bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arsenic induces two different interaction modes of SUMO with promyelocytic leukemia (PML) proteins
Authors: Hirano Seishiro , Udagawa Osamu , Kato-Udagawa Ayaka 
Published: April 2023

AbstractPromyelocytic leukemia-nuclear bodies (PML-NBs) are dot-like protein assemblies and implicated in the pathogenesis of leukemia and viral infection. PML is the scaffold protein of PML-NB and its client proteins such as SUMO, DAXX, and Sp100 reside in PML-NBs. It is known that a short exposure to trivalent arsenic (As3+) induces the solubility change and the subsequent SUMOylation of PML, and the SUMO interacting motif (SIM) is not necessary for these biochemical changes. However, it has not been well studied how As3+initiates or enhances the association of SUMO with PML and the other PML-NB client proteins. Here, we report that As3+enhanced non-covalent association of PML with SUMO via the SUMO-SIM interaction which is dispensable for the solubility change and SUMOylation of PML. We also report that the As3+-induced solubility change of PML was not affected by ML792, a SUMO E1 enzyme inhibitor, even though the nuclear localization of SUMO2/3 and protein SUMOylation were halted by ML792. As3+did not change the solubility of DAXX and SUMOylation enzymes such as SAE1, UBA2, and UBC9. In contrast, As3+induced SUMOylation of Sp100 with a concomitant loss of its solubility like PML in human leukemia cell lines. Our current results indicate that both covalent and non-covalent associations of SUMO with PML are increased in As3+-exposed cells, and Sp100 may play a role in the maintenance of PML-NBs.
Clinical Methods Supporting Recognition of Early Post-Stroke Seizures: A Systematic Scoping Review
Authors: Gordon Clare , Emsley Hedley , Lightbody Catherine Elizabeth , Clegg Andrew , Harris Catherine , Harrison Joanna , Davidson Catherine Emma , Wall Jasmine , Watkins Caroline 
Published: April 2023

ABSTRACTBackgroundStroke is one of the commonest cause of seizures and epilepsy and is the leading cause of epilepsy over the age of 60 (1, 2). Post-stroke seizures and epilepsy are associated with increased mortality, disability and recurrent hospital admissions (3, 4). Seizures occurring in the immediate aftermath of the acute stroke can complicate a patient’s stroke diagnosis and management or can even go undiagnosed resulting in increased risk of mortality, disability and hospital readmissions. There is limited evidence on detection, observation, diagnosis and management of early post-stroke seizures as part of acute stroke treatment.ObjectivesThe objective of this series of scoping reviews is to map the extent and type of literature in relation to in-hospital early post-stroke seizures. For this paper, the specific objectives relate to the clinical methods used in the bedside identification and observation, usually performed by nurses, of early post-stroke seizures (EPSS) in adults being treated and managed for acute stroke.Eligibility criteriaParticipants included adults aged 18 years or older with acute ischaemic stroke or primary intracerebral haemorrhage and a diagnosis, or suspected diagnosis, of post-stroke seizures whilst receiving hospital care for their acute stroke.Sources of evidenceMedline, CINAHL, Embase, and the Cochrane Library databases were searched, including papers published up to October 2021, limited to English language. A broad range of published literature was selected comprising of primary research, including case studies/case reports, conference abstracts, systematic reviews/meta-analyses, clinical guidelines and consensus statements. Reference lists of included studies were also searched.Charting methodsA data charting table was developed by the reviewers, with key information selected for included articles. Findings have been aggregated to an overview of extent and type of evidence and identify gaps in evidence.ResultsWe included two research papers, two clinical guidelines and four discussion papers. There was limited literature on clinical methods used to identify and observe acute stroke patients for seizures. We found no evaluation of different methods aimed at recognising and observing EPSS, and subsequently recommendations lacking detail and consensus on clinical processes.ConclusionEarly post-stroke seizures are important to diagnose due to associated increases in post-stroke complications, mortality, disability and recurrent hospital admissions. Whilst the diagnostic challenge of EPSS is recognised, there is a need for research looking into how to improve the identification and observation of seizure activity in acute stroke settings.
Spatial distribution of hand-grasp motor task activity in spinal cord functional magnetic resonance imaging
Authors: Hemmerling Kimberly J. , Hoggarth Mark A. , Sandhu Milap S. , Parrish Todd B. , Bright Molly G. 
Published: April 2023

