-lactamase) commonly found on conjugative plasmids in Enterobacteriaceae pathogens. By reconstructing the resistance landscape for a small set of mutationally connected alleles in three enteric species (Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae), we uncovered that the landscape topographies were largely aligned with very low levels of host-dependent mutational effects. By simulating gene evolution with and without HGT using the species-specific empirical landscapes, we found that evolutionary outcomes were similar despite HGT. These findings suggest that the adaptive evolution of a mobile gene in one species can translate to adaptation in another species. In such a case, vehicles of cross-species HGT such as plasmids enable a distributed form of genetic evolution across a bacterial community, where species can ‘crowdsource’ adaptation from other community members. The role of evolutionary crowdsourcing on the evolution of bacteria merits further investigation.
Meteorin alleviates Paclitaxel-induced peripheral neuropathy in mice
Authors: Sankaranarayanan Ishwarya , Tavares-Ferreira Diana , He Lucy , Kume Moeno , Mwirigi Juliet , Madsen Torsten M. , Petersen Kenneth A. , Munro Gordon , Price Theodore J. 
Published: September 2022

AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 x 4mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (0.5 and 1.8mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin (0.5 and 1.8mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), blocked the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin43 protein expression in the DRG. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for CIPN treatment.HighlightsMeteorin produces an antinociceptive effect in both male and female mice treated with paclitaxel.Satellite glial cell reactivity induced by paclitaxel treatment is reversed by Meteorin.Retraction of intraepidermal nerve fibre (IENF) is blocked by Meteorin treatment in paclitaxel treated mice.Findings suggest a disease modifying effect of Meteorin in the mouse model of paclitaxel-induced peripheral neuropathy.
Mobility of the human foot’s medial arch enables upright bipedal locomotion
Authors: Welte Lauren , Holowka Nicholas B , Kelly Luke A , Arndt Toni , Rainbow Michael J 
Published: September 2022

AbstractDeveloping the ability to habitually walk and run upright on two feet is one of the most significant transformations to have occurred in human evolution. Many musculoskeletal adaptations enabled bipedal locomotion, including dramatic structural changes to the foot and, in particular, the evolution of an elevated medial arch (H. Elftman and Manter, 1935). The foot’s arched structure has previously been assumed to play a central role in directly propelling the centre of mass forward and upward through leverage about the toes (Herbert Elftman and Manter, 1935) and a spring-like energy recoil (Hicks, 1955). Paradoxically, these roles seemingly require either arch rigidity (for the former) or mobility (for the latter). However, it is unclear whether or how the mobility and height of the medial arch support its propulsive lever function. Here we show, using high-speed biplanar x-ray, that regardless of intraspecific differences in medial arch height, arch recoil enables a longer contact time and favourable propulsive conditions for walking upright on an extended leg. This mechanism presumably helped drive the evolution of the longitudinal arch after our last common ancestor with chimpanzees, who lack this mobility during push-off. We discovered that the previously overlooked navicular-medial cuneiform joint is primarily responsible for this mobility in human arches, suggesting that future morphological investigations of this joint will provide new interpretations of the fossil record. Our work further suggests that enabling the mobility of the longitudinal arch in footwear and surgical interventions is critical for maintaining the ankle’s natural propulsive ability.
Unbalanced response to growth variations reshapes the cell fate decision landscape
Authors: Zhu Jingwen , Chu Pan , Fu Xiongfei 
Published: September 2022

AbstractThe global regulation of cell growth rate on gene expression perturbs the performance of gene networks, which would impose complex variations on the cell-fate decision landscape. Here, we utilize a simple synthetic circuit of mutual repression that allows a bistable landscape, to examine how such global regulation would affect the stability of phenotypic landscape and the accompanying dynamics of cell-fate determination. We show that the landscape experiences a growth-rate-induced bifurcation between monostability and bistability. Theoretical and experimental analyses reveal that this bifurcating deformation of landscape arises from the unbalanced response of gene expression to growth variations. The path of growth transition across the bifurcation would reshape cell-fate decisions. These results demonstrate the importance of growth regulation on cell-fate determination processes, regardless of specific molecular signalling or regulation.
Siderophore-mediated iron partition promotes dynamical coexistence between cooperators and cheaters
Authors: Shao Jiqi , Rong Nan , Wu Zhenchao , Gu Shaohua , Liu Beibei , Shen Ning , Li Zhiyuan 
Published: September 2022

