bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymerization force-regulated actin filament-Arp2/3 complex interaction dominates self-adaptive cell migrations
Authors: Chen Xindong , Li Yuhui , Guo Ming , Xu Bowen , Ma Yanhui , Zhu Hanxing , Feng Xi-Qiao 
Published: April 2023

AbstractCells migrate by adapting their leading-edge behaviours to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviours emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we established a spatiotemporal “resistance-adaptive propulsion” theory based on the protein interactions between Arp2/3 complexes and polymerizing actin filaments, and a multiscale dynamic modelling system spanning from molecular proteins to the cell. Combining spatiotemporal simulations with experiments, we quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggered a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers cells with both powerful and flexible migratory capabilities to deal with complex ECMs, but also endows cells to use their intracellular proteins efficiently. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodelling. We also quantitatively show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force-regulated actin filament-Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modelling system at the protein level.
Limited Diffusion of Scientific Knowledge Forecasts Collapse
Authors: Kang Donghyun , Danziger Robert S. , Rehman Jalees , Evans James A. 
Published: April 2023

AbstractMarket bubbles emerge when asset prices are driven unsustainably higher than asset values and shifts in belief burst them. We demonstrate the same phenomenon for biomedical knowledge when promising research receives inflated attention. We predict deflationary events by developing a diffusion index that captures whether research areas have been amplified within social and scientific bubbles or have diffused and become evaluated more broadly. We illustrate our diffusion approach contrasting the trajectories of cardiac stem cell research and cancer immunotherapy. We then trace the diffusion of unique 28,504 subfields in biomedicine comprising nearly 1.9M papers and more than 80M citations and demonstrate that limited diffusion of biomedical knowledge anticipates abrupt decreases in popularity. Our analysis emphasizes that restricted diffusion, implying a socio-epistemic bubble, leads to dramatic collapses in relevance and attention accorded to scientific knowledge.
Light modulates task-dependent thalamo-cortical connectivity during an auditory attentional task
Authors: Paparella Ilenia , Campbell Islay , Sharifpour Roya , Beckers Elise , Berger Alexandre , Balda Aizpurua Jose Fermin , Koshmanova Ekaterina , Mortazavi Nasrin , Talwar Puneet , Degueldre Christian , Lamalle Laurent , Sherif Siya , Phillips Christophe , Maquet Pierre , Vandewalle Gilles 
Published: April 2023

AbstractExposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. We recorded the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they completed an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We tested if light modulated the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We found that only the blue-enriched light strengthened the connection from the posterior thalamus to the IPS. Our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.
Efficient and Robust Search of Microbial Genomes via Phylogenetic Compression
Authors: Břinda Karel , Lima Leandro , Pignotti Simone , Quinones-Olvera Natalia , Salikhov Kamil , Chikhi Rayan , Kucherov Gregory , Iqbal Zamin , Baym Michael 
Published: April 2023

ABSTRACTComprehensive collections approaching millions of sequenced genomes have become central information sources in the life sciences. However, the rapid growth of these collections has made it effectively impossible to search these data using tools such as BLAST and its successors. Here, we present a technique called phylogenetic compression, which uses evolutionary history to guide compression and efficiently search large collections of microbial genomes using existing algorithms and data structures. We show that, when applied to modern diverse collections approaching millions of genomes, lossless phylogenetic compression improves the compression ratios of assemblies, de Bruijn graphs, andk-mer indexes by one to two orders of magnitude. Additionally, we develop a pipeline for a BLAST-like search over these phylogeny-compressed reference data, and demonstrate it can align genes, plasmids, or entire sequencing experiments against all sequenced bacteria until 2019 on ordinary desktop computers within a few hours. Phylogenetic compression has broad applications in computational biology and may provide a fundamental design principle for future genomics infrastructure.
Heritable changes of epialleles in maize can be triggered in the absence of DNA methylation
Authors: Liu Beibei , Yang Diya , Wang Dafang , Liang Chun , Wang Jianping , Lisch Damon , Zhao Meixia 
Published: April 2023