AbstractUpper extremity motor paradigms during spinal cord functional magnetic resonance imaging (fMRI) can provide insight into the functional organization of the cord. Hand-grasping is an important daily function with clinical significance, but previous studies of similar squeezing movements have not reported consistent areas of activity and are limited by sample size and simplistic analysis methods. Here, we study spinal cord fMRI activation using a unimanual isometric hand-grasping task that is calibrated to participant maximum voluntary contraction (MVC). Two task modeling methods were considered: (1) a task regressor derived from an idealized block design (Ideal) and (2) a task regressor based on the recorded force trace normalized to individual MVC (%MVC). Across these two methods, group motor activity was highly lateralized to the hemicord ipsilateral to the side of the task. Activation spanned C5-C8 and was primarily localized to the C7 spinal cord segment. Specific differences in spatial distribution are also observed, such as an increase in C8 and dorsal cord activity when using the %MVC regressor. Furthermore, we explored the impact of data quantity and spatial smoothing on sensitivity to hand-grasp motor task activation. This analysis shows a large increase in number of active voxels associated with the number of fMRI runs, sample size, and spatial smoothing, demonstrating the impact of experimental design choices on motor activation.
A Nanoparticle RIG-I Agonist for Cancer Immunotherapy
Authors: Wang-Bishop Lihong , Wehbe Mohamed , Pastora Lucinda E. , Yang Jinming , Garland Kyle M. , Becker Kyle W. , Carson Carcia S. , Gibson-Corley Katherine N. , Ulkoski David , Krishnamurthy Venkata , Fedorova Olga , Richmond Ann , Pyle Anna Marie , Wilson John T. 
Published: April 2023

AbstractPharmacological activation of the retinoic acid-inducible gene I (RIG-I) pathway holds promise for increasing tumor immunogenicity and improving response to immune checkpoint inhibitors (ICI). However, the potency and clinical efficacy of 5’-triphosphate RNA (3pRNA) agonists of RIG-I is hindered by multiple pharmacological barriers, including poor pharmacokinetics, nuclease degradation, and inefficient delivery to the cytosol where RIG-I is localized. Here, we address these challenges through the design and evaluation of ionizable lipid nanoparticles (LNPs) for the delivery of 3p-modified stem-loop RNAs (SLRs). Packaging of SLRs into LNPs (SLR-LNPs) yielded surface charge-neutral nanoparticles with a size of ∼100 nm that activated RIG-I signalingin vitroandin vivo. SLR-LNPs were safely administered to mice via both intratumoral and intravenous routes, resulting in RIG-I activation in the tumor microenvironment (TME) and inhibition of tumor growth in mouse models of poorly immunogenic melanoma and breast cancer. Significantly, we found that systemic administration of SLR-LNPs reprogrammed the breast TME to enhance the infiltration of CD8+and CD4+T cells with antitumor function, resulting in enhanced response to αPD-1 ICI in an orthotopic EO771 model of triple negative breast cancer. Therapeutic efficacy was further demonstrated in a metastatic B16.F10 melanoma model, with systemically administered SLR-LNPs significantly reducing lung metastatic burden compared to combined αPD-1 + αCTLA-4 ICI. Collectively, these studies have established SLR-LNPs as a translationally promising immunotherapeutic nanomedicine for potent and selective activation of RIG-I with potential to enhance response to ICIs and other immunotherapeutic modalities.
Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A
Authors: Peng Yan , Zhang Yumeng , Fang Ruan , Jiang Hao , Lan Gongcai , Xu Zhou , Liu Yajie , Nie Zhaoyang , Ren Lu , Wang Fengcan , Zhang Shou-De , Ma Yuyong , Yang Peng , Ge Hong-Hua , Zhang Wei-Dong , Luo Cheng , Li Ang , He Weiwei 
Published: April 2023