AbstractMicrobes shape their habitats through consuming resources, as well as actively producing and secreting diverse chemicals. These chemicals serve various niche-construction functions and can be considered “public good” for the community. Most microorganisms, for instance, release small molecules known as siderophores to scavenge irons from the extracellular environment. Despite being exploitable by cheaters, biosynthetic genes producing such molecules widely exist in nature, invoking active investigation on the possible mechanisms for producers to survive cheater invasion. In this work, we utilized the chemostat-typed model to demonstrate that the division of the iron by private and public siderophores can promote stable or dynamical coexistence between the cheater and “partial cooperators”, an adaptive strategy with the production of both public and private siderophores. Further, our analysis revealed that when microbes not only consume but also produce resources, this type of “resource partition model” exhibit different stability criteria than that of the classical consumer resource model, allowing more complex systems dynamics.
Exocytotic dynamics of glucagon-like peptide-1 from enteroendocrine L cell line is regulated by actin polymerization
Authors: Harada Kazuki , Takashima Maoko , Kitaguchi Tetsuya , Tsuboi Takashi 
Published: September 2022

AbstractStimulus-secretion coupling of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells is important for glucose homeostasis. Although intracellular second messengers including Ca2+ and cAMP, and cellular structures including actin cytoskeleton play roles in induction of exocytosis of GLP-1 granules, little is known about the specific part in the process of exocytosis in which they are involved. Here we explored the role of those molecules by live-cell imaging with mouse L cell line GLUTag cells, and used two stimuli: deoxycholic acid (DCA) and high K+. DCA increased both intracellular Ca2+ and cAMP levels, while high K+ only increased Ca2+. We next monitored a single exocytosis of GLP-1 granules and found that, during the first 10 minutes of stimulation, both stimuli mainly induced the exocytosis from the predocked granules with the plasma membrane before stimulation or granules immediately fused to the plasma membrane without docking. Furthermore, inhibition of actin polymerization suppressed the proportion of exocytosis by the predocked granules. These results suggest that the exocytotic process of GLP-1 granules is determined by interaction with F-actin upon the increase of either Ca2+ or cAMP.Summary statementExocytotic process of glucagon-like peptide-1 granules from a mouse enteroendocrine L cell line is regulated by actin polymerization immediately after elevation of intracellular Ca2+ or cAMP levels.
Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes
Authors: Younis Shady , Jouneau Alice , Larsson Mårten , Oudin Jean-Francois , Brochard Vincent , Andersson Leif 
Published: September 2022

AbstractZC3H11A is a stress-induced mRNA binding protein required for efficient growth of nuclear-replicating viruses, while being dispensable for the viability of cultured human cells. The cellular functions of ZC3H11A during embryo development are unknown. Here we report the generation and phenotypic characterization of Zc3h11a knock-out mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a−/– embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a−/– embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a−/– embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. Furthermore, CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Altogether, the results show that ZC3H11A is participating in export and post-transcriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional knock-out did not lead to obvious phenotypic defects.
Survey of activation-induced genome architecture reveals a novel enhancer of Myc
Authors: Chan Wing Fuk , Coughlan Hannah D , Ruhle Michelle , Iannarella Nadia , Alvarado Carolina , Groom Joanna R. , Keenan Christine R , Kueh Andrew J. , Wheatley Adam K. , Smyth Gordon K , Allan Rhys S , Johanson Timothy M 
Published: September 2022

SUMMARYThe transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 hours post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.
SARS-CoV-2 infection of human neurons requires endosomal cell entry and can be blocked by inhibitors of host phosphoinositol-5 kinase
Authors: Kettunen Pinja , Lesnikova Angelina , Räsänen Noora , Ojha Ravi , Palmunen Leena , Laakso Markku , Lehtonen Šárka , Kuusisto Johanna , Pietiläinen Olli , Vapalahti Olli P. , Kostinaho Jari , Rolova Taisia , Balistreri Giuseppe 
Published: September 2022