AbstractTrans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, very little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene,Mop1(mediator of paramutation1) with that of their parents, wild type siblings, and backcrossed progeny in maize. Our data show that hybridization triggers global changes in bothtrans-chromosomal methylation (TCM) andtrans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in themop1mutant, although the effects of this mutant varied depending on the location of the CHH DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in F1 plants did requireMop1, initiation of the changes in the epigenetic state of TCM DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is not dependent on RNA-directed DNA methylation.
Reprogramming of lipid secretome in senescent synovial fibroblasts ameliorate osteoarthritis development
Authors: Hu Jiajie , Yu Dongsheng , Wu Dongmei , Wang Jiasheng , Cai Youzhi , Du Xiaotian , Ji Junfen , Ouyang Hongwei 
Published: April 2023

AbstractOsteoarthritis (OA) is one of the most common causes of physical disability among older people and its incidence increases with age. Removal of the senescent cells (SNCs) delays OA pathologies, but little is known about the SNCs in OA synovium and their roles in OA pathogenesis. Here, we reported that RCAN1+IL1α+double-positive cells represent a senescent subset of synovial fibroblasts which accelerate cartilage degeneration via saturated fatty acids (SFAs). Using single-cell RNA sequencing and synovial organoids, we found that IL1α+ senescent synovial fibroblasts mainly located at lining layer of human OA synovium and promote cartilage degeneration. We performed genome-wide CRISPR/Cas9 screens to identify novel regulators of cell-surface bounded IL1α in senescent cells. RCAN1, which was a hit as positive regulator of IL1α, governs the cellular senescence and pro-degenerative senescence-associated secretory phenotype (SASP). Mechanistically, we found that RCAN1 mediated the secretion of SFAs from senescent synovial fibroblasts, which promote chondrocytes senescence and cartilage matrix degradation. Intra-articular delivery of synovium-targeted anti-Rcan1 siRNA ameliorates the development of post-traumatic OA in mice, while reducing of SNCs accumulation in synovium and increasing cartilage regeneration. Last, co-culture experiments of human OA cartilage explant with synovial organoids confirmed that RCAN1 silencing in human synovial fibroblasts suppressed chondrocyte senescence and cartilage degradation. Thus, our study revealed a pro-degenerative interaction between RCAN1+IL1α+senescent synovial fibroblasts and chondrocytes through secreted lipid mediators in OA progression. And targeted RCAN1 inhibition in senescent synovium is a promising approach for restore the joint homeostasis.
SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state
Authors: Sebastian-Perez Ruben , Nakagawa Shoma , Tu Xiaochuan , Aranda Sergi , Pesaresi Martina , Gomez-Garcia Pablo Aurelio , Alcoverro-Bertran Marc , Gomez-Vazquez Jose Luis , Carnevali Davide , Borràs Eva , Sabidó Eduard , Martin Laura , Nissim-Rafinia Malka , Meshorer Eran , Neguembor Maria Victoria , Di Croce Luciano , Cosma Maria Pia 
Published: April 2023

AbstractChromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. By profiling the chromatin-bound proteome (chromatome) through genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved inde novoheterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos leads to developmental arrest, reduction of H3K9me3, and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.
Building the Next Generation Workforce: Why We Need Science Policy Training at the Undergraduate Level
Authors: Bogard Gwendolyn , Saybolt Erin , Castro-Faix Moraima , Bankston Adriana 
Published: April 2023

AbstractDiverse pathways into the science policy workforce are necessary for providing opportunities to students at all levels to engage in the field and to bring their talents to the future of policymaking. Both classroom and experiential training opportunities are essential to achieving this goal. In this publication, we assessed the current landscape of science policy training for undergraduate students in the United States by conducting a keyword search for experiential career training opportunities at varying levels of education. We also reviewed existing science policy publications for undergraduate opportunities, an area that has been largely unexplored to date. From these assessments, we found that most experiential training opportunities are geared towards Science, Technology, Engineering and Math (STEM) students in PhDs program or recent PhD graduates, followed by Masters-level students or graduates, and fewer opportunities exist for undergraduate students and Bachelor-degree holders. We then conducted focus group-style interviews with early career scientists involved in science policy, including undergraduate students, to discuss their experiences and ideas for change. Based on our findings, we recommend that universities, organizations, and funding agencies expand upon their existing resources for curriculum, academic advising, training opportunities, and funding, and dedicate resources toward raising awareness and creating additional opportunities in science policy at the undergraduate level. These steps can help create pathways for undergraduate students to enter and contribute to the science policy workforce.
STING activation of IRF3 is tuned by PELI2 to suppress basal activation and reinforce the anti-viral response
Authors: Ritchie Christopher , Li Lingyin 
Published: April 2023