ABSTRACTCentromere protein A (CENP-A), a histone H3 variant specific to centromeres, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. We conducted a structure-activity relationship (SAR) study of the cell cycle-arresting indole terpenoid mimic JP18 and found two more potent analogues, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin was identified as a potential cellular target of these halogenated analogues by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis revealed that both molecules bind to the colchicine-binding site of β-tubulin. Furthermore, we discovered that treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, led to CENP-A accumulation by destabilizing Cdh1, a co-activator of the APC/C E3 ubiquitin ligase. Our study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis.
Chemotactic interactions drive migration of membraneless active droplets
Authors: Dindo Mirco , Bevilacqua Alessandro , Soligo Giovanni , Monti Alessandro , Rosti Marco Edoardo , Laurino Paola 
Published: April 2023

AbstractIn nature, chemotactic interactions are ubiquitous and play a critical role in driving the collective behaviour of living organisms. Reproducing these interactionsin vitrois still a paramount challenge due to the complexity of mimicking and controlling cellular features, such as metabolic density, cytosolic macromolecular crowding and cellular migration, on a microorganism size scale. Here we generate enzymatically-active cell-size droplets able to move freely and, by following a chemical gradient, able to interact with the surrounding droplets in a collective manner. The enzyme within the droplets generates a pH gradient that extends outside the edge of the droplets. We discovered that the external pH gradient triggers droplet migration and controls its directionality, which is selectively towards the neighbouring droplets. Hence, by changing the enzyme activity inside the droplet we tuned the droplet migration speed. Further, we showed that these cellular-like features can facilitate the reconstitution of a simple and linear protometabolic pathway with improved overall activity. Our work suggests that simple and stable membraneless droplets can be applied to reproduce complex biological phenomena opening new perspectives as bioinspired materials and synthetic biology tools.
Quantifying Rift Valley fever virus transmission efficiency in a lamb-mosquito-lamb model
Authors: Bron Gebbiena M. , Wichgers Schreur Paul J. , Jong Mart C.M. de , Keulen Lucien van , Vloet Rianka P.M. , Koenraadt Constantianus J.M. , Kortekaas Jeroen , Bosch Quirine A. ten 
Published: April 2023

AbstractRift Valley fever virus (RVFV) is a (re)emerging mosquito-borne pathogen impacting human and animal health. How RVFV spreads through a population depends on population-level interactions between hosts and vectors (e.g., vector-to-host ratio and biting preference) and also on potential differences in individual following virus exposure (e.g., transmission efficiencies from host to vector and vice versa). Here, we estimated the probability for RVFV to transmit to naive animals by experimentally exposing lambs to a bite of an infectious mosquito (the transmission efficiency) and assessed if and how RVFV infection subsequently developed in the exposed animal.Aedes aegyptimosquitoes, previously infected via feeding on a viremic lamb, were used to expose naive lambs to the virus. Lambs were either exposed to 1-3 (low exposure) or 7-9 (high exposure) infectious mosquitoes. All lambs in the high exposure group became viremic and showed characteristic signs of Rift Valley fever within 2-4 days post exposure. In contrast, 3 out of 12 lambs in the low exposure group developed viremia and disease, with similar peaks in viremia as the high exposure group but with some heterogeneity in the onset of viremia. These results suggest that the likelihood for successful infection of a ruminant host is affected by the number of infectious mosquitoes biting, but also highlights that a lamb can be infected by a single mosquito. The per bite mosquito-to-host transmission efficiency was estimated at 28% (95% confidence interval: 15 - 47%). We subsequently combined this transmission efficiency with estimates for mosquito life traits into a Ross-McDonald mathematical model to illustrate scenarios under which major RVFV outbreaks could occur in naïve populations (i.e., R0>1). The model revealed that for efficient RVFV transmission relatively high vector-to-host ratios as well as strong feeding preference for competent hosts are required. Altogether, this study highlights the importance of experiments that mimic natural exposure to RVFV. The experiments facilitate a better understanding of the natural progression of disease and a direct way to obtain epidemiological parameters for mathematical models.
Competition between transcription and loop extrusion modulates promoter and enhancer dynamics
Authors: Platania Angeliki , Erb Cathie , Barbieri Mariano , Molcrette Bastien , Grandgirard Erwan , de Kort Marit AC , Meaburn Karen , Taylor Tiegh , Shchuka Virlana M , Kocanova Silvia , Monteiro Oliveira Guilherme , Mitchell Jennifer A , Soutoglou Evi , Lenstra Tineke L , Molina Nacho , Papantonis Argyris , Bystricky Kerstin , Sexton Tom 
Published: April 2023