AbstractCOVID-19 is a disease caused by coronavirus SARS-CoV-2. In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms that can last from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to infection of brain cells. We found that a small fraction of cortical neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), which was expressed at very low levels. Although only a limited number of neurons was infectable, the infection was productive, as demonstrated by the presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout the neuronal cell, and an increase in viral RNA in the culture medium within the first 48 h of infection (viral release). The productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface protein spike, which can occur at the plasma membrane or from endo/lysosomes. Using specific combinations of small-molecule inhibitors, we found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases found on the cell surface, including TMPRSS2. In contrast, the infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K) that regulates endosomal maturation.ImportanceCOVID-19 is a disease caused by coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures and encephalopathy, as well as anatomical abnormalities such as changes in brain morphology. Whether these symptoms are linked to brain infection is not clear. The mechanism of the virus entry into neurons has also not been characterized. Here we investigated SARS-CoV-2 infection using a human iPSC-derived neural cell model and found that a small fraction of cortical neurons was naturally susceptible to infection. The infection depended on the ACE2 receptor and was productive. We also found that the virus used the late endosomal/lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of the cellular phosphatidyl-inositol 5 kinase.
The transcriptional and epigenetic reprogramming associated with chronic IL1β-mediated expansion and myeloid priming in TET2 deficient stem and progenitor cells
Authors: McClatchy J. , Strogantsev R. , Wolfe E. , Lin H. , Mohammadhosseini M. , Davis B.A. , Eden C. , Goldman D. , Fleming W.H. , Conley P , Wu G. , Cimmino L. , Mohammed H. , Agarwal A. 
Published: September 2022

ABSTRACTClonal hematopoiesis (CH) increases the risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models withTet2loss-of-function. How IL1β alters population dynamics of hematopoietic cells uponTet2deletion (Tet2-KO) is not well understood. We demonstrated IL1β expandsTet2-KO monocytes/macrophages, and long-term hematopoietic stem cells. IL1β promoted myeloid bias over other lineages ofTet2-KO HSPCs coinciding with the failure to demethylate lineage-associated enhancer and transcription factor binding sites. IL1β enhanced the self-renewal ability ofTet2-KO HSPCs by upregulating genes associated with self-renewal and by resisting the demethylation of binding sites of transcription factors promoting terminal differentiation. The IL1β-mediated premalignant phenotype is suppressed by the IL1β antagonist or deletion of the IL1 receptor-1,in vivoin aged mice. Our results demonstrate that targeting IL1 signaling could be an efficient early intervention strategy in preleukemic disorders.STATEMENT OF SIGNIFICANCEIL1β promoted myeloid expansion and self-renewal capacity ofTET2-nullpre-leukemic cells. Lineage bias occurred early within progenitors towards pro-inflammatory macrophages. Genes specific to aging and with roles in promoting self-renewal capacity, and myeloid bias were upregulated. Hypermethylation occurred within lymphoid and erythroid lineage-specific regulatory elements. Targeting IL1R1 reduced aberrant myeloid bias and premalignant phenotype.
The filipodia-like protrusions of adjacent somatic cells shape the developmental potential of mouse oocytes
Authors: Crozet Flora , Letort Gaëlle , Da Silva Christelle , Eichmuller Adrien , Tortorelli Anna Francesca , Belle Morgane , Dumont Julien , Piolot Tristan , Dauphin Aurélien , Coulpier Fanny , Chédotal Alain , Maître Jean-Léon , Verlhac Marie-Hélène , Clarke Hugh.J , Terret Marie-Emilie 
Published: September 2022

SummaryThe oocyte must grow and mature before fertilization, thanks to a close dialogue with the somatic cells which surround it. Part of this communication is through filopodialike protrusions, called transzonal projections (TZPs), sent by the somatic cells to the oocyte membrane. To investigate the contribution of TZPs to oocyte quality, we impaired their structure by generating a full knockout mouse of the TZP structural component Myosin-X (MYO10). Using spinning disk and super-resolution microscopy combined with a machine learning approach to phenotype oocyte morphology, we show that the lack ofMyo10decreases TZP density during oocyte growth. Reduction in TZPs does not prevent oocyte growth but impairs oocyte-matrix integrity. Importantly, we reveal by transcriptomic analysis that gene expression is altered in TZP-deprived oocytes, and that oocyte maturation and subsequent early embryonic development are partially affected, effectively reducing mouse fertility. We propose that TZPs play a role in the structural integrity of the germline-somatic complex, which is essential for regulating gene expression in the oocyte and thus its developmental potential.