AbstractThe STING pathway is the first line of defense against a variety of threats. STING activation leads to two main signaling branches, IRF3 signaling and NF-κB signaling, that have differential roles in anti-cancer, anti-viral, and anti-bacterial immunity and autoimmunity. However, it is unknown how these two signaling branches are differentially regulated depending on context. Here, we identify PELI2 as a regulator of STING that preferentially inhibits IRF3 signaling while enhancing NF-κB signaling. Mechanistically, we show that PELI2 inhibits IRF3 signaling by binding to phosphorylated Thr354 and Thr356 on the C-terminal tail of STING, leading to ubiquitination and function switching of TBK1. PELI2 is expressed under basal conditions to suppress IRF3 signaling and prevent interferonopathies. During viral infection, however, STING signaling rapidly downregulates PELI2 to unleash production of anti-viral type-I interferons. Normally, PELI2 levels are restored following viral clearance. However, lupus patients have insufficient PELI2 levels and high basal interferon production, suggesting dysregulation of PELI2 may have a causative role in lupus and other interferonopathies.
Atoh1 is required for the formation of lateral line electroreceptors and hair cells, whereas Foxg1 represses an electrosensory fate
Authors: Minařík Martin , Campbell Alexander S. , Franěk Roman , Vazačová Michaela , Havelka Miloš , Gela David , Pšenička Martin , Baker Clare V. H. 
Published: April 2023

AbstractIn electroreceptive jawed fishes and amphibians, individual lateral line placodes form lines of neuromasts on the head containing mechanosensory hair cells, flanked by fields of ampullary organs containing electroreceptors - modified hair cells that respond to weak electric fields. Extensively shared gene expression between neuromasts and ampullary organs suggests that conserved molecular mechanisms are involved in their development, but a few transcription factor genes are restricted either to the developing electrosensory or mechanosensory lateral line. Here, we used CRISPR/Cas9-mediated mutagenesis in F0-injected sterlet embryos (Acipenser ruthenus, a sturgeon) to test the function of three such genes. We found that the ‘hair cell’ transcription factor geneAtoh1is required for both hair cell and electroreceptor differentiation in sterlet, and forPou4f3andGfi1expression in both neuromasts and ampullary organs. These data support the conservation of developmental mechanisms between hair cells and electroreceptors. Targeting ampullary organ-restrictedNeurod4did not yield any phenotype, potentially owing to redundancy with otherNeurodgenes that we found to be expressed in sterlet ampullary organs. After targeting mechanosensory-restrictedFoxg1, ampullary organs formed within neuromast lines, suggesting that Foxg1 normally represses their development. We speculate that electrosensory organs may be the ‘default’ fate of lateral line primordia in electroreceptive vertebrates.
Scalable, flexible carbon fiber electrode thread arrays for three-dimensional spatial profiling of neurochemical activity in deep brain structures of rodents
Authors: Xia Mingyi , Agca Busra Nur , Yoshida Tomoko , Choi Jiwon , Amjad Usamma , Bose Kade , Keren Nikol , Zukerman Shahar , Cima Michael J. , Graybiel Ann M. , Schwerdt Helen N. 
Published: April 2023

AbstractWe developed a flexible “electrode-thread” array for recording dopamine neurochemical activity from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼ 10 µm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial “linear” arrays provide single entry insertion but only allow measurements along the axis of insertion. Horizontally configured neurochemical recording arrays inflict separate penetrations for each individual channel (i.e., electrode). We tested functional performance of our CFET arraysin vivofor recording dopamine neurochemical dynamics and for providing lateral spread to multiple distributed sites in the striatum of rats. Spatial spread was further characterized using agar brain phantoms to measure electrode deflection as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology techniques. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Neurochemical recording operations tested here can be integrated with already widely established capabilities of CF-based electrodes to record single neuron activity and local field potentials, to enable multi-modal recording functions. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson’s disease and major mood disorders.
Structure and function of a hexameric cyanophycin synthetase 2
Authors: Markus Linda M. D. , Sharon Itai , Munro Kim , Grogg Marcel , Hilvert Donald , Strauss Mike , Schmeing T. Martin 
Published: April 2023