SUMMARYThe spatiotemporal configuration of genes with distal regulatory elements, and the impact of chromatin mobility on transcription, remain unclear. Loop extrusion is an attractive model for bringing genetic elements together, but how this functionally interacts with transcription is also largely unknown. We combine live tracking of genomic loci and nascent transcripts with molecular dynamics simulations to assess the 4D arrangement of theSox2gene and its enhancer, in response to a battery of perturbations. We find that alterations in chromatin mobility, not promoter-enhancer distance, is more informative about transcriptional status. Active elements display more constrained mobility, consistent with confinement within specialized nuclear sites, and alterations in enhancer mobility distinguish poised from transcribing alleles. Strikingly, we find that whereas loop extrusion and transcription factor-mediated clustering contribute to promoter-enhancer proximity, they have antagonistic effects on chromatin dynamics. This provides an experimental framework for the underappreciated role of chromatin dynamics in genome regulation.
Introgression underlies phylogenetic uncertainty but not parallel plumage evolution in a recent songbird radiation
Authors: Rancilhac Loïs , Enbody Erik D. , Harris Rebecca , Saitoh Takema , Irestedt Martin , Liu Yang , Lei Fumin , Andersson Leif , Alström Per 
Published: April 2023

AbstractInstances of parallel phenotypic evolution offer great opportunities to understand the evolutionary processes underlying phenotypic changes. However, confirming parallel phenotypic evolution and studying its causes requires a robust phylogenetic framework. One such example is the “black-and-white wagtails”, a group of five species in the songbird genusMotacilla: one species, the White Wagtail (M. alba), shows wide intra-specific plumage variation, while the four others form two pairs of very similar-looking species (African Pied WagtailM. aguimp+ Mekong WagtailM. samveasnaeand Japanese WagtailM. grandis+ White-browed WagtailM. maderaspatensis, respectively). However, the two species in each of these pairs were not recovered as sisters in previous phylogenetic inferences. Their relationships varied depending on the markers used, suggesting that gene tree heterogeneity might have hampered accurate phylogenetic inference. Here, we use whole genome resequencing data to explore the phylogenetic relationships within this group, with a special emphasis on characterizing the extent of gene tree heterogeneity and its underlying causes. We first used multispecies coalescent methods to generate a “complete evidence” phylogenetic hypothesis based on genome-wide variants, while accounting for incomplete lineage sorting and introgression. We then investigated the variation in phylogenetic signal across the genome, to quantify the extent of discordance across genomic regions, and test its underlying causes. We found that wagtail genomes are mosaics of regions supporting variable genealogies, because of ILS and inter-specific introgression. The most common topology across the genome, supportingM. albaandM. aguimpas sister species, appears to be influenced by ancient introgression. Additionally, we inferred another ancient introgression event, betweenM. albaandM. grandis. By combining results from multiple analyses, we propose a phylogenetic network for the black-and-white wagtails that confirms that similar phenotypes evolved in non-sister lineages, supporting parallel plumage evolution. Furthermore, the inferred reticulations do not connect species with similar plumage coloration, suggesting that introgression does not underlie parallel plumage evolution in this group. Our results demonstrate the importance of investigation of genome-wide patterns of gene tree heterogeneity to help understanding the mechanisms underlying phenotypic evolution.
Cdk/Cyclin activity helps set mitotic centrosome size by influencing the centrosome growth rate and growth period
Authors: Wong Siu-Shing , Wainman Alan , Saurya Saroj , Raff Jordan W. 
Published: April 2023

AbstractMitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves in preparation for cell division. How the mitotic PCM grows to the correct size is unclear. InDrosophilasyncytial embryos, thousands of mitotic centrosomes assemble in a common cytoplasm as the embryo proceeds through 13 rounds of near-synchronous nuclear division. During nuclear cycles (NCs) 11-13 these divisions gradually slow, and we find that mitotic centrosomes respond by reciprocally slowing their growth rate and increasing their growth period so that they grow to a consistent size at each cycle. This size homeostasis is enforced, at least in part, by the Cdk/Cyclin cell cycle oscillator (CCO). Moderate levels of CCO activity appear to initially promote centrosome growth by stimulating Polo/PLK1 recruitment to centrosomes, while higher levels of activity subsequently inhibit centrosome growth by phosphorylating centrosome proteins to decrease their centrosomal recruitment and/or maintenance as the embryos enter mitosis. Thus, the CCO initially promotes, and subsequently restricts, mitotic centrosome growth to help ensure that centrosomes grow to a consistent size.
Functional Relations of CSLD2, CSLD3, and CSLD5 Proteins during Cell Wall Synthesis inArabidopsis
Authors: Yang Jiyuan , Sahu Abira , Adams Alexander , Yin Shuyao , Gu Fangwei , Mayes Heather B. , Nielsen Erik 
Published: April 2023

ABSTRACTPlant cell expansion is a dynamic process that is physically constrained by the deposition of new cell wall components. During tip growth, new cell wall materials are delivered at a restricted plasma membrane domain which results in a highly polarized expansion within that specified domain. Previous studies demonstrated that this process requires the activities of members of theCellulose Synthase-Like D (CSLD)subfamily of cell wall synthases. CSLD3 displays β-1,4 glucan synthase activity, but whether other members of CSLD subfamily share this conserved biochemical activity, and whether CSLD proteins form higher-order complexes to perform β-1,4 glucan synthase activities have not been determined. Here, we use genetic methods to demonstrate that CSLD2 and CSLD3 functions are interchangeable during root hair elongation and cell plate formation, while CSLD5 provides a unique and irreplaceable function in the formation of cell plates. Importantly, genetic analysis with inactivated versions of CSLD3 show that, unlike CESA proteins, CSLDs do not require the simultaneous presence of different isoforms to perform catalytic cell wall synthase activities.In vitrobiochemical activity experiments confirmed that CSLD2, CSLD3, and CSLD5 proteins displayed β-1,4 glucan synthases activities. Taken together, these results indicated that while all three vegetatively expressed CSLD proteins possess conserved β-1,4 glucan synthase activities, that CSLD5 has a more complicated and specialized role during cell plate formation.
Primary Ciliary Dyskinesia patient specific hiPSC-derived airway epithelium in Air Liquid Interface culture recapitulates disease specific phenotypesin vitro
Authors: von Schledorn Laura , Martín David Puertollano , Cleve Nicole , Zöllner Janina , Roth Doris , Staar Ben Ole , Hegermann Jan , Ringshausen Felix C. , Nawroth Janna , Martin Ulrich , Olmer Ruth 
Published: April 2023

AbstractPrimary ciliary dyskinesia (PCD) is a rare heterogenic genetic disorder associated with perturbed biogenesis or function of motile cilia. Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage. Current approaches to treat PCD are symptomatic, only, indicating an urgent need for curative therapeutic options. Here, we developed anin vitromodel for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures. Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient specific hiPSC lines carrying mutations inDNAH5andNME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
A high-throughput nematode sensory assay reveals an inhibitory effect of ivermectin on parasite gustation
Authors: Nunn Leonardo R. , Juang Terry D. , Beebe David J. , Wheeler Nicolas J. , Zamanian Mostafa 
Published: April 2023

AbstractSensory pathways first elucidated inCaenorhabditis elegansare conserved across free-living and parasitic nematodes, even though each species responds to a diverse array of compounds. Most nematode sensory assays are performed by tallying observations of worm behavior on two-dimensional planes using agarose plates. These assays have been successful in the study of volatile sensation but are poorly suited for investigation of water-soluble gustation or parasitic nematodes without a free-living stage. In contrast, gustatory assays tend to be tedious, often limited to the manipulation of a single individual at a time. We have designed a nematode sensory assay using a microfluidics device that allows for the study of gustation in a 96-well, three-dimensional environment. This device is suited for free-living worms and parasitic worms that spend their lives in an aqueous environment, and we have used it to show that ivermectin inhibits the gustatory ability of vector-borne parasitic nematodes.