AbstractCyanophycin is a natural polymer composed of a poly-aspartate backbone with arginine attached to each of the aspartate sidechains. Produced by a wide range of bacteria, which mainly use it as a store of fixed nitrogen, it has many promising industrial applications. Cyanophycin can be synthesized from the amino acids Asp and Arg by the widespread cyanophycin synthetase 1 (CphA1), or from the dipeptide β-Asp-Arg by the cyanobacterial enzyme cyanophycin synthetase 2 (CphA2). CphA2 enzymes display a range of oligomeric states, from dimers to dodecamers. Recently, the crystal structure of a CphA2 dimer was solved but could not be obtained in complex with substrate. Here, we report cryo-EM structures of the hexameric CphA2 fromStanieriasp. at ~2.8 Å resolution, both with and without ATP and cyanophycin. The structures show a trimer-of-dimers hexameric architecture, and substrate-binding interactions that are similar to those of CphA1. Mutagenesis experiments demonstrate the importance of several conserved substrate-binding residues. We also find that a Q416A/R528G double mutation prevents hexamer formation and use this double mutant to show that hexamerization augments the rate of cyanophycin synthesis. Together, these results increase our mechanistic understanding of how an interesting green polymer is biosynthesized.
Gardnerellavaginolysin potentiates glycan molecular mimicry byNeisseria gonorrhoeae
Authors: Morrill Sydney , Saha Sudeshna , Varki Ajit P , Lewis Warren G. , Ram Sanjay , Lewis Amanda L. 
Published: April 2023

AbstractBacterial vaginosis (BV) is a condition of the vaginal microbiome in which there are lower levels of “healthy”Lactobacillusspecies and an outgrowth of diverse anaerobic bacteria. BV is associated with increased risk of infection by the bacteriumNeisseria gonorrhoeae- the causative agent of gonorrhea. Here we test if one known facet of BV - the presence of bacterial cytolysins – leads to the mobilization of specific intracellular contents that aid in gonococcal virulence. We cloned and expressed recombinant vaginolysin (VLY), a cytolysin produced by the BV-associated bacteriumGardnerella, verifying that it liberates the contents of red blood cells and cervical epithelial (HeLa) cells while vector control preparations made in parallel did not. We tested if VLY mediates a well-known virulence mechanism of gonococcus – the molecular mimicry of host glycans. To evade host immunity,N. gonorrhoeaecaps its surface lipooligosaccharide (LOS) with α2-3-linked sialic acid. To do this, gonococci must scavenge an intermediate metabolite made and used inside host cells. Flow-cytometry based lectin-binding assays showed that, compared to controls, gonococci exposed to vaginolysin-liberated contents of HeLa cells displayed greater sialic acid capping of their LOS. This higher level of bacterial sialylation was accompanied by increased binding of the complement regulatory protein Factor H, and greater resistance to complement attack. Together these results suggest that cytolytic activities present during BV may enhance the ability ofN. gonorrhoeaeto capture intracellular metabolites and evade host immunity via glycan molecular mimicry.
High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR-Cas9 editing
Authors: Lazar Nathan H. , Celik Safiye , Chen Lu , Fay Marta , Irish Jonathan C. , Jensen James , Tillinghast Conor A. , Urbanik John , Bone William P. , Roberts Genevieve H. L. , Gibson Christopher C. , Haque Imran S. 
Published: April 2023

SummaryCRISPR-Cas9 editing is a scalable technology for mapping of biological pathways, but it has been reported to cause a variety of undesired large-scale structural changes to the genome. We performed an arrayed CRISPR-Cas9 scan of the genome in primary human cells, targeting 17,065 genes for knockout with 101,029 guides. High-dimensional phenomics reveals a “proximity bias” in which CRISPR knockouts bear unexpected phenotypic similarity to knockouts of biologically-unrelated genes on the same chromosome arm, recapitulating both canonical genome structure and structural variants. Transcriptomics connects proximity bias to chromosome-arm truncations. Analysis of published large-scale knockout and knockdown experiments confirms that this effect is general across cell types, labs, Cas9 delivery mechanisms, and assay modalities, and suggests proximity bias is caused by DNA double-strand-breaks with cell cycle control in a mediating role. Finally, we demonstrate a simple correction for large-scale CRISPR screens to mitigate this pervasive bias while preserving biological relationships.